Xu, J., Zwaigenbaum, L., Szatmari, P. and Scherer, S.W.
Molecular Cytogenetics of Autism.
Current Genomics 5(4), 347-364. 2004.
Autism is a neurodevelopmental disorder characterized by clinical, etiologic and genetic heterogeneity. It is often associated with other conditions, such as disorders of the CNS (tuberous sclerosis), developmental delay, attention deficit, epilepsy, and anxiety and mood disorders. Our survey found cytogenetically visible chromosomal anomalies in ~7.4% (129/1749) of autistic patients documented as well as several sub-microscopic variants. Almost every chromosome is affected by numeric or structural aberrations. Among the most consistent cytogenetics findings are fragile X and duplication of maternal 15q11-q13. Molecular cytogenetics, together with genome scans and linkage/association studies, point to ³22 chromosome regions harbouring putative autism susceptibility genes, such as 2q32, 3q25-q27, 7q31-q35, 15q11-q13, 16p13, Xp22, and Xq13. We hypothesize that there might be at least three types of autism susceptibility genes/mutations that can be (i) specific to an individual patient or family, (ii) in a genetically isolated sub-population and (iii) a common factor shared amongst different populations. The genes/mutations could act alone or interact with other genetic and/or epigenetic or environmental factors, causing autism or related disorders. This review emphasizes the potential of analysing chromosomal rearrangements as a means to rapidly define candidate disease loci for further investigation. To facilitate ongoing research we have established a new database of autism-associated chromosomal anomalies [http://projects.tcag.ca/autism/] [PDF]

Ramoz N, Reichert JG, Smith CJ, Silverman JM, Bespalova IN, Davis KL, Buxbaum JD
Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism.
Am J Psychiatry. 2004 Apr;161(4):662-9.
OBJECTIVE: Autism/autistic disorder (MIM number 209850) is a complex, largely genetic psychiatric disorder. The authors recently mapped a susceptibility locus for autism to chromosome region 2q24-q33 (MIM number 606053). In the present study, genes across the 2q24-q33 interval were analyzed to identify an autism susceptibility gene in this region. METHOD: Mutation screening of positional candidate genes was performed in two stages. The first stage involved identifying, in unrelated subjects showing linkage to 2q24-q33, genetic variants in exons and flanking sequence within candidate genes and comparing the frequency of the variants between autistic and unrelated nonautistic subjects. Two single nucleotide polymorphisms (SNPs) that showed evidence for divergent distribution between autistic and nonautistic subjects were identified, both within SLC25A12, a gene encoding the mitochondrial aspartate/glutamate carrier (AGC1). In the second stage, the two SNPs in SLC25A12 were further genotyped in 411 autistic families, and linkage and association tests were carried out in the 197 informative families. RESULTS: Linkage and association were observed between autistic disorder and the two SNPs, rs2056202 and rs2292813, found in SLC25A12. Using either a single affected subject per family or all affected subjects, evidence for excess transmission was found by the Transmission Disequilibrium Test for rs2056202, rs2292813, and a two-locus G*G haplotype. Similar results were observed using TRANSMIT for the analyses. Evidence for linkage was supported by linkage analysis with the two SNPs, with a maximal multipoint nonparametric linkage score of 1.57 and a maximal multipoint heterogeneity lod score of 2.11. Genotype relative risk could be estimated to be between 2.4 and 4.8 for persons homozygous at these loci. CONCLUSIONS: A strong association of autism with SNPs within the SLC25A12 gene was demonstrated. Further studies are needed to confirm this association and to decipher any potential etiological role of AGC1 in autism. [Abstract]

OMIM - Online Mendelian Inheritance in Man: SLC25A12
[The SLC25A12 gene has been located at 2q24]

Shao Y, Raiford KL, Wolpert CM, Cope HA, Ravan SA, Ashley-Koch AA, Abramson RK, Wright HH, DeLong RG, Gilbert JR, Cuccaro ML, Pericak-Vance MA
Phenotypic homogeneity provides increased support for linkage on chromosome 2 in autistic disorder.
Am J Hum Genet. 2002 Apr;70(4):1058-61.
Autistic disorder (AutD) is a neurodevelopmental disorder characterized by significant disturbances in social, communicative, and behavioral functioning. A two-stage genomic screen analysis of 99 families with AutD revealed suggestive evidence for linkage to chromosome 2q (D2S116 nonparametric sib-pair LOD score [MLS] 1.12 at 198 cM). In addition, analysis of linkage disequilibrium for D2S116 showed an allele-specific P value of <.01. Recently, linkage to the same region of 2q was reported in an independent genome screen. This evidence for linkage increased when analysis was restricted to the subset of patients with AutD who had delayed onset (>36 mo) of phrase speech (PSD). We similarly classified our data set of 82 sib pairs with AutD, identifying 45 families with AutD and PSD. Analysis of this PSD subset increased our support for linkage to 2q (MLS 2.86 and HLOD 2.12 for marker D2S116). These data support evidence for a gene on chromosome 2 contributing to risk of AutD, and they suggest that phenotypic homogeneity increases the power to find susceptibility genes for AutD. [Abstract]

Wolff DJ, Clifton K, Karr C, Charles J
Pilot assessment of the subtelomeric regions of children with autism: detection of a 2q deletion.
Genet Med. 2002 Jan-Feb;4(1):10-4.
PURPOSE: Autism is a chronic neurodevelopmental disorder characterized by deficits in reciprocal social interaction, language and communication, and by the presence of stereotypical behaviors. The disorder is a complex genetic trait with no known predisposing genes. We report the results of a pilot project to screen for aberrations in the gene-rich subtelomeric chromosomal regions of a cohort of children with autism. METHODS: For our pilot project, we used a multiprobe system that includes probes for the subtelomeric regions of all human chromosomes. We assessed the subtelomeric regions of chromosomes from 10 children with a diagnosis of autism. RESULTS: The screen identified one child with an apparent deletion of the subtelomeric region of chromosome 2q; nine children and pooled control samples yielded normal results. The deletion in our patient was confirmed with two other subtelomeric probes and a targeted cytogenetic study revealed a subtle difference in appearance for one chromosome 2 homologue. CONCLUSION: There have been several reports of children with dysmorphic features, autistic behaviors, and 2q deletions detectable with standard cytogenetic techniques. It may be that the distal region of chromosome 2q harbors a gene or genes that may predispose to autism. [Abstract]

Weiss LA, Escayg A, Kearney JA, Trudeau M, MacDonald BT, Mori M, Reichert J, Buxbaum JD, Meisler MH
Sodium channels SCN1A, SCN2A and SCN3A in familial autism.
Mol Psychiatry. 2003 Feb;8(2):186-94.
Autism is a psychiatric disorder with estimated heritability of 90%. One-third of autistic individuals experience seizures. A susceptibility locus for autism was mapped near a cluster of voltage-gated sodium channel genes on chromosome 2. Mutations in two of these genes, SCN1A and SCN2A, result in the seizure disorder GEFS+. To evaluate these sodium channel genes as candidates for the autism susceptibility locus, we screened for variation in coding exons and splice sites in 117 multiplex autism families. A total of 27 kb of coding sequence and 3 kb of intron sequence were screened. Only six families carried variants with potential effects on sodium channel function. Five coding variants and one lariat branchpoint mutation were each observed in a single family, but were not present in controls. The variant R1902C in SCN2A is located in the calmodulin binding site and was found to reduce binding affinity for calcium-bound calmodulin. R542Q in SCN1A was observed in one autism family and had previously been identified in a patient with juvenile myoclonic epilepsy. The effect of the lariat branchpoint mutation was tested in cultured lymphoblasts. Additional population studies and functional tests will be required to evaluate pathogenicity of the coding and lariat site variants. SNP density was 1/kb in the genomic sequence screened. We report 38 sodium channel SNPs that will be useful in future association and linkage studies. [Abstract]

Jamain S, Betancur C, Quach H, Philippe A, Fellous M, Giros B, Gillberg C, Leboyer M, Bourgeron T
Linkage and association of the glutamate receptor 6 gene with autism.
Mol Psychiatry. 2002;7(3):302-10.
A genome scan was previously performed and pointed to chromosome 6q21 as a candidate region for autism. This region contains the glutamate receptor 6 (GluR6 or GRIK2) gene, a functional candidate for the syndrome. Glutamate is the principal excitatory neurotransmitter in the brain and is directly involved in cognitive functions such as memory and learning. We used two different approaches, the affected sib-pair (ASP) method and the transmission disequilibrium test (TDT), to investigate the linkage and association between GluR6 and autism. The ASP method, conducted with additional markers on the 51 original families and in eight new sibling pairs, showed a significant excess of allele sharing, generating an elevated multipoint maximum LOD score (ASPEX MLS = 3.28). TDT analysis, performed in the ASP families and in an independent data set of 107 parent-offspring trios, indicated a significant maternal transmission disequilibrium (TDTall P = 0.0004). Furthermore, TDT analysis (with only one affected proband per family) showed significant association between GluR6 and autism (TDT association P = 0.008). In contrast to maternal transmission, paternal transmission of GluR6 alleles was as expected in the absence of linkage, suggesting a maternal effect such as imprinting. Mutation screening was performed in 33 affected individuals, revealing several nucleotide polymorphisms (SNPs), including one amino acid change (M867I) in a highly conserved domain of the intracytoplasmic C-terminal region of the protein. This change is found in 8% of the autistic subjects and in 4% of the control population and seems to be more maternally transmitted than expected to autistic males (P = 0.007). Taken together, these data suggest that GluR6 is in linkage disequilibrium with autism. [Abstract]

Philippe A, Martinez M, Guilloud-Bataille M, Gillberg C, Råstam M, Sponheim E, Coleman M, Zappella M, Aschauer H, Van Maldergem L, Penet C, Feingold J, Brice A, Leboyer M, van Malldergerme L
Genome-wide scan for autism susceptibility genes. Paris Autism Research International Sibpair Study.
Hum Mol Genet. 1999 May;8(5):805-12.
Family and twin studies have suggested a genetic component in autism. We performed a genome-wide screen with 264 microsatellites markers in 51 multiplex families, using non-parametric linkage methods. Families were recruited by a collaborative group including clinicians from Sweden, France, Norway, the USA, Italy, Austria and Belgium. Using two-point and multipoint affected sib-pair analyses, 11 regions gave nominal P -values of 0.05 or lower. Four of these regions overlapped with regions on chromosomes 2q, 7q, 16p and 19p identified by the first genome-wide scan of autism performed by the International Molecular Genetic Study of Autism Consortium. Another of our potential susceptibility regions overlapped with the 15q11-q13 region identified in previous candidate gene studies. Our study revealed six additional regions on chromosomes 4q, 5p, 6q, 10q, 18q and Xp. We found that the most significant multipoint linkage was close to marker D6S283 (maximum lod score = 2.23, P = 0.0013). [Abstract]

Liu J, Nyholt DR, Magnussen P, Parano E, Pavone P, Geschwind D, Lord C, Iversen P, Hoh J, Ott J, Gilliam TC
A genomewide screen for autism susceptibility loci.
Am J Hum Genet. 2001 Aug;69(2):327-40.
We report the analysis of 335 microsatellite markers genotyped in 110 multiplex families with autism. All families include at least two "affected" siblings, at least one of whom has autism; the remaining affected sibs carry diagnoses of either Asperger syndrome or pervasive developmental disorder. Affected sib-pair analysis yielded multipoint maximum LOD scores (MLS) that reach the accepted threshold for suggestive linkage on chromosomes 5, X, and 19. Nominal evidence for linkage (point-wise P<.05) was obtained on chromosomes 2, 3, 4, 8, 10, 11, 12, 15, 16, 18, and 20, and secondary loci were found on chromosomes 5 and 19. Analysis of families sharing alleles at the putative X chromosomal linked locus and one or more other putative linked loci produced an MLS of 3.56 for the DXS470-D19S174 marker combination. In an effort to increase power to detect linkage, scan statistics were used to evaluate the significance of peak LOD scores based on statistical evidence at adjacent marker loci. This analysis yielded impressive evidence for linkage to autism and autism-spectrum disorders with significant genomewide P values <.05 for markers on chromosomes 5 and 8 and with suggestive linkage evidence for a marker on chromosome 19. [Abstract]

OMIM - Online Mendelian Inheritance in Man: Excitatory amino acid transporter 1
[The EAAT1 gene has been located at 5p13]

Purcell AE, Jeon OH, Zimmerman AW, Blue ME, Pevsner J.
Postmortem brain abnormalities of the glutamate neurotransmitter system in autism.
Neurology. 2001 Nov 13;57(9):1618-28.
BACKGROUND: Studies examining the brains of individuals with autism have identified anatomic and pathologic changes in regions such as the cerebellum and hippocampus. Little, if anything, is known, however, about the molecules that are involved in the pathogenesis of this disorder. OBJECTIVE: To identify genes with abnormal expression levels in the cerebella of subjects with autism. METHOD: Brain samples from a total of 10 individuals with autism and 23 matched controls were collected, mainly from the cerebellum. Two cDNA microarray technologies were used to identify genes that were significantly up- or downregulated in autism. The abnormal mRNA or protein levels of several genes identified by microarray analysis were investigated using PCR with reverse transcription and Western blotting. alpha-Amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA)- and NMDA-type glutamate receptor densities were examined with receptor autoradiography in the cerebellum, caudate-putamen, and prefrontal cortex. RESULTS: The mRNA levels of several genes were significantly increased in autism, including excitatory amino acid transporter 1 and glutamate receptor AMPA 1, two members of the glutamate system. Abnormalities in the protein or mRNA levels of several additional molecules in the glutamate system were identified on further analysis, including glutamate receptor binding proteins. AMPA-type glutamate receptor density was decreased in the cerebellum of individuals with autism (p < 0.05). CONCLUSIONS: Subjects with autism may have specific abnormalities in the AMPA-type glutamate receptors and glutamate transporters in the cerebellum. These abnormalities may be directly involved in the pathogenesis of the disorder. [Abstract]

Serajee FJ, Zhong H, Nabi R, Huq AH
The metabotropic glutamate receptor 8 gene at 7q31: partial duplication and possible association with autism.
J Med Genet. 2003 Apr;40(4):e42. [Abstract]

Hutcheson HB, Olson LM, Bradford Y, Folstein SE, Santangelo SL, Sutcliffe JS, Haines JL
Examination of NRCAM, LRRN3, KIAA0716, and LAMB1 as autism candidate genes.
BMC Med Genet. 2004 May 5;5(1):12.
BACKGROUND: A substantial body of research supports a genetic involvement in autism. Furthermore, results from various genomic screens implicate a region on chromosome 7q31 as harboring an autism susceptibility variant. We previously narrowed this 34 cM region to a 3 cM critical region (located between D7S496 and D7S2418) using the Collaborative Linkage Study of Autism (CLSA) chromosome 7 linked families. This interval encompasses about 4.5 Mb of genomic DNA and encodes over fifty known and predicted genes. Four candidate genes (NRCAM, LRRN3, KIAA0716, and LAMB1) in this region were chosen for examination based on their proximity to the marker most consistently cosegregating with autism in these families (D7S1817), their tissue expression patterns, and likely biological relevance to autism. METHODS: Thirty-six intronic and exonic single nucleotide polymorphisms (SNPs) and one microsatellite marker within and around these four candidate genes were genotyped in 30 chromosome 7q31 linked families. Multiple SNPs were used to provide as complete coverage as possible since linkage disequilibrium can vary dramatically across even very short distances within a gene. Analyses of these data used the Pedigree Disequilibrium Test for single markers and a multilocus likelihood ratio test. RESULTS: As expected, linkage disequilibrium occurred within each of these genes but we did not observe significant LD across genes. None of the polymorphisms in NRCAM, LRRN3, or KIAA0716 gave p < 0.05 suggesting that none of these genes is associated with autism susceptibility in this subset of chromosome 7-linked families. However, with LAMB1, the allelic association analysis revealed suggestive evidence for a positive association, including one individual SNP (p = 0.02) and three separate two-SNP haplotypes across the gene (p = 0.007, 0.012, and 0.012). CONCLUSIONS: NRCAM, LRRN3, KIAA0716 are unlikely to be involved in autism. There is some evidence that variation in or near the LAMB1 gene may be involved in autism. [Abstract]

Cisternas FA, Vincent JB, Scherer SW, Ray PN
Cloning and characterization of human CADPS and CADPS2, new members of the Ca2+-dependent activator for secretion protein family.
Genomics. 2003 Mar;81(3):279-91.
The recent identification of some of the components involved in regulated and constitutive exocytotic pathways has yielded important insights into the mechanisms of membrane trafficking and vesicle secretion. To understand precisely the molecular events taking place during vesicle exocytosis, we must identify all of the proteins implicated in these pathways. In this paper we describe the full-length cloning and characterization of human CADPS and CADPS2, two new homologs of the mouse Cadps protein involved in large dense-core vesicle (LDCV)-regulated exocytosis. We show that these two genes have disparate RNA expression patterns, with CADPS restricted to neural and endocrine tissues and CADPS2 expressed ubiquitously. We also identify a C2 domain, a known protein motif involved in calcium and phospholipid interactions, in both CADPS and CADPS2. We propose that CADPS functions as a calcium sensor in regulated exocytosis, whereas CADPS2 acts as a calcium sensor in constitutive vesicle trafficking and secretion. CADPS and CADPS2 were determined to span 475 kb and 561 kb on human chromosomes 3p21.1 and 7q31.3, respectively. The q31-q34 of human chromosome 7 has recently been identified to contain a putative susceptibility locus for autism (AUTS1). The function, expression profile, and location of CADPS2 make it a candidate gene for autism, and thus we conducted mutation screening for all 28 exons in 90 unrelated autistic individuals. We identified several nucleotide substitutions, including only one that would affect the amino acid sequence. No disease-specific variants were identified. [Abstract]

Alarcón M, Cantor RM, Liu J, Gilliam TC, Geschwind DH
Evidence for a language quantitative trait locus on chromosome 7q in multiplex autism families.
Am J Hum Genet. 2002 Jan;70(1):60-71.
Autism is a syndrome characterized by deficits in language and social skills and by repetitive behaviors. We hypothesized that potential quantitative trait loci (QTLs) related to component autism endophenotypes might underlie putative or significant regions of autism linkage. We performed nonparametric multipoint linkage analyses, in 152 families from the Autism Genetic Resource Exchange, focusing on three traits derived from the Autism Diagnostic Interview: "age at first word," "age at first phrase," and a composite measure of "repetitive and stereotyped behavior." Families were genotyped for 335 markers, and multipoint sib pair linkage analyses were conducted. Using nonparametric multipoint linkage analysis, we found the strongest QTL evidence for age at first word on chromosome 7q (nonparametric test statistic [Z] 2.98; P=.001), and subsequent linkage analyses of additional markers and association analyses in the same region supported the initial result (Z=2.85, P=.002; chi(2)=18.84, df 8, P=.016). Moreover, the peak fine-mapping result for repetitive behavior (Z=2.48; P=.007) localized to a region overlapping this language QTL. The putative autism-susceptibility locus on chromosome 7 may be the result of separate QTLs for the language and repetitive or stereotyped behavior deficits that are associated with the disorder. [Abstract]

Further characterization of the autism susceptibility locus AUTS1 on chromosome 7q.
Hum Mol Genet. 2001 Apr 15;10(9):973-82.
Autism is a neurodevelopmental disorder that usually arises on the basis of a complex genetic predisposition. The most significant susceptibility region in the first whole genome screen of multiplex families was on chromosome 7q, although this linkage was evident only in UK IMGSAC families. Subsequently all other genome screens of non-UK families have found some evidence of increased allele sharing in an overlapping 40 cM region of 7q. To further characterize this susceptibility locus, linkage analysis has now been completed on 170 multiplex IMGSAC families. Using a 5 cM marker grid, analysis of 125 sib pairs meeting stringent inclusion criteria resulted in a multipoint maximum LOD score (MLS) of 2.15 at D7S477, whereas analysis of all 153 sib pairs generated an MLS of 3.37. The 71 non-UK sib pairs now contribute to this linkage. Linkage disequilibrium mapping identified two regions of association-one lying under the peak of linkage, the other some 27 cM distal. These results are supported in part by findings in independent German and American singleton families. [Abstract]

Warburton P, Baird G, Chen W, Morris K, Jacobs BW, Hodgson S, Docherty Z
Support for linkage of autism and specific language impairment to 7q3 from two chromosome rearrangements involving band 7q31.
Am J Med Genet. 2000 Apr 3;96(2):228-34.
Childhood autism is characterised by impairments in communication and reciprocal social interaction together with restricted/stereotyped interests, which are evident before 3 years of age. Specific developmental disorders of speech and language (SDDSL) are characterised by impairment in the development of expressive and/or receptive language skills which is not associated with intellectual, sensory, physical, or neurological impairment. Family and twin studies indicate a substantial genetic component in the aetiology of both disorders. They also reveal increased rates of SDDSL in relatives of autistic individuals, suggesting that this phenotype can represent one manifestation of the genetic liability for autism. Modelling of the recurrence risk for autism and milder phenotypes, such as SDDSL, suggest that three or four epistatic loci may be aetiologically involved. A recently published linkage study of an exceptional family with an apparently dominantly inherited SDDSL implicated chromosome band 7q31 as the site of the putative susceptibility locus (SPCH1). This region of chromosome 7 also shows strong linkage in multiplex families with autism. We present two individuals (one has autism, the other SDDSL) with different, apparently balanced chromosome rearrangements involving a breakpoint at 7q31.3. Fluorescence in situ hybridisation was used to localise the breakpoints to an approximately 1 cM interval between CFTR and D7S643. Our findings may be of interest and relevance to the genetic aetiology of autism, and helpful in the search for susceptibility loci for SDDSL and autism. Am. J. Med. Genet. (Neuropsychiatr. Genet. ) 96:228-234, 2000. [Abstract]

O'Brien EK, Zhang X, Nishimura C, Tomblin JB, Murray JC
Association of specific language impairment (SLI) to the region of 7q31.
Am J Hum Genet. 2003 Jun;72(6):1536-43.
FOXP2 (forkhead box P2) was the first gene characterized in which a mutation affects human speech and language abilities. A common developmental language disorder, specific language impairment (SLI), affects 6%-7% of children with normal nonverbal intelligence and has evidence of a genetic basis in familial and twin studies. FOXP2 is located on chromosome 7q31, and studies of other disorders with speech and language impairment, including autism, have found linkage to this region. In the present study, samples from children with SLI and their family members were used to study linkage and association of SLI to markers within and around FOXP2, and samples from 96 probands with SLI were directly sequenced for the mutation in exon 14 of FOXP2. No mutations were found in exon 14 of FOXP2, but strong association was found to a marker within the CFTR gene and another marker on 7q31, D7S3052, both adjacent to FOXP2, suggesting that genetic factors for regulation of common language impairment reside in the vicinity of FOXP2. [Abstract]

Newbury DF, Bonora E, Lamb JA, Fisher SE, Lai CS, Baird G, Jannoun L, Slonims V, Stott CM, Merricks MJ, Bolton PF, Bailey AJ, Monaco AP
FOXP2 is not a major susceptibility gene for autism or specific language impairment.
Am J Hum Genet. 2002 May;70(5):1318-27.
The FOXP2 gene, located on human 7q31 (at the SPCH1 locus), encodes a transcription factor containing a polyglutamine tract and a forkhead domain. FOXP2 is mutated in a severe monogenic form of speech and language impairment, segregating within a single large pedigree, and is also disrupted by a translocation in an isolated case. Several studies of autistic disorder have demonstrated linkage to a similar region of 7q (the AUTS1 locus), leading to the proposal that a single genetic factor on 7q31 contributes to both autism and language disorders. In the present study, we directly evaluate the impact of the FOXP2 gene with regard to both complex language impairments and autism, through use of association and mutation screening analyses. We conclude that coding-region variants in FOXP2 do not underlie the AUTS1 linkage and that the gene is unlikely to play a role in autism or more common forms of language impairment. [Abstract]

Gong X, Jia M, Ruan Y, Shuang M, Liu J, Wu S, Guo Y, Yang J, Ling Y, Yang X, Zhang D
Association between the FOXP2 gene and autistic disorder in Chinese population.
Am J Med Genet. 2004 May 15;127B(1):113-6.
Several genomewide screens indicated that chromosome 7q was linked to autistic disorder. FOXP2, located on 7q31, is a putative transcription factor containing a polyglutamine tract and a forkhead DNA binding domain. It is one member of the forkhead family who are known to be key regulators of embryogenesis. A point mutation at a highly conserved residue within the forkhead domain co-segregated with affected status in the KE family who was a unique three generation pedigree with a severe speech and language disorder and FOXP2 was directly disrupted by a translocation in an individual who had similar deficits as those of the KE family. Several studies have investigated the role of FOXP2 polymorphisms in autism and none of them found positive association. We performed a family-based association study of three single nucleotide polymorphisms (SNPs) of FOXP2 in 181 Chinese Han trios using the analyses of transmission/disequilibrium test (TDT) and haplotype. We found a significant association between autistic disorder and one SNP, as well as with specific haplotypes formed by this SNP with two other SNPs we investigated. Our findings suggest that the FOXP2 gene may be involved in the pathogenesis of autism in Chinese population. [Abstract]

Gauthier J, Joober R, Mottron L, Laurent S, Fuchs M, De Kimpe V, Rouleau GA
Mutation screening of FOXP2 in individuals diagnosed with autistic disorder.
Am J Med Genet. 2003 Apr 15;118A(2):172-5.
Although it is well established that genetic factors play an important role in the etiology of autistic disorder (AD), no specific genes have as yet been implicated. Genetic epidemiological data, particularly the sharp fall in concordance rates from monozygotic to dizygotic twins, indicate that the mode of transmission of this disorder is complex and may involve several genes. The 7q31 locus has been repeatedly linked to AD, suggesting that this chromosomal region is likely to harbor a susceptibility gene for AD. Recently, variations in the FOXP2 gene were reported to be responsible for a severe speech and language disorder. Because of the chromosomal location of FOXP2 (7q31) and the putative implication of the 7q31 region both in autistic and in language disorders (a feature of AD), it has been hypothesized that FOXP2 may be implicated in the pathophysiology of AD. To test this hypothesis, we screened the FOXP2 gene coding sequence for mutations in subjects diagnosed with AD and in normal controls. We identified four silent polymorphisms that were equally distributed between patients and controls. Using an intra-family association design, we identified no transmission disequilibrium in any of the four identified alleles, suggesting that the FOXP2 gene does not play a significant role in AD. [Abstract]

Wassink TH, Piven J, Vieland VJ, Pietila J, Goedken RJ, Folstein SE, Sheffield VC
Evaluation of FOXP2 as an autism susceptibility gene.
Am J Med Genet. 2002 Jul 8;114(5):566-9.
A mutation in the gene FOXP2 was recently identified as being responsible for a complicated speech and language phenotype in a single large extended pedigree. This gene is of interest to autism because it lies in one of the most consistently linked autism chromosomal regions of interest. We therefore tested this gene for its involvement in autism in a large sample of autism families. We completely sequenced the exon containing the mutation, screened the remaining coding sequence using SSCP technology, and identified and genotyped two novel intronic tetranucleotide repeat polymorphisms that were then analyzed for evidence of linkage and linkage disequilibrium (LD). We identified two families in which heterozygous deletions of a small number of glutamines in a long poly-glutamine stretch were found in one parent and the autistic probands; no other non-conservative coding sequence changes were identified. Linkage and LD analyses were performed in 75 affected sibling pair families and in two subgroups of this sample defined by the presence/absence of severe language impairment. One allele appeared to have an opposite pattern of transmission in the language based subgroups, but otherwise the linkage and LD analyses were negative. We conclude that FOXP2 is unlikely to contribute significantly to autism susceptibility. [Abstract]

Hutcheson HB, Bradford Y, Folstein SE, Gardiner MB, Santangelo SL, Sutcliffe JS, Haines JL
Defining the autism minimum candidate gene region on chromosome 7.
Am J Med Genet. 2003 Feb15;117B(1):90-6.
Previous genetic and cytogenetic studies provide evidence that points to one or more autism susceptibility genes residing on chromosome 7q (AUTS1, 115-149 cM on the Marshfield map). However, further localization using linkage analysis has proven difficult. To overcome this problem, we examined the Collaborative Linkage Study of Autism (CLSA) data-set to identify only the families potentially linked to chromosome 7. Out of 94, 47 families were identified and 17 markers were used to generate chromosomal haplotypes. We performed recombination breakpoint analysis to determine if any portion of the chromosome was predominately shared across families. The most commonly shared region spanned a 6 cM interval between D7S501 and D7S2847. Additional markers at 1 cM intervals within this region were genotyped and association and recombination breakpoint analysis was again performed. Although no significant allelic association was found, the recombination breakpoint data points to a shared region between D7S496-D7S2418 (120-123 cM) encompassing about 4.5 Mb of genomic DNA containing over 50 genes. [Abstract]

Yu CE, Dawson G, Munson J, D'Souza I, Osterling J, Estes A, Leutenegger AL, Flodman P, Smith M, Raskind WH, Spence MA, McMahon W, Wijsman EM, Schellenberg GD
Presence of large deletions in kindreds with autism.
Am J Hum Genet. 2002 Jul;71(1):100-15.
Autism is caused, in part, by inheritance of multiple interacting susceptibility alleles. To identify these inherited factors, linkage analysis of multiplex families is being performed on a sample of 105 families with two or more affected sibs. Segregation patterns of short tandem repeat polymorphic markers from four chromosomes revealed null alleles at four marker sites in 12 families that were the result of deletions ranging in size from 5 to >260 kb. In one family, a deletion at marker D7S630 was complex, with two segments deleted (37 kb and 18 kb) and two retained (2,836 bp and 38 bp). Three families had deletions at D7S517, with each family having a different deletion (96 kb, 183 kb, and >69 kb). Another three families had deletions at D8S264, again with each family having a different deletion, ranging in size from <5.9 kb to >260 kb. At a fourth marker, D8S272, a 192-kb deletion was found in five families. Unrelated subjects and additional families without autism were screened for deletions at these four sites. Families screened included 40 families from Centre d'Etude du Polymorphisme Humaine and 28 families affected with learning disabilities. Unrelated samples were 299 elderly control subjects, 121 younger control subjects, and 248 subjects with Alzheimer disease. The deletion allele at D8S272 was found in all populations screened. For the other three sites, no additional deletions were identified in any of the groups without autism. Thus, these deletions appear to be specific to autism kindreds and are potential autism-susceptibility alleles. An alternative hypothesis is that autism-susceptibility alleles elsewhere cause the deletions detected here, possibly by inducing errors during meiosis. [Abstract]

Ashley-Koch A, Wolpert CM, Menold MM, Zaeem L, Basu S, Donnelly SL, Ravan SA, Powell CM, Qumsiyeh MB, Aylsworth AS, Vance JM, Gilbert JR, Wright HH, Abramson RK, DeLong GR, Cuccaro ML, Pericak-Vance MA
Genetic studies of autistic disorder and chromosome 7.
Genomics. 1999 Nov 1;61(3):227-36.
Genome-wide scans have suggested that a locus on 7q is involved in the etiology of autistic disorder (AD). We have identified an AD family in which three sibs inherited from their mother a paracentric inversion in the chromosome 7 candidate region (inv(7)(q22-q31.2)). Clinically, the two male sibs have AD, while the female sib has expressive language disorder. The mother carries the inversion, but does not express AD. Haplotype data on the family suggest that the chromosomal origin of the inversion was from the children's maternal grandfather. Based on these data, we have genotyped 76 multiplex (>/=2 AD affecteds/family) families for markers in this region of 7q. Two-point linkage analysis yielded a maximum heterogeneity lod score of 1.47 and maximum lod score (MLS) of 1.03 at D7S495. Multipoint MLS and NPL analyses resulted in peak scores of 1.77 at D7S2527 and 2.01 at D7S640. Examination of affected sibpairs revealed significant paternal (P = 0.007), but not maternal (P = 0. 75), identity-by-descent sharing at D7S640. Significant linkage disequilibrium was detected with paternal (P = 0.02), but not maternal (P = 0.15), transmissions at D7S1824 in multiplex and singleton families. There was also evidence for an increase in recombination in the region (D7S1817 to D7S1824) in the AD families versus non-AD families (P = 0.03, sex-averaged; and P = 0.01, sex-specific). These results provide further evidence for the presence of an AD locus on chromosome 7q, as well as provide evidence suggesting that this locus may be paternally expressed. [Abstract]

Tentler D, Brandberg G, Betancur C, Gillberg C, Annerén G, Orsmark C, Green ED, Carlsson B, Dahl N
A balanced reciprocal translocation t(5;7)(q14;q32) associated with autistic disorder: molecular analysis of the chromosome 7 breakpoint.
Am J Med Genet. 2001 Dec 8;105(8):729-36.
Autism is a neuropsychiatric disorder characterized by impairments in social interaction, restricted and stereotypic pattern of interest with onset by 3 years of age. The results of genetic linkage studied for autistic disorder (AD) have suggested a susceptibility locus for the disease on the long arm of chromosome 7. We report a girl with AD and a balanced reciprocal translocation t(5;7)(q14;q32). The mother carries the translocation but do not express the disease. Fluorescent in situ hybridization (FISH) analysis with chromosome 7-specific YAC clones showed that the breakpoint coincides with the candidate region for AD. We identified a PAC clone that spans the translocation breakpoint and the breakpoint was mapped to a 2 kb region. Mutation screening of the genes SSBP and T2R3 located just centromeric to the breakpoint was performed in a set of 29 unrelated autistic sibling pairs who shared at least one chromosome 7 haplotype. We found no sequence variations, which predict amino acid alterations. Two single nucleotide polymorphisms were identified in the T2R3 gene, and associations between allele variants and AD in our population were not found. The methylation pattern of different chromosome 7 regions in the patient's genomic DNA appears normal. Here we report the clinical presentation of the patient with AD and the characterization of the genomic organization across the breakpoint at 7q32. The precise localization of the breakpoint on 7q32 may be relevant for further linkage studies and molecular analysis of AD in this region. [Abstract]

Bradford Y, Haines J, Hutcheson H, Gardiner M, Braun T, Sheffield V, Cassavant T, Huang W, Wang K, Vieland V, Folstein S, Santangelo S, Piven J
Incorporating language phenotypes strengthens evidence of linkage to autism.
Am J Med Genet. 2001 Aug 8;105(6):539-47.
We investigated the effect of incorporating information about proband and parental structural language phenotypes into linkage analyses in the two regions for which we found the highest signals in our first-stage affected sibling pair genome screen: chromosomes 13q and 7q. We were particularly interested in following up on our chromosome 7q finding in light of two prior reports of linkage of this region to developmental language disorder, since one of the diagnostic criteria for autism is absent or abnormal language development. We hypothesized that if the language phenotype were genetically relevant to linkage at the chromosome 7q locus, then incorporating parents phenotypes would increase the signal at that locus, and most of the signal would originate from the subset of families in which both probands had severe language delay. The results support these hypotheses. The linkage signals we obtained on chromosome 7q as well as at least one signal on chromosome 13q are mainly attributable to the subgroup of families in which both probands had language delay. This became apparent only when the parents' history of language-related difficulties was also incorporated into the analyses. Although based on our data, we were not able to distinguish between epistasis or heterogeneity models, we tentatively concluded that there may be more than one autism susceptibility locus related to language development. [Abstract]

Smith M, Woodroffe A, Smith R, Holguin S, Martinez J, Filipek PA, Modahl C, Moore B, Bocian ME, Mays L, Laulhere T, Flodman P, Spence MA
Molecular genetic delineation of a deletion of chromosome 13q12-->q13 in a patient with autism and auditory processing deficits.
Cytogenet Genome Res. 2002;98(4):233-9.
In a sporadic case of autism and language deficit due to auditory processing defects, molecular genetic studies revealed that a chromosomal deletion occurred in the 13q12-->q13 region. No chromosome abnormalities were detected in the parents. We determined that the deletion occurred on the paternally derived chromosome 13. There are two previous reports of chromosome 13 abnormalities in patients with autism. The deletion in the subject described in this paper maps between the two chromosome 13 linkage peaks described by Bradford et al. (2001) in studies of subjects with autism and language deficits. The 9-Mb region deleted in the patient described here contains at least four genes that are expressed in brain and that play a role in brain development. They are NBEA, MAB21L1, DCAMKL1 and MADH9. These genes therefore represent candidate genes for autism and specific language deficits. [Abstract]

Castermans D, Wilquet V, Parthoens E, Huysmans C, Steyaert J, Swinnen L, Fryns JP, Van de Ven W, Devriendt K
The neurobeachin gene is disrupted by a translocation in a patient with idiopathic autism.
J Med Genet. 2003 May;40(5):352-6. [Abstract]

OMIM - Online Mendelian Inheritance in Man: Neurobeachin
[The NBEA gene has been located at 13q13]

Steele MM, Al-Adeimi M, Siu VM, Fan YS
Brief report: A case of autism with interstitial deletion of chromosome 13.
J Autism Dev Disord. 2001 Apr;31(2):231-4.
A case of an 18-year-old male who meets the DSM-IV criteria for autistic disorder and borderline intelligence is described. Cytogenetic evaluation revealed a karyotype of 46, XY, del(13)(q14q22). The relevance of this case to the etiology of autism is discussed. [Abstract]

Robinson PD, Schutz CK, Macciardi F, White BN, Holden JJ
Genetically determined low maternal serum dopamine beta-hydroxylase levels and the etiology of autism spectrum disorders.
Am J Med Genet. 2001 Apr 15;100(1):30-6.
Autism, a neurodevelopmental disability characterized by repetitive stereopathies and deficits in reciprocal social interaction and communication, has a strong genetic basis. Since previous findings showed that some families with autistic children have a low level of serum dopamine beta-hydroxylase (DbetaH), which catalyzes the conversion of dopamine to norepinephrine, we examined the DBH gene as a candidate locus in families with two or more children with autism spectrum disorder using the affected sib-pair method. DBH alleles are defined by a polymorphic AC repeat and the presence/absence (DBH+/DBH-) of a 19-bp sequence 118 bp downstream in the 5' flanking region of the gene. There was no increased concordance for DBH alleles in affected siblings, but the mothers had a higher frequency of alleles containing the 19-bp deletion (DBH-), compared to an ethnically similar Canadian comparison group (chi(2) = 4.20, df = 1, P = 0.02 for all multiplex mothers; chi(2) = 4.71, df = 1, P < 0.02 for mothers with only affected sons). Although the odds ratios suggested only a moderate relevance for the DBH- allele as a risk allele, the attributable risk was high (42%), indicating that this allele is an important factor in determining the risk for having a child with autism. DBH genotypes also differed significantly among mothers and controls, with 37% of mothers with two affected sons having two DBH- alleles, compared to 19% of controls (chi(2) = 5.81, df = 2, P = 0.03). DbetaH enzyme activity was lower in mothers of autistic children than in controls (mean was 23.20 +/- 15.35 iU/liter for mothers vs. 33.14 +/- 21.39 iU/liter for controls; t = - 1.749, df = 46, P = 0.044). The DBH- allele was associated with lower mean serum DbetaH enzyme activity (nondeletion homozygotes: 41.02 +/- 24.34 iU/liter; heterozygotes: 32.07 +/- 18.10 iU/liter; and deletion homozygotes: 22.31 +/- 13.48 iU/liter; F = 5.217, df = 2, P = 0.007) in a pooled sample of mothers and controls. Taken together, these findings suggest that lowered maternal serum DbetaH activity results in a suboptimal uterine environment (decreased norepinephrine relative to dopamine), which, in conjunction with genotypic susceptibility of the fetus, results in autism spectrum disorder in some families. [Abstract]

Laumonnier F, Bonnet-Brilhault F, Gomot M, Blanc R, David A, Moizard MP, Raynaud M, Ronce N, Lemonnier E, Calvas P, Laudier B, Chelly J, Fryns JP, Ropers HH, Hamel BC, Andres C, Barthélémy C, Moraine C, Briault S
X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family.
Am J Hum Genet. 2004 Mar;74(3):552-7.
A large French family including members affected by nonspecific X-linked mental retardation, with or without autism or pervasive developmental disorder in affected male patients, has been found to have a 2-base-pair deletion in the Neuroligin 4 gene (NLGN4) located at Xp22.33. This mutation leads to a premature stop codon in the middle of the sequence of the normal protein and is thought to suppress the transmembrane domain and sequences important for the dimerization of neuroligins that are required for proper cell-cell interaction through binding to beta-neurexins. As the neuroligins are mostly enriched at excitatory synapses, these results suggest that a defect in synaptogenesis may lead to deficits in cognitive development and communication processes. The fact that the deletion was present in both autistic and nonautistic mentally retarded males suggests that the NLGN4 gene is not only involved in autism, as previously described, but also in mental retardation, indicating that some types of autistic disorder and mental retardation may have common genetic origins. [Abstract]

Jamain S, Quach H, Betancur C, Råstam M, Colineaux C, Gillberg IC, Soderstrom H, Giros B, Leboyer M, Gillberg C, Bourgeron T
Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism.
Nat Genet. 2003 May;34(1):27-9.
Many studies have supported a genetic etiology for autism. Here we report mutations in two X-linked genes encoding neuroligins NLGN3 and NLGN4 in siblings with autism-spectrum disorders. These mutations affect cell-adhesion molecules localized at the synapse and suggest that a defect of synaptogenesis may predispose to autism. [Abstract]

Vincent JB, Kolozsvari D, Roberts WS, Bolton PF, Gurling HM, Scherer SW
Mutation screening of X-chromosomal neuroligin genes: no mutations in 196 autism probands.
Am J Med Genet. 2004 Aug 15;129B(1):82-4.
Autism, a childhood neuropsychiatric disorder with a strong genetic component, is currently the focus of considerable attention within the field of human genetics as well many other medical-related disciplines. A recent study has implicated two X-chromosomal neuroligin genes, NLGN3 and NLGN4, as having an etiological role in autism, having identified a frameshift mutation in one gene and a substitution mutation in the other, segregating in multiplex autism spectrum families (Jamain et al. [2003: Nat Genet 34:27-29]). The function of neuroligin as a trigger for synapse formation would suggest that such mutations would likely result in some form of pathological manifestation. Our own study, screening a larger sample of 196 autism probands, failed to identify any mutations that would affect the coding regions of these genes. Our findings suggest that mutations in these two genes are infrequent in autism. [Abstract]

Marui T, Hashimoto O, Nanba E, Kato C, Tochigi M, Umekage T, Kato N, Sasaki T.
Gastrin-releasing peptide receptor (GRPR) locus in Japanese subjects with autism.
Brain Dev. 2004 Jan;26(1):5-7.
Gastrin-releasing peptide receptor (GRPR) gene is considered a candidate locus for infantile autism for several reasons. The present study investigated two polymorphic sites (C/450/T and C/661/T) in the second exon of the GRPR gene in Japanese patients with autism (DSM-IV) and healthy subjects. The two polymorphic sites were at high linkage disequilirium, consistent with a previous study in a North American population. The C450-C661 allele, which was observed in one-third of the chromosomes from the North American subjects, was less frequent (6-7%) in the Japanese subjects, suggesting a large ethnic difference in the frequency of the polymorphism. The allele frequencies and genotype distributions were not significantly different between the patients and controls. However, further studies are required to exclude the GRPR locus as a candidate locus for autism, considering the low frequency of the polymorphism in the Japanese subjects. [Abstract]

Maslen GL, Boyd Y.
Comparative mapping of the Grpr locus on the X chromosomes of man and mouse.
Genomics. 1993 Jul;17(1):106-9.
Studies in man indicate that GRPR maps to the Xp21.2-p22.3 region of the human X chromosome and not to the Xp11-q11 interval as previously reported. [Abstract]

Ishikawa-Brush Y, Powell JF, Bolton P, Miller AP, Francis F, Willard HF, Lehrach H, Monaco AP
Autism and multiple exostoses associated with an X;8 translocation occurring within the GRPR gene and 3' to the SDC2 gene.
Hum Mol Genet. 1997 Aug;6(8):1241-50.
An X;8 translocation was identified in a 27-year-old female patient manifesting multiple exostoses and autism accompanied by mental retardation and epilepsy. Through molecular analysis using yeast artificial chromosomes (YACs) and cosmid clones, the translocation breakpoint was isolated and confirmed to be reciprocal within a 5'-GGCA-3' sequence found on both X and 8 chromosomes without gain or loss of a single nucleotide. The translocation breakpoint on the X chromosome occurred in the first intron of the gastrin-releasing peptide receptor (GRPR) gene and that on chromosome 8 occurred approximately 30 kb distal to the 3' end of the Syndecan-2 gene (SDC2), also known as human heparan sulfate proteoglycan or fibroglycan. The GRPR gene was shown to escape X-inactivation. A dosage effect of the GRPR and a position effect of the SDC2 gene may, however, contribute the phenotype observed in this patient since the orientation of these genes with respect to the translocation was incompatible with the formation of a fusion gene. Investigation of mutations in these two genes in unrelated patients with either autism or multiple exostoses as well as linkage and association studies is needed to validate them as candidate genes. [Abstract]

Rao PN, Klinepeter K, Stewart W, Hayworth R, Grubs R, Pettenati MJ
Molecular cytogenetic analysis of a duplication Xp in a male: further delineation of a possible sex influencing region on the X chromosome.
Hum Genet. 1994 Aug;94(2):149-53.
We describe a male infant with severe mental retardation and autism with a duplication of the short arm of the X chromosome. Chromosome painting confirmed the origin of this X duplication. Molecular cytogenetic analysis with fluorescence in situ hybridization (FISH) identified one copy of the zinc finger protein on the X chromosome (ZFX) and two copies of the steroid sulfatase gene (STS), further delineating the breakpoints. Based on cytogenetic and molecular comparisons of cases from the literature of sex-reversal in dup(X),Y patients and our patient, we suggest that a possible secondary sex-influencing gene involved in the regulation of sex determination or testis morphogenesis is present at the distal Xp21.1 to p21.2 region. [Abstract]

Thomas NS, Sharp AJ, Browne CE, Skuse D, Hardie C, Dennis NR
Xp deletions associated with autism in three females.
Hum Genet. 1999 Jan;104(1):43-8.
We report eight females with small deletions of the short arm of the X chromosome, three of whom showed features of autism. Our results suggest that there may be a critical region for autism in females with Xp deletions between the pseudoautosomal boundary and DXS7103. We hypothesise that this effect might be due either to the loss of function of a specific gene within the deleted region or to functional nullisomy resulting from X inactivation of the normal X chromosome. [Abstract]

Comings DE, Wu S, Chiu C, Muhleman D, Sverd J
Studies of the c-Harvey-Ras gene in psychiatric disorders.
Psychiatry Res. 1996 Jun 26;63(1):25-32.
Hérault et al. (1993) previously reported a significant association between autism and the larger fragments of the c-Harvey-Ras (HRAS) Bam H1 polymorphism. We have sought to verify this finding and determine if there was any evidence for an association with other psychiatric disorders. Because of its greater sensitivity, we have examined the HRAS Msp 1 polymorphism. We found a just significant increase in the prevalence of the > 2.1 kb alleles in 48 subjects with autism versus 50 control subjects. There was no increase in the prevalence of the > 2.1 kb alleles in 164 probands with Tourette's syndrome. Examination of 16 preselected symptom clusters, however, showed a significant trend toward higher scores for obsessive-compulsive and phobic symptoms in > 2.1 kb homozygotes. While this locus requires further study, in conjunction with the results of Hérault et al., the present findings suggest that genetic defects in HRAS, and possibly other components of the G protein secondary messenger system, may play a role in some psychiatric disorders. [Abstract]

Hérault J, Petit E, Martineau J, Perrot A, Lenoir P, Cherpi C, Barthélémy C, Sauvage D, Mallet J, Müh JP
Autism and genetics: clinical approach and association study with two markers of HRAS gene.
Am J Med Genet. 1995 Aug 14;60(4):276-81.
Twin studies and familial aggregation studies indicate that genetic factors could play a role in infantile autism. In an earlier study, we identified a possible positive association between autism and a c-Harvey-ras (HRAS) oncogene marker at the 3' end of the coding region. In an attempt to confirm this finding, we studied a larger population, well-characterized clinically and genetically. We report a positive association between autism and two HRAS markers, the 3' marker used in the initial study and an additional marker in exon 1. [Abstract]

Hérault J, Perrot A, Barthélémy C, Büchler M, Cherpi C, Leboyer M, Sauvage D, Lelord G, Mallet J, Müh JP
Possible association of c-Harvey-Ras-1 (HRAS-1) marker with autism.
Psychiatry Res. 1993 Mar;46(3):261-7.
We tested for an association between autism and genes coding for enzymes involved in monoaminergic metabolism and for a linked marker, c-Harvey-Ras-1 (HRAS 1), using restriction fragment length polymorphisms. We did not find evidence of an association between autism and genes coding for tyrosine hydroxylase, dopamine-beta-hydroxylase (DBH), and tryptophan hydroxylase. However, we report a positive association between autism and the locus containing the gene for HRAS-1. [Abstract]

Yamagata T, Aradhya S, Mori M, Inoue K, Momoi MY, Nelson DL
The human secretin gene: fine structure in 11p15.5 and sequence variation in patients with autism.
Genomics. 2002 Aug;80(2):185-94.
Secretin is a peptide hormone involved in digestion that has been studied as a potential therapeutic agent in patients with autism. We characterized the human secretin locus to determine whether mutations in this gene might play a role in a fraction of autism patients. While the secretin gene (SCT) was not found to be mutated in the majority of autistic patients, rare heterozygous sequence variants were identified in three patients. We also investigated length variation in a variable number of tandem repeats (VNTR) immediately upstream of SCT and found no significant differences in length between patients with autism and normal controls. SCT is located on 11p15.5, adjacent to DRD4 and HRAS. This region has been reported to be associated with both autism and attention deficit hyperactivity disorder (ADHD). Although imprinting is a characteristic of some genes in the vicinity, we could find no evidence for methylation of SCT in lymphoblast cells from patients or control individuals. [Abstract]

Serajee FJ, Nabi R, Zhong H, Mahbubul Huq AH
Association of INPP1, PIK3CG, and TSC2 gene variants with autistic disorder: implications for phosphatidylinositol signalling in autism.
J Med Genet. 2003 Nov;40(11):e119.
Epidemiological studies have shown that about 43–86% of individuals with tuberous sclerosis complex have a pervasive developmental disorder similar to autism.1 Mutations in tuberous sclerosis genes TSC1 and TSC2 disrupt the phosphatidylinositol signalling pathway downstream of the insulin / insulin-like growth factor receptor in the control of cell growth.2–5 We investigated single nucleotide polymorphisms in three phosphatidylinositol signalling genes that map to consensus areas of linkage to autism, using 196 trios from the Autism Genetics Resource Exchange. Polymorphisms in inositol polyphosphate-1-phosphatase (INPP1) at the 2q32, gamma catalytic subunit of phosphatidyl 3-OH-kinase gene (PIK3CG) at 7q22, and TSC2 gene at 16p13.3, were investigated for association with autistic disorder. Transmission disequilibrium tests and haplotype analyses demonstrated a nominally positive association of polymorphisms in INPP1, PIK3CG, and TSC2 genes with autism, suggesting that phosphatidylinositol signalling may have a role in susceptibility to autism. [Abstract]

Hebebrand J, Martin M, Körner J, Roitzheim B, de Braganca K, Werner W, Remschmidt H
Partial trisomy 16p in an adolescent with autistic disorder and Tourette's syndrome.
Am J Med Genet. 1994 Sep 15;54(3):268-70.
A partial trisomy 16p was identified in a 14-year-old male adolescent with autistic disorder. He additionally showed complex motor and vocal phenomena, including some simple tics which had first appeared in childhood. Whereas these simple tics were of subclinical significance, an additional diagnosis of Tourette's syndrome (TS) appears justified. The case report illustrates the diagnostic difficulties in assessing psychiatric symptomatology associated with both disorders, especially complex motor and vocal phenomena. The cytogenetic finding is discussed critically in the light of other chromosome abnormalities reported in both TS and autistic disorder. Chromosome 16p should be considered as a candidate region especially for autistic disorder. [Abstract]

A full genome screen for autism with evidence for linkage to a region on chromosome 7q. International Molecular Genetic Study of Autism Consortium.
Hum Mol Genet. 1998 Mar;7(3):571-8.
Autism is characterized by impairments in reciprocal social interaction and communication, and restricted and sterotyped patterns of interests and activities. Developmental difficulties are apparent before 3 years of age and there is evidence for strong genetic influences most likely involving more than one susceptibility gene. A two-stage genome search for susceptibility loci in autism was performed on 87 affected sib pairs plus 12 non-sib affected relative-pairs, from a total of 99 families identified by an international consortium. Regions on six chromosomes (4, 7, 10, 16, 19 and 22) were identified which generated a multipoint maximum lod score (MLS) > 1. A region on chromosome 7q was the most significant with an MLS of 3.55 near markers D7S530 and D7S684 in the subset of 56 UK affected sib-pair families, and an MLS of 2.53 in all 87 affected sib-pair families. An area on chromosome 16p near the telomere was the next most significant, with an MLS of 1.97 in the UK families, and 1.51 in all families. These results are an important step towards identifying genes predisposing to autism; establishing their general applicability requires further study. [Abstract]

Buxbaum JD, Silverman JM, Smith CJ, Kilifarski M, Reichert J, Hollander E, Lawlor BA, Fitzgerald M, Greenberg DA, Davis KL
Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity.
Am J Hum Genet. 2001 Jun;68(6):1514-20.
Although there is considerable evidence for a strong genetic component to idiopathic autism, several genomewide screens for susceptibility genes have been performed with limited concordance of linked loci, reflecting either numerous genes of weak effect and/or sample heterogeneity. Because decreasing sample heterogeneity would increase the power to identify genes, the effect on evidence for linkage of restricting a sample of autism-affected relative pairs to those with delayed onset (at age >36 mo) of phrase speech (PSD, for phrase speech delay) was studied. In the second stage of a two-stage genome screen for susceptibility loci involving 95 families with two or more individuals with autism or related disorders, a maximal multipoint heterogeneity LOD score (HLOD) of 1.96 and a maximal multipoint nonparametric linkage (NPL) score of 2.39 was seen on chromosome 2q. Restricting the analysis to the subset of families (n=49) with two or more individuals having a narrow diagnosis of autism and PSD generated a maximal multipoint HLOD score of 2.99 and an NPL score of 3.32. The increased scores in the restricted sample, together with evidence for heterogeneity in the entire sample, indicate that the restricted sample comprises a population that is more genetically homogeneous, which could therefore increase the likelihood of positional cloning of susceptibility loci. [Abstract]

Bacchelli E, Blasi F, Biondolillo M, Lamb JA, Bonora E, Barnby G, Parr J, Beyer KS, Klauck SM, Poustka A, Bailey AJ, Monaco AP, Maestrini E
Screening of nine candidate genes for autism on chromosome 2q reveals rare nonsynonymous variants in the cAMP-GEFII gene.
Mol Psychiatry. 2003 Nov;8(11):916-24.
The results from several genome scans indicate that chromosome 2q21-q33 is likely to contain an autism susceptibility locus. We studied the potential contribution of nine positional and functional candidate genes: TBR-1; GAD1; DLX1; DLX2; cAMP-GEFII; CHN1; ATF2; HOXD1 and NEUROD1. Screening these genes for DNA variants and association analysis using intragenic single nucleotide polymorphisms did not provide evidence for a major role in the aetiology of autism. Four rare nonsynonymous variants were identified, however, in the cAMP-GEFII gene. These variants were present in five families, where they segregate with the autistic phenotype, and were not observed in control individuals. The significance of these variants is unclear, as their low frequency in IMGSAC families does not account for the relatively strong linkage signal at the 2q locus. Further studies are needed to clarify the contribution of cAMP-GEFII gene variants to autism susceptibility. [Abstract]

Bottini N, De Luca D, Saccucci P, Fiumara A, Elia M, Porfirio MC, Lucarelli P, Curatolo P
Autism: evidence of association with adenosine deaminase genetic polymorphism.
Neurogenetics. 2001 Mar;3(2):111-3.
Reduced adenosine deaminase (ADA) activity has been reported in sera of autistic children relative to controls. Additionally, the Asn allele of the ADA Asp8Asn polymorphism has been associated with reduced enzymatic activity. Therefore, we studied this polymorphism in autistic children and controls from two Italian populations. We observed a significantly elevated frequency of the low-activity Asn allele in the total sample of autistic cases relative to controls (P < 0.00001), and in both study populations (P < 0.001 and P < 0.025). We suggest that this putative genotype-dependent reduction in ADA activity may be a risk factor for the development of autism. [Abstract]

OMIM - Online Mendelian Inheritance in Man: Adenosine deaminase
[The ADA gene has been located at 20q13.11]

Persico AM, Militerni R, Bravaccio C, Schneider C, Melmed R, Trillo S, Montecchi F, Palermo MT, Pascucci T, Puglisi-Allegra S, Reichelt KL, Conciatori M, Baldi A, Keller F
Adenosine deaminase alleles and autistic disorder: case-control and family-based association studies.
Am J Med Genet. 2000 Dec 4;96(6):784-90.
Adenosine deaminase (ADA) plays a relevant role in purine metabolism, immune responses, and peptidase activity, which may be altered in some autistic patients. Codominant ADA1 and ADA2 alleles code for ADA1 and ADA2 allozymes, the most frequent protein isoforms in the general population. Individuals carrying one copy of the ADA2 allele display 15 to 20% lower catalytic activity compared to ADA1 homozygotes. Recent preliminary data suggest that ADA2 alleles may be more frequent among autistic patients than healthy controls. The present study was undertaken to replicate these findings in a new case-control study, to test for linkage/association using a family-based design, and to characterize ADA2-carrying patients by serotonin blood levels, peptiduria, and head circumference. ADA2 alleles were significantly more frequent in 91 Caucasian autistic patients of Italian descent than in 152 unaffected controls (17.6% vs. 7.9%, P = 0.018), as well as among their fathers. Family-based tests involving these 91 singleton families, as well as 44 additional Caucasian-American trios, did not support significant linkage/association. However, the observed preferential maternal transmission of ADA2 alleles, if replicated, may point toward linkage disequilibrium between the ADA2 polymorphism and an imprinted gene variant located in its vicinity. Racial and ethnic differences in ADA allelic distributions, together with the low frequency of the ADA2 allele, may pose methodological problems to future linkage/association studies. Direct assessments of ADA catalytic activity in autistic individuals and unaffected siblings carrying ADA1/ADA1 vs ADA1/ADA2 genotypes may provide stronger evidence of ADA2 contributions to autistic disorder. [Abstract]

Lucarelli P, Saccucci P, Bottini N, De Luca D, Fiumara A, Elia M, Bottini N, Porfirio MC, Curatolo P
Two-loci ADA haplotypes in autistic disorder.
Am J Med Genet. 2002 Apr 1;108(4):339-40. [Abstract]

Gharani N, Benayed R, Mancuso V, Brzustowicz LM, Millonig JH
Association of the homeobox transcription factor, ENGRAILED 2, 3, with autism spectrum disorder.
Mol Psychiatry. 2004 May;9(5):474-84.
Mouse mutants of the homeobox transcription factor Engrailed2 (En2) and autistic individuals display similar cerebellar morphological abnormalities, which include hypoplasia and a decrease in the number of Purkinje cells. Human EN2 maps to 7q36, a chromosomal region that has demonstrated suggestive linkage to autism spectrum disorder (ASD). To investigate EN2 for evidence of association with ASD, four single-nucleotide polymorphisms (SNPs) (rs3735653, rs1861972, rs1861973, rs2361689) that span the majority of the 8.0 kb gene were assessed by the transmission/disequilibrium test. Initially, 138 triads of autistic individuals and their parents were tested. Two intronic SNPs (rs1861972 and rs1861973) demonstrated significant association with autism (rs1861972, P=0.0018; rs1861973, P=0.0003; haplotype, P=0.000005). Flanking exonic SNPs (rs3735653 and rs2361689) did not display association. This analysis was then extended to include 167 small nuclear ASD pedigrees and significant association was again only observed for rs1861972 and rs1861973 under both the narrow and broad diagnostic criteria (narrow: rs1861972 P=0.0290, rs1861973 P=0.0073, haplotype P=0.0009; broad: rs1861972 P=0.0175, rs1861973 P=0.0107, haplotype P=0.0024). These data demonstrate association between a cerebellar patterning gene and ASD, suggesting a role for EN2 as a susceptibility locus and supporting a neurodevelopmental defect hypothesis in the etiology of autism. [Abstract]

Petit E, Hérault J, Martineau J, Perrot A, Barthélémy C, Hameury L, Sauvage D, Lelord G, Müh JP
Association study with two markers of a human homeogene in infantile autism.
J Med Genet. 1995 Apr;32(4):269-74.
Epidemiological data and family studies in autism show that there is a genetic susceptibility factor in the aetiology of this syndrome. We carried out an association study in infantile autism. Two markers of the homeogene EN2 involved in cerebellar development were tested in a population of 100 autistic children and in a population of 100 control children. With the MP4 probe showing a PvuII polymorphism, significant differences in the allele frequencies between the two populations were found (chi 2 = 7.99, df = 1, p < 0.01). With the MP5 probe showing an SstI polymorphism, no difference appeared (chi 2 = 1.17, not significant). Several clinical examinations allowed us to characterise the autistic children. Most of them had high scores for autistic behaviour and language disorders but low scores for neurological syndromes. Two children had a significant family history and six children had confirmed syndromes or diseases of genetic origin. Discriminant analysis between clinical and molecular data did not give significant results. These preliminary results must be supported by further analyses of this gene and by studies of its potential involvement in the pathophysiology of the autistic syndrome. [Abstract]

Zhong H, Serajee FJ, Nabi R, Huq AH
No association between the EN2 gene and autistic disorder.
J Med Genet. 2003 Jan;40(1):e4. [Abstract]

Estécio M, Fett-Conte AC, Varella-Garcia M, Fridman C, Silva AE
Molecular and cytogenetic analyses on Brazilian youths with pervasive developmental disorders.
J Autism Dev Disord. 2002 Feb;32(1):35-41.
The Pervasive Developmental Disorders (PDDs) constitute a group of behavioral and neurobiological impairment conditions whose main features are delayed communicative and cognitive development. Genetic factors are reportedly associated with PDDs and particular genetic abnormalities are frequently found in specific diagnostic subgroups such as the autism spectrum disorders. This study evaluated cytogenetic and molecular parameters in 30 youths with autism or other PDDs. The fragile X syndrome was the most common genetic abnormality detected, presented by 1 patient with autism and 1 patient with PPD not-otherwise specified (PPD-NOS). One girl with PDD-NOS was found to have tetrasomy for the 15q11-q13 region, and one patient with autism exhibited in 2/100 metaphases an inv(7)(p35q36), thus suggesting a mosaicism 46,XX/46,XX,inv(7)(p15q36) or representing a coincidental finding. The high frequency of chromosomopathies support the hypothesis that PDDs may develop as a consequence to chromosomal abnormalities and justify the cytogenetic and molecular assessment in all patients with PDDs for establishment of diagnosis. [Abstract]

Ramanathan S, Woodroffe A, Flodman PL, Mays LZ, Hanouni M, Modahl CB, Steinberg-Epstein R, Bocian ME, Spence MA, Smith M
A case of autism with an interstitial deletion on 4q leading to hemizygosity for genes encoding for glutamine and glycine neurotransmitter receptor sub-units (AMPA 2, GLRA3, GLRB) and neuropeptide receptors NPY1R, NPY5R.
BMC Med Genet. 2004 Apr 16;5(1):10.
BACKGROUND: Autism is a pervasive developmental disorder characterized by a triad of deficits: qualitative impairments in social interactions, communication deficits, and repetitive and stereotyped patterns of behavior. Although autism is etiologically heterogeneous, family and twin studies have established a definite genetic basis. The inheritance of idiopathic autism is presumed to be complex, with many genes involved; environmental factors are also possibly contributory. The analysis of chromosome abnormalities associated with autism contributes greatly to the identification of autism candidate genes. CASE PRESENTATION: We describe a child with autistic disorder and an interstitial deletion on chromosome 4q. This child first presented at 12 months of age with developmental delay and minor dysmorphic features. At 4 years of age a diagnosis of Pervasive Developmental Disorder was made. At 11 years of age he met diagnostic criteria for autism. Cytogenetic studies revealed a chromosome 4q deletion. The karyotype was 46, XY del 4 (q31.3-q33). Here we report the clinical phenotype of the child and the molecular characterization of the deletion using molecular cytogenetic techniques and analysis of polymorphic markers. These studies revealed a 19 megabase deletion spanning 4q32 to 4q34. Analysis of existing polymorphic markers and new markers developed in this study revealed that the deletion arose on a paternally derived chromosome. To date 33 genes of known or inferred function are deleted as a consequence of the deletion. Among these are the AMPA 2 gene that encodes the glutamate receptor GluR2 sub-unit, GLRA3 and GLRB genes that encode glycine receptor subunits and neuropeptide Y receptor genes NPY1R and NPY5R. CONCLUSIONS: The deletion in this autistic subject serves to highlight specific autism candidate genes. He is hemizygous for AMPA 2, GLRA3, GLRB, NPY1R and NPY5R. GluR2 is the major determinant of AMPA receptor structure. Glutamate receptors maintain structural and functional plasticity of synapses. Neuropeptide Y and its receptors NPY1R and NPY5R play a role in hippocampal learning and memory. Glycine receptors are expressed in very early cortical development. Molecular cytogenetic studies and DNA sequence analysis in other patients with autism will be necessary to confirm that these genes are involved in autism. [Abstract]

Nabi R, Serajee FJ, Chugani DC, Zhong H, Huq AH
Association of tryptophan 2,3 dioxygenase gene polymorphism with autism.
Am J Med Genet. 2004 Feb 15;125B(1):63-8.
Although elevation of blood and platelet serotonin has been documented in autism, genetic analyses of serotonin transporter gene have given conflicting results. Tryptophan 2,3 dioxygenase (TDO2) is the rate-limiting enzyme in the catabolism of tryptophan, the precursor of serotonin. A mutation that results in decreased activity of the TDO2 can decrease catabolism of tryptophan and increase the level of whole body serotonin. As such it is a potential candidate gene for autism. We have investigated five single nucleotide polymorphisms in the TDO2 gene for association with autistic disorder. One hundred and ninety six multiplex autistic disorder families were tested using transmission disequilibrium test. There was a significant difference in the transmission of a promoter variant to autistic subjects (P = 0.0006). Haplotype analysis also demonstrated significant difference in the transmission of TDO2 haplotypes to autistic subjects (P = 0.0027). Our results suggest the presence of a susceptibility mutation in the TDO2 or a nearby gene, but may also represent a chance finding. [Abstract]

OMIM - Online Mendelian Inheritance in Man: tryptophan 2,3 dioxygenase
[The TDO2 gene has been located at 4q31-q32]

Persico AM, D'Agruma L, Zelante L, Militerni R, Bravaccio C, Schneider C, Melmed R, Trillo S, Montecchi F, Elia M, Palermo M, Rabinowitz D, Pascucci T, Puglisi-Allegra S, Reichelt KL, Muscarella L, Guarnieri V, Melgari JM, Conciatori M, Keller F
Enhanced APOE2 transmission rates in families with autistic probands.
Psychiatr Genet. 2004 Jun;14(2):73-82.
We have previously described linkage/association between reelin gene polymorphisms and autistic disorder. APOE also participates in the Reelin signaling pathway, by competitively antagonizing Reelin binding to APOE receptor 2 and to very-low-density lipoprotein receptors. The APOE2 protein variant displays the lowest receptor binding affinity compared with APOE3 and APOE4. In this study, we assess linkage/association between primary autism and APOE alleles in 223 complete trios, from 119 simplex Italian families and 44 simplex and 29 multiplex Caucasian-American families. Statistically significant disequilibrium favors the transmission of epsilon2 alleles to autistic offspring, over epsilon3 and epsilon4 (allele-wise transmission/disequilibrium test [TDT], chi2 = 6.16, 2 degrees of freedom [d.f.], P<0.05; genotype-wise TDT, chi2 = 10.68, 3 d.f., P<0.05). A novel epsilon3r allele was also discovered in an autistic child and his mother. Autistic patients do not differ significantly from unaffected siblings (allele-wise TDT comparing autistic patients versus unaffected sibs, chi2 = 1.83, 2 d.f., P<0.40, not significant). The major limitation of this study consists of our small sample size of trios including one unaffected sibling, currently not possessing the statistical power necessary to conclusively discriminate a specific association of epsilon2 with autism, from a distorted segregation pattern characterized by enhanced epsilon2 transmission rates both to affected and unaffected offspring. Our findings are thus compatible with either (a) pathogenetic contributions by epsilon2 alleles to autism spectrum vulnerability, requiring additional environmental and/or genetic factors to yield an autistic syndrome, and/or (b) a protective effect of epsilon2 alleles against the enhanced risk of miscarriage and infertility previously described among parents of autistic children. [Abstract]

Raiford KL, Shao Y, Allen IC, Martin ER, Menold MM, Wright HH, Abramson RK, Worley G, DeLong GR, Vance JM, Cuccaro ML, Gilbert JR, Pericak-Vance MA
No association between the APOE gene and autism.
Am J Med Genet. 2004 Feb 15;125B(1):57-60.
Autism is a neurodevelopmental disorder characterized by stereotypic and repetitive behavior and interests, together with social and communicative deficiencies. The results of several genomic screens suggest the presence of an autism susceptibility locus on chromosome 19p13.2-q13.4. The apolipoprotein E (APOE) gene on chromosome 19 encodes for a protein, apoE, whose different isoforms (E2, E3, E4) influence neuronal growth. APOE participates in lipid transport and metabolism, repair, growth, and maintenance of axons and myelin during neuronal development. The APOE protein competes with the Reelin protein for VLDL/APOER2 receptor binding. Several studies have reported evidence for an association between autism and the Reelin gene. Based on these data we tested for association between APOE and autism using family-based association methods in a data set of 322 autism families. Three promoter, one intronic, and one 3' UTR single nucleotide polymorphisms (SNPs) in the APOE gene (-491a/t, -427c/t, -219g/t, 113c/g, and 5361c/t) as well as the APOE functional polymorphism (E2, E3, E4) were examined and failed to reveal significant evidence that autism is associated with APOE. [Abstract]

Wassink TH, Piven J, Vieland VJ, Pietila J, Goedken RJ, Folstein SE, Sheffield VC
Examination of AVPR1a as an autism susceptibility gene.
Mol Psychiatry. 2004 Apr 6;
Impaired reciprocal social interaction is one of the core features of autism. While its determinants are complex, one biomolecular pathway that clearly influences social behavior is the arginine-vasopressin (AVP) system. The behavioral effects of AVP are mediated through the AVP receptor 1a (AVPR1a), making the AVPR1a gene a reasonable candidate for autism susceptibility. We tested the gene's contribution to autism by screening its exons in 125 independent autistic probands and genotyping two promoter polymorphisms in 65 autism affected sibling pair (ASP) families. While we found no nonconservative coding sequence changes, we did identify evidence of linkage and of linkage disequilibrium. These results were most pronounced in a subset of the ASP families with relatively less severe impairment of language. Thus, though we did not demonstrate a disease-causing variant in the coding sequence, numerous nontraditional disease-causing genetic abnormalities are known to exist that would escape detection by traditional gene screening methods. Given the emerging biological, animal model, and now genetic data, AVPR1a and genes in the AVP system remain strong candidates for involvement in autism susceptibility and deserve continued scrutiny. [Abstract]

Kim SJ, Young LJ, Gonen D, Veenstra-VanderWeele J, Courchesne R, Courchesne E, Lord C, Leventhal BL, Cook EH, Insel TR
Transmission disequilibrium testing of arginine vasopressin receptor 1A (AVPR1A) polymorphisms in autism.
Mol Psychiatry. 2002;7(5):503-7.
Impairment in social reciprocity is a central component of autism. In preclinical studies, arginine vasopressin (AVP) has been shown to increase a range of social behaviors, including affiliation and attachment, via the V(1a) receptor (AVPR1A) in the brain. Both the behavioral effects of AVP and the neural distribution of the V1a receptor vary greatly across mammalian species. This difference in regional receptor expression as well as differences in social behavior may result from a highly variable repetitive sequence in the 5' flanking region of the V1a gene (AVPR1A). Given this comparative evidence for a role in inter-species variation in social behavior, we explored whether within our own species, variation in the human AVPR1A may contribute to individual variations in social behavior, with autism representing an extreme form of social impairment. We genotyped two microsatellite polymorphisms from the 5' flanking region of AVPR1A for 115 autism trios and found nominally significant transmission disequilibrium between autism and one of the microsatellite markers by Multiallelic Transmission/Disequilibrium test (MTDT) that was not significant after Bonferroni correction. We also screened approximately 2 kb of the 5' flanking region and the coding region and identified 10 single nucleotide polymorphisms. [Abstract]

Shibayama A, Cook EH, Feng J, Glanzmann C, Yan J, Craddock N, Jones IR, Goldman D, Heston LL, Sommer SS
MECP2 structural and 3'-UTR variants in schizophrenia, autism and other psychiatric diseases: a possible association with autism.
Am J Med Genet. 2004 Jul 1;128B(1):50-3.
Mutations in the gene coding for methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome (RTT) and have also been reported in a number of X-linked mental retardation syndromes. Furthermore, putative mutations recently have been described in a few autistic patients and a boy with language disorder and schizophrenia. In this study, DNA samples from individuals with schizophrenia and other psychiatric diseases were scanned in order to explore whether the phenotypic spectrum of mutations in the MECP2 gene can extend beyond the traditional diagnoses of RTT in females and severe neonatal encephalopathy in males. The coding regions, adjacent splicing junctions, and highly conserved segments of the 3'-untranslated region (3'-UTR) were examined in 214 patients, including 106 with schizophrenia, 24 with autism, and 84 patients with other psychiatric diseases by detection of virtually all mutations-single strand conformation polymorphism (SSCP) (DOVAM-S). To our knowledge, this is the first analysis of variants in conserved regions of the 3'-UTR of this gene. A total of 5.2 kb per haploid gene was analyzed (1.5 Mb for 214 patients). A higher frequency of missense and 3'-UTR variants was found in autism. One missense and two 3'-UTR variants were found in 24 patients with autism versus one patient with a missense change in 144 ethnically similar individuals without autism (P = 0.009). These mutations suggest that a possible association between MECP2 mutations and autism may warrant further study. [Abstract]

Carney RM, Wolpert CM, Ravan SA, Shahbazian M, Ashley-Koch A, Cuccaro ML, Vance JM, Pericak-Vance MA
Identification of MeCP2 mutations in a series of females with autistic disorder.
Pediatr Neurol. 2003 Mar;28(3):205-11.
Rett disorder and autistic disorder are both pervasive developmental disorders. Recent studies indicate that at least 80% of Rett Disorder cases are caused by mutations in the methyl-CpG-binding protein 2 (MeCP2) gene. Since there is some phenotypic overlap between autistic disorder and Rett disorder, we analyzed 69 females clinically diagnosed with autistic disorder for the presence of mutations in the MeCP2 gene. Two autistic disorder females were found to have de novo mutations in the MeCP2 gene. These data provide additional evidence of variable expression in the Rett disorder phenotype and suggest MeCP2 testing may be warranted for females presenting with autistic disorder. [Abstract]

Zappella M, Meloni I, Longo I, Canitano R, Hayek G, Rosaia L, Mari F, Renieri A
Study of MECP2 gene in Rett syndrome variants and autistic girls.
Am J Med Genet. 2003 May 15;119B(1):102-7.
Mutations in MECP2 gene account for approximately 80% of cases of Rett syndrome (RTT), an X-linked severe developmental disorder affecting young girls, as well as for most cases of Preserved Speech Variant (PSV), a mild RTT variant in which autistic behavior is common. The aim of this study is to determine whether MECP2 mutations are responsible for PSV only or may cause other forms of autistic disorders. We screened for mutations by SSCP 19 girls with a clinical diagnosis of autism, two of them fulfilling the PSV criteria. A pathogenic mutation was found only in the latter two cases (R133C and R453X). A long follow-up of these two girls revealed a unique clinical course. They initially developed the first three stages of RTT, they were severely retarded and had autistic behavior. Over the years their abilities increased progressively and by early adolescence they lost autistic behavior, becoming adequately accustomed to people and reaching an IQ close to 45. These results confirm previous clinical studies suggesting that a wide spectrum of RTT exists including girls with mental abilities considerably higher than in classic RTT. We conclude that MECP2 mutations (missense or late truncating) can be found in girls with an IQ close to 45 and a clinical history of PSV of Rett syndrome. Furthermore, MECP2 mutations are not found in patients in which autism remains stable over the years. [Abstract]

Lobo-Menendez F, Sossey-Alaoui K, Bell JM, Copeland-Yates SA, Plank SM, Sanford SO, Skinner C, Simensen RJ, Schroer RJ, Michaelis RC
Absence of MeCP2 mutations in patients from the South Carolina autism project.
Am J Med Genet. 2003 Feb15;117B(1):97-101.
The methyl-CpG binding protein 2 (MeCP2) gene has recently been identified as the gene responsible for Rett syndrome (RS), a pervasive developmental disorder considered by many to be one of the autism spectrum disorders. Most female patients with MeCP2 mutations exhibit the classic features of RS, including autistic behaviors. Most male patients with MeCP2 mutations exhibit moderate to severe developmental delay/mental retardation. Ninety nine patients from the South Carolina autism project (SCAP) were screened for MeCP2 mutations, including all 41 female patients from whom DNA samples were available plus the 58 male patients with the lowest scores on standard IQ tests and/or the Vineland Adaptive Behavior Scale. No pathogenic mutations were observed in these patients. One patient had the C582T variant, previously reported in the unaffected father of an RS patient. Two other patients had single nucleotide polymorphisms in the 3' UTR of the gene, G1470A and C1516G. These variants were seen in 12/82 and 1/178 phenotypically normal male controls, respectively. The findings from this and other studies suggest that mutations in the coding sequence of the MeCP2 gene are not a significant etiological factor in autism. [Abstract]

Beyer KS, Blasi F, Bacchelli E, Klauck SM, Maestrini E, Poustka A
Mutation analysis of the coding sequence of the MECP2 gene in infantile autism.
Hum Genet. 2002 Oct;111(4-5):305-9.
Mutations in the coding region of the methyl-CpG-binding protein 2 ( MECP2) gene cause Rett syndrome and have also been reported in a number of X-linked mental retardation syndromes. Furthermore, such mutations have recently been described in a few autistic patients. In this study, a large sample of individuals with autism was screened in order to elucidate systematically whether specific mutations in MECP2 play a role in autism. The mutation analysis of the coding sequence of the gene was performed by denaturing high-pressure liquid chromatography and direct sequencing. Taken together, 14 sequence variants were identified in 152 autistic patients from 134 German families and 50 unrelated patients from the International Molecular Genetic Study of Autism Consortium affected relative-pair sample. Eleven of these variants were excluded for having an aetiological role as they were either silent mutations, did not cosegregate with autism in the pedigrees of the patients or represented known polymorphisms. The relevance of the three remaining mutations towards the aetiology of autism could not be ruled out, although they were not localised within functional domains of MeCP2 and may be rare polymorphisms. Taking into account the large size of our sample, we conclude that mutations in the coding region of MECP2 do not play a major role in autism susceptibility. Therefore, infantile autism and Rett syndrome probably represent two distinct entities at the molecular genetic level. [Abstract]

Vourc'h P, Bienvenu T, Beldjord C, Chelly J, Barthélémy C, Müh JP, Andres C
No mutations in the coding region of the Rett syndrome gene MECP2 in 59 autistic patients.
Eur J Hum Genet. 2001 Jul;9(7):556-8.
Autistic disorder is a pervasive developmental disorder considered to have a multigenic origin. Mental retardation is present in 75% of autistic patients. Autistic features are found in Rett syndrome, a neurological disorder affecting girls and associated with severe mental retardation. Recently, the gene responsible for the Rett syndrome, methyl CpG-binding protein (MECP2) gene, was identified on the X chromosome by a candidate gene strategy. Mutations in this gene were also observed in some mentally retarded males. In this study we tested MECP2 as a candidate gene in autistic disorder by a DGGE analysis of its coding region and intron-exon boundaries. Among 59 autistic patients, 42 males and 17 females, mentally retarded or not, no mutations or polymorphisms were present in the MECP2 gene. Taking into account the size of our sample, we conclude that MECP2 coding sequence mutations are not an important factor (less than 5% of cases) in the aetiology of autistic disorder. [Abstract]

Longo I, Russo L, Meloni I, Ricci I, Ariani F, Pescucci C, Giordano CT, Canitano R, Hayek G, Zappella M, Neri G, Renieri A, Gurrieri F
Three Rett patients with both MECP2 mutation and 15q11-13 rearrangements.
Eur J Hum Genet. 2004 Aug;12(8):682-5.
Autism and Rett syndrome, a severe neurological disorder with autistic behavior, are classified as separate disorders on clinical and etiological ground. Rett syndrome is a monogenic X-linked dominant condition due to de novo mutations in the MECP2 gene, whereas autism is a neurodevelopmental and behavioral disorder with complex genetic basis. Maternally inherited duplications on 15q11-q13 are found in a fraction of autistic children suggesting that an abnormal dosage of gene(s) within this region might cause susceptibility to autism. Now we show that three Rett patients are carriers of both a MECP2 mutation and a 15q11-q13 rearrangement, suggesting that there might be a relationship between autism-related genes and the MECP2 gene. [Abstract]

Schutz CK, Polley D, Robinson PD, Chalifoux M, Macciardi F, White BN, Holden JJ
Autism and the X chromosome: no linkage to microsatellite loci detected using the affected sibling pair method.
Am J Med Genet. 2002 Apr 15;109(1):36-41.
The etiology of autism spectrum disorders (ASDs) is poorly understood, although it is clear that genetic factors play a major role. ASDs appear to be a heterogeneous group of disorders, making genetic analysis difficult in the absence of etiologically definable subgroups. The excess of males in the affected population has led to suggestions that an X-linked locus could play a role in the causation of autism or a related pervasive developmental disorder. To examine this, we have investigated the genotypes of 31 families with two or more affected boys, at a series of 16 highly polymorphic loci distributed along the X chromosome with an average interlocus distance of 12 cM, in order to identify regions of significantly increased concordance among pairs of affected brothers. No locus tested showed a significant increase in concordance, supporting findings by others that there are no genes of major effect located on the X chromosome that contribute to increased susceptibility to ASD. [Abstract]

Hallmayer J, Hebert JM, Spiker D, Lotspeich L, McMahon WM, Petersen PB, Nicholas P, Pingree C, Lin AA, Cavalli-Sforza LL, Risch N, Ciaranello RD
Autism and the X chromosome. Multipoint sib-pair analysis.
Arch Gen Psychiatry. 1996 Nov;53(11):985-9.
BACKGROUND: Genetic factors undoubtedly play a major etiologic role in autism, but how it is inherited remains unanswered. The increased incidence in males suggests possible involvement of the X chromosome. METHODS: Using data from 38 multiplex families with autism (2 or more autistic siblings), we performed a multipoint sib-pair linkage analysis between autism and 35 microsatellite markers located on the X chromosome. The model included a single parameter, the risk ratio lambda xs (i.e., ratio of risk to siblings compared with the population prevalence), owing to an X-linked gene. Different lambda xs values were assumed and regions of exclusion were established. RESULTS: The entire X chromosome could be excluded for a lambda xs value of 4. The ability to exclude an X-linked gene decreased with smaller lambda xs values, and some positive evidence was obtained with smaller values. A maximum lod score of 1.24 was obtained at locus DXS424 with a lambda xs value of 1.5. CONCLUSIONS: We were able to exclude any moderate to strong gene effect causing autism on the X chromosome. Smaller gene effects (lambda xs < 4) could not be excluded, in particular, a gene of small effect located between DXS453 and DXS1001. [Abstract]

Hallmayer J, Spiker D, Lotspeich L, McMahon WM, Petersen PB, Nicholas P, Pingree C, Ciaranello RD
Male-to-male transmission in extended pedigrees with multiple cases of autism.
Am J Med Genet. 1996 Feb 16;67(1):13-8.
Despite strong genetic influences in autism, the true mode of inheritance remains unknown. Sex differences in autism have been described in both singleton and multiplex families [Lord et al., 1982; Volkmar et al., 1993; McLennan et al., 1993; Lord, 1992]: Boys outnumber girls by 3 or 4 to 1, and so a sex-linked mode of transmission must also be considered. The key characteristic of X-linkage is that all sons of affected men are unaffected (no male-to-male transmission). In the present study, which is part of an ongoing linkage project in autism, we describe 77 multiplex autism families, 11 of who are affected cousin or half-sibling families. By using these families, it is possible to trace the path of genetic transmission and observe whether the hypothesis of X-linkage is tenable. Of 11 extended pedigrees from 77 multiplex families, six show male-to-male transmission; in these families, X-linkage can be excluded as the genetic basis for their autism. The data from the other five families are compatible with either an autosomal or an X-linked mode of transmission. The key point to emerge, then, is that autism cannot be exclusively an X-linked disorder; there must be an autosomal mode of transmission at least in some families. Thus we must consider the alternative hypotheses that autism is either entirely autosomal, or it is genetically heterogeneous, involving at least one autosomal locus with genderspecific expression, as well as a possible locus on the X-chromosome. [Abstract]

Poon PM, Chen QL, Lai KY, Wong CK, Pang CP
CGG repeat interruptions in the FMR1 gene in patients with infantile autism.
Clin Chem Lab Med. 1998 Aug;36(8):649-53.
We determined the CGG repeat length and AGG interruptions in the FMR1 gene in normal Chinese subjects and patients with infantile autism and mild mental retardation. Genomic DNA was investigated by PCR and Southern hybridisation for CGG repeat number and PCR with Mnl I restriction analysis for AGG interruption. Both the normal subjects and the patients with autism have 53 CGG repeats in FMR1, and the majority have two interspersed AGG. Our normal Chinese subjects have a similar number of interspersed AGG as other populations. When compared with the normal subjects, the autism patients have less AGG interruptions and a different pattern of AGG distribution. There was a significant difference in the CGG configurations between normal subjects and patients with autism. The latter had less interspersed AGG, as in fragile X patients, but they did not have fragile X. A study on mentally retarded patients with no infantile autism should also be carried out to ascertain whether mental retardation alone may have contributed to such AGG pattern. [Abstract]

Jones MB, Palmour RM, Zwaigenbaum L, Szatmari P
Modifier effects in autism at the MAO-A and DBH loci.
Am J Med Genet. 2004 Apr 1;126B(1):58-65.
Autism is one of a group of pervasive developmental disorders (PDD) characterized by qualitative impairments in reciprocal social communication and by a preference for repetitive, stereotyped activities, interests, and behaviors. The disorder is caused in large part by genetic mechanisms, though no disease genes have yet been identified. The objective of this study was to investigate three markers, two in the DBH gene and one in the MAO-A gene, for maternal or fetal modifier effects on level of functioning (IQ). At the same time, the possibility of maternal or fetal susceptibility effects was also examined. We assembled 67 affected sibpairs and 45 singletons and determined allele frequencies at the three markers among the affected children and first degree relatives. Sizeable and significant modifier effects were found at the MAO locus and, to a lesser extent, at the DBH locus. Susceptibility effects were also found but not without qualification. We conclude that maternal genotypes at the MAO-A locus, and possibly at the DBH one, may modify IQ in children with autism through the intrauterine environment. [Abstract]

Cohen IL, Liu X, Schutz C, White BN, Jenkins EC, Brown WT, Holden JJ
Association of autism severity with a monoamine oxidase A functional polymorphism.
Clin Genet. 2003 Sep;64(3):190-7.
A functional polymorphism (the upstream variable-number tandem repeat region, or uVNTR) in the monoamine oxidase A (MAOA) promoter region has been reported to be associated with behavioral abnormalities as well as increased serotonergic responsivity. We examined the relation between MAOA-uVNTR alleles and the phenotypic expression of autism in 41 males younger than 12.6 years of age. Children with the low-activity MAOA allele had both lower intelligence quotients (IQ) and more severe autistic behavior than children with the high-activity allele. In follow-up testing of 34 of the males at the 1-year time-point, those with the low-activity allele showed a worsening in IQ but no change in the severity of their autistic behavior. We conclude that functional MAOA-uVNTR alleles may act as a genetic modifier of the severity of autism in males. [Abstract]

Yirmiya N, Pilowsky T, Tidhar S, Nemanov L, Altmark L, Ebstein RP
Family-based and population study of a functional promoter-region monoamine oxidase A polymorphism in autism: possible association with IQ.
Am J Med Genet. 2002 Apr 8;114(3):284-7.
Although the etiology of autism remains to be elucidated, genetic elements significantly contribute to this disorder, and genes on the X chromosome are of special interest because there is a 4:1 predominance of male probands in autism. In the current study, we therefore examined, using the robust transmission disequilibrium test (TDT), possible preferential transmission of variants of a functional monoamine oxidase A (MAO A) promoter region polymorphism for linkage to autism. In the 49 families examined (33 families with one proband and 15 families with two affected siblings), we did not find preferential transmission of MAO A from 33 heterozygous mothers to affected child (TDT chi-square = 0.29, NS). Nor was any significant difference in MAO A allele frequency observed between 43 male autism subjects versus a group of 108 non-autism control subjects (chi-square = 1.23, P = 0.27, NS). However, a trend was observed for an association between IQ in the probands and the MAO A genotype that just attained significance (F = 3.5, P = 0.046, N = 28) in the small group of autism subjects recruited from families with two affected siblings. [Abstract]

Vourc'h P, Martin I, Marouillat S, Adrien JL, Barthélémy C, Moraine C, Müh JP, Andres C
Molecular analysis of the oligodendrocyte myelin glycoprotein gene in autistic disorder.
Neurosci Lett. 2003 Feb 27;338(2):115-8.
We previously observed in four autistic patients a new allele (GXAlu 5) of the GXAlu microsatellite marker located in intron 27b of the neurofibromatosis type 1 (NF1) gene (17q11.2). This large intron contains the OMGP gene, coding for the oligodendrocyte myelin glycoprotein expressed by neurons and oligodendrocytes. In the present work, we analysed the distribution of a coding single nucleotide polymorphism (OMGP62) of the OMGP gene, the nearest gene to the GXAlu marker, in a control population (n=101) and in an autistic group (n=65). We observed no significant difference in allele distribution comparing these two groups (chi(2)=1.81; P=0.179). When distinguishing an autistic group with a developmental quotient (DQ) higher than 30 (n=37) and one with a DQ lower than 30 (n=28), we observed an association between allele A and the group with the highest DQ (P=0.015). We found no other polymorphism using SSCP screening and DNA sequencing in the OMGP coding region in 16 autistic patients bearing OMGP62 allele A. [Abstract]

Mbarek O, Marouillat S, Martineau J, Barthélémy C, Müh JP, Andres C
Association study of the NF1 gene and autistic disorder.
Am J Med Genet. 1999 Dec 15;88(6):729-32.
Neurofibromatosis type 1 (NF1) is increased about 150-fold in autistic patients. The aim of this study was to test for an association between the NF1 locus and autistic disorder. The allele distributions of three markers of the NF1 gene were studied in 85 autistic patients and 90 controls. No differences in allele distributions were observed. However, we found a new allele (allele 5) of the GXAlu marker in four autistic patients. Allele 5 was absent in a larger control population (213 individuals). The patients with allele 5 had a more severe clinical picture, mainly in the fields of motility and tonus. Our preliminary results suggest that the NF1 region is not a major susceptibility locus for autism. However, the GXAlu marker of the NF1 gene appears as a possible candidate for a susceptibility locus in a small subgroup of severely affected autistic patients. [Abstract]

Plank SM, Copeland-Yates SA, Sossey-Alaoui K, Bell JM, Schroer RJ, Skinner C, Michaelis RC
Lack of association of the (AAAT)6 allele of the GXAlu tetranucleotide repeat in intron 27b of the NF1 gene with autism.
Am J Med Genet. 2001 Jul 8;105(5):404-5.
A novel allele of the GXAlu tetranucleotide repeat in intron 27b of the neurofibromatosis 1 (NF1) gene has recently been reported to be present in 4.7% of autistic patients but not in controls. We have found the novel GXAlu allele absent in 204 patients from the South Carolina Autism Project and 200 controls. The autism population studied includes a significant number of patients with hypotonia, stereotyped behaviors, or postural, gait, and motor abnormalities similar to those seen in the patients previously reported to possess the novel GXAlu allele. This suggests that the novel (AAAT)6 GXAlu allele is not associated with autism. [Abstract]

Turner G, Partington M, Kerr B, Mangelsdorf M, Gecz J
Variable expression of mental retardation, autism, seizures, and dystonic hand movements in two families with an identical ARX gene mutation.
Am J Med Genet. 2002 Nov 1;112(4):405-11.
Two families, originally diagnosed as having nonsyndromic X-linked mental retardation (NSXLMR), were reviewed when it was shown that they had a 24-bp duplication (428-45 1dup(24bp)) in the ARX gene [Stromme et al., 2002: Nat Genet 30:441-445]. This same duplication had also been found in three other families: one with X-linked infantile spasms and hypsarrhythmia (X-linked West syndrome, MIM 308350) and two with XLMR and dystonic movements of the hands (Partington syndrome, MIM 309510). On review, manifestations of both West and Partington syndromes were found in some individuals from both families. In addition, it was found that one individual had autism and two had autistic behavior, one of whom had epilepsy. The degree of mental retardation ranged from mild to severe. A GCG trinucleotide expansion (GCG)10+7 and a deletion of 1,517 bp in the ARX gene have also been found in association with the West syndrome, and a missense mutation (1058C>T) in a family with a newly recognized form of myoclonic epilepsy, severe mental retardation, and spastic paraplegia [Scheffer et al., 2002: Neurology, in press]. Evidently all these disorders are expressions of mutations in the same gene. It remains to be seen what proportions of patients with infantile spasms, focal dystonia, autism, epilepsy, and nonsyndromic mental retardation are accounted for by mutations in the ARX gene. [Abstract]

Strømme P, Mangelsdorf ME, Scheffer IE, Gécz J
Infantile spasms, dystonia, and other X-linked phenotypes caused by mutations in Aristaless related homeobox gene, ARX.
Brain Dev. 2002 Aug;24(5):266-8.
Clinical data from 50 mentally retarded (MR) males in nine X-linked MR families, syndromic and non-specific, with mutations (duplication, expansion, missense, and deletion mutations) in the Aristaless related homeobox gene, ARX, were analysed. Seizures were observed with all mutations and occurred in 29 patients, including one family with a novel myoclonic epilepsy syndrome associated with the missense mutation. Seventeen patients had infantile spasms. Other phenotypes included mild to moderate MR alone, or with combinations of dystonia, ataxia or autism. These data suggest that mutations in the ARX gene are important causes of MR, often associated with diverse neurological manifestations. [Abstract]

Ylisaukko-oja T, Nieminen-von Wendt T, Kempas E, Sarenius S, Varilo T, von Wendt L, Peltonen L, Järvelä I
Genome-wide scan for loci of Asperger syndrome.
Mol Psychiatry. 2004 Feb;9(2):161-8.
Asperger syndrome (AS), characterised by inadequate social interaction, lack of empathy and a dependence of routines and rituals, is classified as belonging to the autism spectrum disorders (DSM-IV and ICD-10). Although the prevalence of AS has been estimated to range from 0.3 up to 48.4 per 10 000, the phenotype still remains relatively unrecognised by clinicians. Several reports, including the original description by Hans Asperger (1944), have suggested that AS has a strong genetic component. Here, we have performed a genome-wide scan on Finnish families ascertained for AS with a strictly defined phenotype. In the initial scan, Z(max)>1.5 was observed on nine chromosomal regions, 1q21-22, 3p14-24, 3q25-27, 4p14, 4q32, 6p25, 6q16, 13q31-33 and 18p11. In the fine mapping stage, the highest two-point LOD scores were observed on chromosomes 1q21-22 (D1S484, Z(max dom)=3.58), 3p14-24 (D3S2432, Z(max dom)=2.50) and 13q31-33 (D13S793, Z(max dom)=1.59). The loci on 1q21-22 and 3p14-24 overlap with previously published autism susceptibility loci, and the loci on 1q21-22 and 13q31-33 overlap with the reported schizophrenia susceptibility loci. The present study is the first genome-wide screen in AS and therefore replication data sets are needed to evaluate further the significance of the AS-loci identified here. [Abstract]

Tentler D, Johannesson T, Johansson M, Råstam M, Gillberg C, Orsmark C, Carlsson B, Wahlström J, Dahl N
A candidate region for Asperger syndrome defined by two 17p breakpoints.
Eur J Hum Genet. 2003 Feb;11(2):189-95.
Asperger syndrome (AS) is a mild form of autistic disorder characterised by impairment in social interaction as well as a restricted pattern of behaviour, interests, and activities. Two patients with AS and balanced translocations t(13;17) and t(17;19), respectively, were identified. Fluorescent in situ hybridisation (FISH) analysis with chromosome 17 specific clones to metaphase chromosomes from both patients showed that the chromosome 17 breakpoints are located within a 300 kb region at 17p13. The region spans 14 known genes. The expression of these genes was analysed in lymphoblastoid RNA derived from the patients and healthy control individuals. The CHRNE, DKFZP566H073, LOC90048, PFN1, SPAG7, KIAA0909, ZNF232 and KIF1C genes showed similar levels of expression in cell lines with the translocations when compared with cell lines with normal karyotype. No expression was detected for the MINK, GP1BA, SLC25A11, ENO3, FLJ10060 and USP6 genes in any of the cell lines. The close physical relation of the two 17p breakpoints suggest a common genetic aetiology for the phenotype in the patients. Structural and functional analysis of the genes located around the two 17p breakpoints in t(13;17) and t(17;19) patients may reveal candidate sequences for the AS phenotype. [Abstract]

Annerén G, Dahl N, Uddenfeldt U, Janols LO
Asperger syndrome in a boy with a balanced de novo translocation: t(17;19)(p13.3;p11)
Am J Med Genet. 1995 Apr 10;56(3):330-1. [Abstract]

Auranen M, Varilo T, Alen R, Vanhala R, Ayers K, Kempas E, Ylisaukko-Oja T, Peltonen L, Järvelä I
Evidence for allelic association on chromosome 3q25-27 in families with autism spectrum disorders originating from a subisolate of Finland.
Mol Psychiatry. 2003 Oct;8(10):879-84.
Recent molecular studies on autism and related disorders have supported a multilocus etiology for the disease spectrum. To maximize genetic and cultural homogeneity, we have focused our molecular studies to families originating from a subisolate of Central Finland. Genealogical studies enabled the identification of a megapedigree comprising of 12 core families with autism and Asperger syndrome (AS). We analyzed two chromosomal regions on Iq and 3q showing highest lod scores in our genome-wide scan, as well as the AUTS1 locus on chromosome 7q. For markers on 3q25-27, more significant association was observed in families from subisolate compared to families from the rest of Finland. In contrast, no clear evidence for association on AUTS1 locus was obtained. The wide interval showing association, in particular, on chromosome 3q suggests a locus for autism spectrum of disorders on this chromosomal region. [Abstract]

Auranen M, Vanhala R, Varilo T, Ayers K, Kempas E, Ylisaukko-Oja T, Sinsheimer JS, Peltonen L, Järvelä I
A genomewide screen for autism-spectrum disorders: evidence for a major susceptibility locus on chromosome 3q25-27.
Am J Hum Genet. 2002 Oct;71(4):777-90.
To identify genetic loci for autism-spectrum disorders, we have performed a two-stage genomewide scan in 38 Finnish families. The detailed clinical examination of all family members revealed infantile autism, but also Asperger syndrome (AS) and developmental dysphasia, in the same set of families. The most significant evidence for linkage was found on chromosome 3q25-27, with a maximum two-point LOD score of 4.31 (Z(max )(dom)) for D3S3037, using infantile autism and AS as an affection status. Six markers flanking over a 5-cM region on 3q gave Z(max dom) >3, and a maximum parametric multipoint LOD score (MLS) of 4.81 was obtained in the vicinity of D3S3715 and D3S3037. Association, linkage disequilibrium, and haplotype analyses provided some evidence for shared ancestor alleles on this chromosomal region among affected individuals, especially in the regional subisolate. Additional potential susceptibility loci with two-point LOD scores >2 were observed on chromosomes 1q21-22 and 7q. The region on 1q21-22 overlaps with the previously reported candidate region for infantile autism and schizophrenia, whereas the region on chromosome 7q provided evidence for linkage 58 cM distally from the previously described autism susceptibility locus (AUTS1). [Abstract]

Pearl PL, Gibson KM, Acosta MT, Vezina LG, Theodore WH, Rogawski MA, Novotny EJ, Gropman A, Conry JA, Berry GT, Tuchman M
Clinical spectrum of succinic semialdehyde dehydrogenase deficiency.
Neurology. 2003 May 13;60(9):1413-7.
Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder affecting CNS gamma-aminobutyric acid (GABA) degradation. SSADH, in conjunction with GABA transaminase, converts GABA to succinate. In the absence of SSADH, GABA is converted to 4-OH-butyrate. The presence of 4-OH-butyrate, a highly volatile compound, may be undetected on routine organic acid analysis. Urine organic acid testing was modified at the authors' institution in 1999 to screen for the excretion of 4-OH-butyrate by selective ion monitoring gas chromatography-mass spectrometry in addition to total ion chromatography. Since then, five patients with 4-hydroxybutyric aciduria have been identified. The authors add the clinical, neuroimaging, and EEG findings from a new cohort of patients to 51 patients reported in the literature with clinical details. Ages ranged from 1 to 21 years at diagnosis. Clinical findings include mild-moderate mental retardation, disproportionate language dysfunction, hypotonia, hyporeflexia, autistic behaviors, seizures, and hallucinations. Brain MRI performed in five patients at the authors' institution revealed symmetric increased T2 signal in the globus pallidi. SSADH deficiency is an under-recognized, potentially manageable neurometabolic disorder. Urine organic acid analysis should include a sensitive method for the detection of 4-hydroxybutyrate and should be obtained from patients with mental retardation or neuropsychiatric disturbance of unknown etiology. [Abstract]

Stone RL, Aimi J, Barshop BA, Jaeken J, Van den Berghe G, Zalkin H, Dixon JE
A mutation in adenylosuccinate lyase associated with mental retardation and autistic features.
Nat Genet. 1992 Apr;1(1):59-63.
We have examined the molecular basis of three cases of severe mental retardation with autistic features in one family. A point mutation in a purine nucleotide biosynthetic enzyme, adenylosuccinate lyase (ASL), segregates with the disorder. The affected children are homozygous for the point mutation while the parents and all four unaffected children are heterozygous. The point mutation is absent in control subjects. The point mutation results in a Ser413Pro substitution which leads to structural instability of the recombinant mutant enzyme, and this instability lowers ASL levels in lymphocytes. These observations suggest that the instability of ASL underlies the severe developmental disorder in the affected children, and that mutations in the ASL gene may result in other cases of mental retardation and autistic features. [Abstract]

Fon EA, Sarrazin J, Meunier C, Alarcia J, Shevell MI, Philippe A, Leboyer M, Rouleau GA
Adenylosuccinate lyase (ADSL) and infantile autism: absence of previously reported point mutation.
Am J Med Genet. 1995 Dec 18;60(6):554-7.
Autism is a heterogeneous neuropsychiatric syndrome of unknown etiology. There is evidence that a deficiency in the enzyme adenylosuccinate lyase (ADSL), essential for de novo purine biosynthesis, could be involved in the pathogenesis of certain cases. A point mutation in the ADSL gene, resulting in a predicted serine-to-proline substitution and conferring structural instability to the mutant enzyme, has been reported previously in 3 affected siblings. In order to determine the prevalence of the mutation, we PCR-amplified the exon spanning the site of this mutation from the genomic DNA of patients fulfilling DSM-III-R criteria for autistic disorder. None of the 119 patients tested were found to have this mutation. Furthermore, on preliminary screening using singlestrand conformation polymorphism (SSCP), no novel mutations were detected in the coding sequence of four ADSL exons, spanning approximately 50% of the cDNA. In light of these findings, it appears that mutations in the ADSL gene represent a distinctly uncommon cause of autism. [Abstract]

Muhle R, Trentacoste SV, Rapin I
The genetics of autism.
Pediatrics. 2004 May;113(5):e472-86.
Autism is a complex, behaviorally defined, static disorder of the immature brain that is of great concern to the practicing pediatrician because of an astonishing 556% reported increase in pediatric prevalence between 1991 and 1997, to a prevalence higher than that of spina bifida, cancer, or Down syndrome. This jump is probably attributable to heightened awareness and changing diagnostic criteria rather than to new environmental influences. Autism is not a disease but a syndrome with multiple nongenetic and genetic causes. By autism (the autistic spectrum disorders [ASDs]), we mean the wide spectrum of developmental disorders characterized by impairments in 3 behavioral domains: 1) social interaction; 2) language, communication, and imaginative play; and 3) range of interests and activities. Autism corresponds in this article to pervasive developmental disorder (PDD) of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition and International Classification of Diseases, Tenth Revision. Except for Rett syndrome--attributable in most affected individuals to mutations of the methyl-CpG-binding protein 2 (MeCP2) gene--the other PDD subtypes (autistic disorder, Asperger disorder, disintegrative disorder, and PDD Not Otherwise Specified [PDD-NOS]) are not linked to any particular genetic or nongenetic cause. Review of 2 major textbooks on autism and of papers published between 1961 and 2003 yields convincing evidence for multiple interacting genetic factors as the main causative determinants of autism. Epidemiologic studies indicate that environmental factors such as toxic exposures, teratogens, perinatal insults, and prenatal infections such as rubella and cytomegalovirus account for few cases. These studies fail to confirm that immunizations with the measles-mumps-rubella vaccine are responsible for the surge in autism. Epilepsy, the medical condition most highly associated with autism, has equally complex genetic/nongenetic (but mostly unknown) causes. Autism is frequent in tuberous sclerosis complex and fragile X syndrome, but these 2 disorders account for but a small minority of cases. Currently, diagnosable medical conditions, cytogenetic abnormalities, and single-gene defects (eg, tuberous sclerosis complex, fragile X syndrome, and other rare diseases) together account for <10% of cases. There is convincing evidence that "idiopathic" autism is a heritable disorder. Epidemiologic studies report an ASD prevalence of approximately 3 to 6/1000, with a male to female ratio of 3:1. This skewed ratio remains unexplained: despite the contribution of a few well characterized X-linked disorders, male-to-male transmission in a number of families rules out X-linkage as the prevailing mode of inheritance. The recurrence rate in siblings of affected children is approximately 2% to 8%, much higher than the prevalence rate in the general population but much lower than in single-gene diseases. Twin studies reported 60% concordance for classic autism in monozygotic (MZ) twins versus 0 in dizygotic (DZ) twins, the higher MZ concordance attesting to genetic inheritance as the predominant causative agent. Reevaluation for a broader autistic phenotype that included communication and social disorders increased concordance remarkably from 60% to 92% in MZ twins and from 0% to 10% in DZ pairs. This suggests that interactions between multiple genes cause "idiopathic" autism but that epigenetic factors and exposure to environmental modifiers may contribute to variable expression of autism-related traits. The identity and number of genes involved remain unknown. The wide phenotypic variability of the ASDs likely reflects the interaction of multiple genes within an individual's genome and the existence of distinct genes and gene combinations among those affected. There are 3 main approaches to identifying genetic loci, chromosomal regions likely to contain relevant genes: 1) whole genome screens, searching for linkage of autism to shared genetic markers in populations of multiplex families (families with >1 affected family member; 2) cytogenetic studies that may guide molecular studies by pointing to relevant inherited or de novo chromosomal abnormalities in affected individuals and their families; and 3) evaluation of candidate genes known to affect brain development in these significantly linked regions or, alternatively, linkage of candidate genes selected a priori because of their presumptive contribution to the pathogenesis of autism. Data from whole-genome screens in multiplex families suggest interactions of at least 10 genes in the causation of autism. Thus far, a putative speech and language region at 7q31-q33 seems most strongly linked to autism, with linkages to multiple other loci under investigation. Cytogenetic abnormalities at the 15q11-q13 locus are fairly frequent in people with autism, and a "chromosome 15 phenotype" was described in individuals with chromosome 15 duplications. Among other candidate genes are the FOXP2, RAY1/ST7, IMMP2L, and RELN genes at 7q22-q33 and the GABA(A) receptor subunit and UBE3A genes on chromosome 15q11-q13. Variant alleles of the serotonin transporter gene (5-HTT) on 17q11-q12 are more frequent in individuals with autism than in nonautistic populations. In addition, animal models and linkage data from genome screens implicate the oxytocin receptor at 3p25-p26. Most pediatricians will have 1 or more children with this disorder in their practices. They must diagnose ASD expeditiously because early intervention increases its effectiveness. Children with dysmorphic features, congenital anomalies, mental retardation, or family members with developmental disorders are those most likely to benefit from extensive medical testing and genetic consultation. The yield of testing is much less in high-functioning children with a normal appearance and IQ and moderate social and language impairments. Genetic counseling justifies testing, but until autism genes are identified and their functions are understood, prenatal diagnosis will exist only for the rare cases ascribable to single-gene defects or overt chromosomal abnormalities. Parents who wish to have more children must be told of their increased statistical risk. It is crucial for pediatricians to try to involve families with multiple affected members in formal research projects, as family studies are key to unraveling the causes and pathogenesis of autism. Parents need to understand that they and their affected children are the only available sources for identifying and studying the elusive genes responsible for autism. Future clinically useful insights and potential medications depend on identifying these genes and elucidating the influences of their products on brain development and physiology. [Abstract]

Jones MB, Szatmari P
A risk-factor model of epistatic interaction, focusing on autism.
Am J Med Genet. 2002 Jul 8;114(5):558-65.
Research to date on the genetics of autism has not uncovered a major susceptibility locus and indications are that a number of genes, perhaps as many as 15-20, may play detectable but minor roles in the etiology of the condition. To cope with this situation, a risk-factor model based on standard epidemiologic designs is proposed. The model supposes that adding a factor to a fixed set of existing factors always increases the total risk. Thus, according to the model genetic contributions cumulate but are not necessarily additive. A threshold, hence, epistasis is required. The model is applied to several conditions in which the risk of autism is elevated, some genetic (fragile X, tuberous sclerosis) and some exogenous (rubella and thalidomide embryopathies). Male gender is discussed as a risk factor. This approach is contrasted primarily with Gillberg and Coleman's view of autism as "a syndrome or series of syndromes caused by many different separate individual diseases." The principal point of difference is whether the effects of different causes cumulate or do not cumulate. In the present approach they do, in Gillberg and Coleman's they do not. [Abstract]

Kolevzon A, Smith CJ, Schmeidler J, Buxbaum JD, Silverman JM
Familial symptom domains in monozygotic siblings with autism.
Am J Med Genet. 2004 Aug 15;129B(1):76-81.
Autism is characterized by a triad of symptom domains (impaired social interaction, communication deficits, and repetitive behaviors) that vary significantly in their clinical presentation across the population. Within families with more than one affected member, however, discrepant findings exist with regard to symptom variability. Reduced intrafamily variance is of particular importance because it supports an underlying model of genetic heterogeneity in the transmission of autism, and the identification of familial clinical subtypes can be used to select more homogeneous samples for linkage analysis in the future. This study examines whether there are specific features of autism that show decreased variance within 16 families with monozygotic siblings concordant for autism. Evidence for familiality was defined as significantly decreased variance of symptom levels within monozygotic siblingships as compared to between siblingships. Using regression analysis, we demonstrated significant aggregation of symptoms within monozygotic siblingships for two of the three main symptom domains in autism: impairments in communication and social interaction showed significant familiality. Within the repetitive behavior domain, only the categories of circumscribed interests and preoccupation with part-objects showed reduced variance within siblingships. In addition, with the exception of a negative association between the social and behavior domains, partial correlation coefficients did not reveal significant associations between the levels of different symptom domains within families, suggesting that the levels of clinical features seen in autism may be a result of mainly independent genetic traits. Because of presumed genetic heterogeneity and the wide clinical variation seen in autism and other pervasive developmental disorders, selecting probands according to specific features known to show reduced variance within families may provide more homogeneous samples for genetic analysis and strengthen the power to detect the specific genes involved in autism. [Abstract]

Hallmayer J, Glasson EJ, Bower C, Petterson B, Croen L, Grether J, Risch N
On the twin risk in autism.
Am J Hum Genet. 2002 Oct;71(4):941-6.
Autism is considered by many to be the most strongly genetically influenced multifactorial childhood psychiatric disorder. In the absence of any known gene or genes, the main support for this is derived from family and twin studies. Two recent studies (Greenberg et al. 2001; Betancur et al. 2002) suggested that the twinning process itself is an important risk factor in the development of autism. If true, this would have major consequences for the interpretation of twin studies. Both studies compared the number of affected twin pairs among affected sib pairs to expected values in two separate samples of multiplex families and reported a substantial and significant excess of twin pairs. Using data from our epidemiological study in Western Australia, we investigated the possibility of an increased rate of autism in twins. All children born between 1980 and 1995 with autism, Asperger syndrome, or pervasive developmental disorder not otherwise specified (PDD-NOS) were ascertained. Of the 465 children with a diagnosis, 14 were twin births (rate 30.0/1,000) compared to 9,640 children of multiple births out of a total of 386,637 births in Western Australia between 1980 and 1995 (twin rate weighted to number of children with autism or PDD per year 26.3/1,000). These data clearly do not support twinning as a substantial risk factor in the etiology of autism. We demonstrate that the high proportion of twins found in affected-sib-pair studies can be adequately explained by the high ratio of concordance rates in monozygotic (MZ) twins versus siblings and the distribution of family size in the population studied. Our results are in agreement with those of two similar studies by Croen et al. (2002) in California and Hultman et al. (2002) in Sweden. [Abstract]

Cuccaro ML, Shao Y, Bass MP, Abramson RK, Ravan SA, Wright HH, Wolpert CM, Donnelly SL, Pericak-Vance MA
Behavioral comparisons in autistic individuals from multiplex and singleton families.
J Autism Dev Disord. 2003 Feb;33(1):87-91.
Autistic disorder (AD) is a complex neurodevelopmental disorder. The role of genetics in AD etiology is well established, and it is postulated that anywhere from 2 to 10 genes could be involved. As part of a larger study to identify these genetic effects we have ascertained a series of AD families: Sporadic (SP, 1 known AD case per family and no known history of AD) and multiplex (MP, > or = 2 cases per family). The underlying etiology of both family types is unknown. It is possible that MP families may constitute a unique subset of families in which the disease phenotype is more likely due to genetic factors. Clinical differences between the two family types could represent underlying genetic heterogeneity. We examined ADI-R data for 69 probands from MP families and 88 from SP families in order to compare and contrast the clinical phenotypes for each group as a function of verbal versus nonverbal status. Multivariate analysis controlling for covariates of age at examination, gender, and race (MANCOVA) revealed no differences between either the verbal or nonverbal MP and SP groups for the three ADI-R area scores: social interaction, communication, and restricted/repetitive interests or behaviors. These data failed to find clinical heterogeneity between MP and SP family types. This supports previous work that indicated that autism features are not useful as tools to index genetic heterogeneity. Thus, although there may be different underlying etiologic mechanisms in the SP and MP probands, there are no distinct behavioral patterns associated with probands from MP families versus SP families. These results suggests the possibility that common etiologic mechanisms, either genetic and/or environmental, could underlie all of AD. [Abstract]

Constantino JN, Todd RD
Autistic traits in the general population: a twin study.
Arch Gen Psychiatry. 2003 May;60(5):524-30.
BACKGROUND: Recent research has indicated that autism is not a discrete disorder and that family members of autistic probands have an increased likelihood of exhibiting autistic symptoms with a wide range of severity, often below the threshold for a diagnosis of an autism spectrum disorder. OBJECTIVE: To examine the distribution and genetic structure of autistic traits in the general population using a newly established quantitative measure of autistic traits, the Social Responsiveness Scale (formerly known as the Social Reciprocity Scale). METHODS: The sample consisted of 788 pairs of twins aged 7 to 15 years, randomly selected from the pool of participants in a large epidemiologic study (the Missouri Twin Study). One parent of each pair of twins completed the Social Responsiveness Scale on each child. The data were subjected to structural equation modeling. RESULTS: Autistic traits as measured by the Social Responsiveness Scale were continuously distributed and moderately to highly heritable. Levels of severity of autistic traits at or above the previously published mean for patients with pervasive developmental disorder not otherwise specified were found in 1.4% of boys and 0.3% of girls. Structural equation modeling revealed no evidence for the existence of sex-specific genetic influences, and suggested specific mechanisms by which females may be relatively protected from vulnerability to autistic traits. CONCLUSIONS: These data indicate that the social deficits characteristic of autism spectrum disorders are common. Given the continuous distribution of these traits, it may be arbitrary where cutoffs are made between research designations of being "affected" vs "unaffected" with a pervasive developmental disorder. The genes influencing autistic traits appear to be the same for boys and girls. Lower prevalence (and severity) of autistic traits in girls may be the result of increased sensitivity to early environmental influences that operate to promote social competency. [Abstract]

Silverman JM, Smith CJ, Schmeidler J, Hollander E, Lawlor BA, Fitzgerald M, Buxbaum JD, Delaney K, Galvin P
Symptom domains in autism and related conditions: evidence for familiality.
Am J Med Genet. 2002 Jan 8;114(1):64-73.
Heterogeneity in autism impairs efforts to localize and identify the genes underlying this disorder. As autism comprises severe but variable deficits and traits in three symptom domains (social interaction, communication, and repetitive behaviors) and shows variability in the presence and emergence of useful phrase speech, different genetic factors may be associated with each. The affected cases (n=457) in multiply affected siblingships (n=212), including a proband with autism and one or more siblings with either autism or marked deficits in autism symptom domains, were assessed using the Autism Diagnostic Interview, Revised. Symptom domain scores and language features were examined to determine their similarity within siblingships. The variance within siblingships was reduced for the repetitive behavior domain and for delays in and the presence of useful phrase speech. These features and the nonverbal communication subdomain provided evidence of familiality when we considered only the diagnosis of autism to define multiply affected siblingships (cases: n=289; siblingships: n=136). In addition, the same familial features identified also appeared familial for those with autism-related conditions. Finally, the level of severity of almost all of the familial features varied within multiplex siblingships independently. The features identified as familial replicate the combined set suggested in earlier, smaller studies. Furthermore, the familiality of these features extend to related conditions of milder severity than autism and appear to be independent. Making distinctions among families by the severity of these features may be useful for identifying more genetically homogeneous subgroups in studies targeted at genes for specific autism-related symptom domains. [Abstract]

Jorde LB, Mason-Brothers A, Waldmann R, Ritvo ER, Freeman BJ, Pingree C, McMahon WM, Petersen B, Jenson WR, Mo A
The UCLA-University of Utah epidemiologic survey of autism: genealogical analysis of familial aggregation.
Am J Med Genet. 1990 May;36(1):85-8.
To assess familial aggregation of autism, 86 autistic subjects were linked to the Utah Genealogical Database. Kinship coefficients were estimated for all possible pairs of autistic subjects and then averaged. Fifty replicate sets of matched control subjects (86 members in each set) were drawn randomly from the database, and the average kinship coefficient was computed for all possible pairs of individuals in each set. The average kinship coefficient for the autistic subjects was approximately 1/1,000, while the average kinship coefficients for the 50 control groups ranged from 4/100,000 to 1.6./10,000. These results indicate a strong tendency for autism to cluster in families. When kinship was analyzed by specific degrees of relationship, it was shown that the familial aggregation of autism is confined exclusively to sib pairs and does not extend to more remote degrees of relationship. This finding indicates that a single-gene model is unlikely to account for most cases of autism. [Abstract]

Pickles A, Starr E, Kazak S, Bolton P, Papanikolaou K, Bailey A, Goodman R, Rutter M
Variable expression of the autism broader phenotype: findings from extended pedigrees.
J Child Psychol Psychiatry. 2000 May;41(4):491-502.
Factors influencing the rate, form, and severity of phenotypic expression among relatives of autistic probands are examined. Family history data on 3095 first- and second-degree relatives and cousins from 149 families with a child with autism and 36 families with a child with Down syndrome are studied. The results provide further evidence of an increased risk among autism relatives for the broadly defined autism phenotype. Of proband characteristics, severity of autism and obstetric optimality were confirmed as being related to familial loading for probands with speech. There was little variation in loading among probands lacking speech. The type of phenotypic profile reported in relatives appeared little influenced by characteristics of the relative or the proband, except for variation by degree of relative, parental status of relative, and perhaps proband's birth optimality score. Phenotypic rates among parents suggested reduced fitness for the severest and more communication-related forms of expression but not for the more mild and social forms of expression. Patterns of expression within the families did not support a simple X-linked nor an imprinted X-linked mode of inheritance. The basis for sex differences in rates of expression is discussed. [Abstract]

Fombonne E, Du Mazaubrun C, Cans C, Grandjean H
Autism and associated medical disorders in a French epidemiological survey.
J Am Acad Child Adolesc Psychiatry. 1997 Nov;36(11):1561-9.
OBJECTIVE: To estimate the prevalence of autism, to assess the strength of its association with specific medical disorders, and to test for a secular increase in its incidence. METHOD: An epidemiological survey was conducted among 325,347 French children born between 1976 and 1985 and living in three different French départements. Diagnosis, educational level, and associated medical conditions were abstracted from the records of children known to local educational authorities. Data were also pooled with those from another similar survey. RESULTS: One hundred seventy-four children (mean age: 11.6 years) with autism were identified. The prevalence rate was 5.35/10,000 (16.3/10,000 if other pervasive developmental disorders are included), with no difference according to geographical area or social class. Rates of medical conditions were as follows: 1.1% for tuberous sclerosis, 2.9% for chromosomal abnormalities including fragile X, 2.9% for cerebral palsy, 4.6% for sensory impairments, 0.6% for neurofibromatosis, 0.6% for congenital rubella, and 1.7% for Down syndrome. In the combined sample of 328 children with autism, the level and pattern of medical correlates were comparable, with tuberous sclerosis having a consistently strong association with autism. Prevalence rates were similar in successive birth cohorts. CONCLUSION: Medical disorders (excluding epilepsy and sensory impairments) accounted for fewer than 10% of the cases of autism. No secular increase in the prevalence of autism was found. [Abstract]

Gillberg C
Subgroups in autism: are there behavioural phenotypes typical of underlying medical conditions?
J Intellect Disabil Res. 1992 Jun;36 ( Pt 3)201-14.
Fifty-nine cases with infantile autism/autistic disorder were subclassified according to associated medical condition (fragile-X, tuberous sclerosis, neurofibromatosis, hypo-melanosis of Ito, Moebius syndrome, Rett syndrome, and a 'new' syndrome associated with a marker chromosome). It was concluded that, even within a group of cases fitting currently accepted criteria for autism, there is considerable variation in symptom profile depending on the exact type of associated medical condition. [Abstract]

Brown WA, Cammuso K, Sachs H, Winklosky B, Mullane J, Bernier R, Svenson S, Arin D, Rosen-Sheidley B, Folstein SE
Autism-related language, personality, and cognition in people with absolute pitch: results of a preliminary study.
J Autism Dev Disord. 2003 Apr;33(2):163-7; discussion 169.
Reports of a relatively high prevalence of absolute pitch (AP) in autistic disorder suggest that AP is associated with some of the distinctive cognitive and social characteristics seen in autism spectrum disorders. Accordingly we examined cognition, personality, social behavior, and language in 13 musicians with strictly defined AP (APS) and 33 musician controls (MC) without AP using standardized interviews and tests previously applied to identify the broad autism phenotype seen in the relatives of autistic probands. These included the Pragmatic Rating Scale (PRS) (social aspects of language) the Personality Assessment Schedule (PAS) (rigidity, aloofness, anxiety/worry, hypersensitivity), and WAIS performance subtests (PIQ). On the basis of their behavior in the interviews, subjects were classified as socially eccentric, somewhat eccentric, or not eccentric. Forty-six percent of the APS, but only 15% of the MC, were classified as socially eccentric (p < .03). APS but not MC showed higher scores on block design than on the other PIQ tests (p < .06), a PIQ pattern seen in autism spectrum disorders. Although APS and MC did not differ significantly on other measures it is of note that APS mean scores on the PRS and PAS (5.69, 4.92) were almost twice as high as those for the MC (3.03, 2.45). Thus, musicians with AP show some of the personality, language, and cognitive features associated with autism. Piecemeal information processing, of which AP is an extreme and rare example, is characteristic of autism and may be associated as well with subclinical variants in language and behavior. We speculate that the gene or genes that underlie AP may be among the genes that contribute to autism. [Abstract]

Rapin I, Dunn M
Update on the language disorders of individuals on the autistic spectrum.
Brain Dev. 2003 Apr;25(3):166-72.
Inadequate language is a defining feature of the autism spectrum disorders (autism). Autism is a behaviorally and dimensionally defined developmental disorder of the immature brain that has a broad range of severity and many etiologies, with multiple genes involved. Early studies, which focused on the language of verbal children on the autistic spectrum, emphasized aberrant features of their speech such as unusual word choices, pronoun reversal, echolalia, incoherent discourse, unresponsiveness to questions, aberrant prosody, and lack of drive to communicate. Persistent lack of speech of some individuals was attributed to the severity of their autism and attendant mental retardation rather than possible inability to decode auditory language. Clinical study of unselected children with autism indicated that the language deficits of preschoolers fall into two broad types, perhaps with subtypes, those that involve reception and production of phonology (sounds of speech) and syntax (grammar), and those that do not but involve semantics (meaning) and pragmatics (communicative use of language, processing, and production of discourse). Except for the preschoolers' universally deficient pragmatics and comprehension of speech, many of their language deficits parallel those of non-autistic preschoolers with developmental language disorders. There is now biological support for the clinical observation that young autistic children are language disordered as well as autistic. Recent electrophysiological studies disclose auditory input abnormalities in lateral temporal cortex even in verbal individuals on the autistic spectrum. Severe receptive deficits for phonology enhance the risk for epilepsy. Genetic studies indicate that linkage to chromosome 7q31-33 is limited to families with evidence for phonologic impairment as well as autism. Clearly, social and cognitive disorders alone provide an inadequate explanation for the range of language deficits in autism. [Abstract]

Bolton P, Macdonald H, Pickles A, Rios P, Goode S, Crowson M, Bailey A, Rutter M
A case-control family history study of autism.
J Child Psychol Psychiatry. 1994 Jul;35(5):877-900.
Family history data on 99 autistic and 36 Down's syndrome probands are reported. They confirmed a raised familial loading for both autism and more broadly defined pervasive developmental disorders in siblings (2.9% and 2.9%, respectively, vs 0% in the Down's group) and also evidence for the familial aggregation of a lesser variant of autism, comprising more subtle communication/social impairments or stereotypic behaviours, but not mental retardation alone. Between 12.4 and 20.4% of the autism siblings and 1.6% and 3.2% of the Down's siblings exhibited this lesser variant, depending on the stringency of its definition. Amongst autistic probands with speech, various features of their disorder (increased number of autistic symptoms; reduced verbal and performance ability) as well as a history of obstetric complications, indexed an elevation in familial loading. No such association was seen in the probands without speech, even though familial loading for the lesser variant in this subgroup, was significantly higher than in the Down's controls. The findings suggest that the autism phenotype extends beyond autism as traditionally diagnosed; that aetiology involves several genes; that autism is genetically heterogeneous; and that obstetric abnormalities in autistic subjects may derive from abnormality in the foetus. [Abstract]

Torres AR, Maciulis A, Stubbs EG, Cutler A, Odell D
The transmission disequilibrium test suggests that HLA-DR4 and DR13 are linked to autism spectrum disorder.
Hum Immunol. 2002 Apr;63(4):311-6.
We have evaluated possible contributions of HLA-DRB1 alleles to autism spectrum disorder (ASD) in 103 families of Caucasian descent. The DR4 allele occurred more often in probands than controls (0.007), whereas the DR13,14 alleles occurred less often in probands than controls (p = 0.003). The transmission disequilibrium test (TDT) indicated that the ASD probands inherited the DR4 allele more frequently than expected (p = 0.026) from the fathers. The TDT also revealed that fewer DR13 alleles than expected were inherited from the mother by ASD probands (p = 0.006). We conclude that the TDT results suggest that DR4 and DR13 are linked to ASD. Reasons for the parental inheritance of specific alleles are poorly understood but coincide with current genetic research noting possible parent-of-origin effects in autism. [Abstract]

Daniels WW, Warren RP, Odell JD, Maciulis A, Burger RA, Warren WL, Torres AR
Increased frequency of the extended or ancestral haplotype B44-SC30-DR4 in autism.
Neuropsychobiology. 1995;32(3):120-3.
Autism likely results from several different etiologies or a combination of pathological mechanisms. Recent studies suggest that this disorder may be associated with immune abnormalities, pathogen-autoimmune processes and perhaps the major histocompatibility complex (MHC). In a preliminary study we found that 22 autistic subjects had an increased frequency of the extended or ancestral MHC haplotype B44-SC30-DR4. The current study attempted to confirm this observation by studying 23 additional randomly chosen autistic subjects, most of their parents and 64 unrelated normal subjects. In agreement with earlier findings B44-SC30-DR4 was associated with autism. In combining the data from the original and current studies, B44-SC30-DR4 or a substantial fragment of this extended haplotype was represented in 40% of the autistic subjects and/or their mothers as compared to about 2% of the unrelated subjects. It is concluded that one or more genes of the MHC is (are) involved in the development of some cases of autism. [Abstract]

Warren RP, Odell JD, Warren WL, Burger RA, Maciulis A, Daniels WW, Torres AR
Strong association of the third hypervariable region of HLA-DR beta 1 with autism.
J Neuroimmunol. 1996 Jul;67(2):97-102.
We reported that the major histocompatibility complex (MHC) including the null allele of the C4B gene and the extended haplotype B44-C30-DR4 is associated with autism. We report now that the third hypervariable region (HVR-3) of certain DR beta 1 alleles have very strong association with autism. The HVR-3 of DR beta 1* 0401 or the shared HVR-3 alleles DR beta 1* 0404 and DR beta 1* 0404 and DR *0101, was expressed on extended haplotypes in 23 of 50 (46%) autistic subjects as compared to only 6 of 79 (7.5%) normal subjects. Another HVR-3 sequence, the DR beta 1* 0701 allele, was carried on extended haplotypes in 16 (32.0%) of the autistic subjects as compared to 8 (10.1%) of the normal subjects. [Abstract]

Warren RP, Singh VK, Averett RE, Odell JD, Maciulis A, Burger RA, Daniels WW, Warren WL
Immunogenetic studies in autism and related disorders.
Mol Chem Neuropathol. 1996 May-Aug;28(1-3):77-81.
The major histocompatibility complex comprises a number of genes that control the function and regulation of the immune system. One of these genes, the C4B gene, encodes a product that is involved in eliminating pathogens such as viruses and bacteria from the body. We previously reported that a deficient form of the C4B gene, termed the C4B null allele (no C4B protein produced) had an increased frequently in autism. In this study we attempted to confirm the increased incidence of the C4B null allele in autism and investigated the presence of a C4B null allele in two other childhood disorders, attention-deficit hyperactivity disorder and dyslexia (reading disability). In addition, we explored the relationship of autism to the DR beta 1 gene, a gene located close to the C4B in autism. We confirmed the finding of an increased frequency of the C4B null allele in autism and found that the related disorders also had an increased frequency of this null allele. In addition, two alleles of the DR beta 1 gene also had significantly increased representation in the autistic subjects. [Abstract]

Warren RP, Singh VK, Cole P, Odell JD, Pingree CB, Warren WL, DeWitt CW, McCullough M
Possible association of the extended MHC haplotype B44-SC30-DR4 with autism.
Immunogenetics. 1992;36(4):203-7.
We previously reported that the complement C4B null allele appears to be associated with infantile autism. Since the C4B null allele is known to be part of the extended or ancestral haplotype [B44-SC30-DR4], we investigated the incidence of [B44-SC30-DR4] in 21 autistic children and their parents. This extended haplotype was increased by almost six-fold in the autistic subjects as compared with healthy controls. Moreover, the total number of extended haplotypes expressed on chromosomes of autistic subjects was significantly increased as compared with those expressed on chromosomes of healthy subjects. We conclude that a gene related to, or included in, the extended major histocompatibility complex may be associated with autism. [Abstract]

Warren RP, Singh VK, Cole P, Odell JD, Pingree CB, Warren WL, White E
Increased frequency of the null allele at the complement C4b locus in autism.
Clin Exp Immunol. 1991 Mar;83(3):438-40.
Associations between C4 deficiency and autoimmune disorders have been found over the past several years. Since autism has several autoimmune features, the frequencies of null (no protein produced) alleles at the C4A and C4B loci were studied in 19 subjects with autism and their family members. The autistic subjects and their mothers had significantly increased phenotypic frequencies of the C4B null allele (58% in both the autistic subjects and mothers, compared with 27% in control subjects). The siblings of the autistic subjects also had an increased frequency of the C4B null allele, but this increase was not significant. The fathers had normal frequencies of this null allele. All family members had normal frequencies of the C4A null allele, all normal C4A and C4B alleles and all BF and C2 alleles. [Abstract]

Warren RP, Burger RA, Odell D, Torres AR, Warren WL
Decreased plasma concentrations of the C4B complement protein in autism.
Arch Pediatr Adolesc Med. 1994 Feb;148(2):180-3.
OBJECTIVE: To determine complement C4 protein concentrations in the plasmas of autistic subjects and their family members. DESIGN: Cross-sectional study. SETTING: Center for Persons with Disabilities and the Department of Biology, Utah State University, Logan. PARTICIPANTS: Forty-two autistic subjects (34 males [81%] and eight females [19%]), 50 of their biologic parents, 21 siblings, and 105 normal subjects (56 females [53%] and 49 males [47%]; all white) living in northern Utah. INTERVENTIONS: None. METHODS: The enzyme-linked immunosorbent assay was used to determine C4 protein concentrations in autistic subjects. MAIN RESULTS: Plasma concentration (median, 14.7 g/L of the C4B protein) in autistic patients was significantly (P = .01) decreased compared with that of normal subjects (median, 22.4 g/L). The C4B concentrations in parents and siblings of autistic children were decreased, but not significantly. The C4A protein concentrations in the plasma of autistic subjects and their family members were normal. CONCLUSION: Decreased protein concentrations of C4B may be associated with autism. [Abstract]

Rogers T, Kalaydjieva L, Hallmayer J, Petersen PB, Nicholas P, Pingree C, McMahon WM, Spiker D, Lotspeich L, Kraemer H, McCague P, Dimiceli S, Nouri N, Peachy T, Yang J, Hinds D, Risch N, Myers RM
Exclusion of linkage to the HLA region in ninety multiplex sibships with autism.
J Autism Dev Disord. 1999 Jun;29(3):195-201.
Several studies have suggested a role for the histocompatibility complex of loci (HLA) in the genetic susceptibility to autism. We have tested this hypothesis by linkage analysis using genetic marker loci in the HLA region on chromosome 6p in multiplex families with autism. We have examined sharing of alleles identical by descent in 97 affected sib pairs from 90 families. Results demonstrate no deviation from the null expectation of 50% sharing of alleles in this region; in fact, for most marker loci, the observed sharing was less than 50%. Thus, it is unlikely that loci in this region contribute to the genetic etiology of autism to any significant extent in our families. [Abstract]

Warren RP, Singh VK
Elevated serotonin levels in autism: association with the major histocompatibility complex.
Neuropsychobiology. 1996;34(2):72-5.
Two of the most consistently observed biological findings in autism are increased serotonin levels in the blood and immunological abnormalities (including autoreactivity with tissues of the central nervous system). The purpose of this investigation was to determine if any relationship exists between these two sets of observations. Our laboratory has found and confirmed associations of the major histocompatibility complex (MHC) with autism. Since the MHC is known to regulate the immune system and is also associated with autoimmune disorders, we studied serum serotonin levels in 20 autistic subjects with or without MHC types previously found to be associated with autism. A positive relationship was observed between elevated serotonin levels and the MHC types previously associated with autism. [Abstract]

Shao Y, Cuccaro ML, Hauser ER, Raiford KL, Menold MM, Wolpert CM, Ravan SA, Elston L, Decena K, Donnelly SL, Abramson RK, Wright HH, DeLong GR, Gilbert JR, Pericak-Vance MA
Fine mapping of autistic disorder to chromosome 15q11-q13 by use of phenotypic subtypes.
Am J Hum Genet. 2003 Mar;72(3):539-48.
Autistic disorder (AutD) is a complex genetic disease. Available evidence suggests that several genes contribute to the underlying genetic risk for the development of AutD. However, both etiologic heterogeneity and genetic heterogeneity confound the discovery of AutD-susceptibility genes. Chromosome 15q11-q13 has been identified as a strong candidate region on the basis of both the frequent occurrence of chromosomal abnormalities in that region and numerous suggestive linkage and association findings. Ordered-subset analysis (OSA) is a novel statistical method to identify a homogeneous subset of families that contribute to overall linkage at a given chromosomal location and thus to potentially help in the fine mapping and localization of the susceptibility gene within a chromosomal area. For the present analysis, a factor that represents insistence on sameness (IS)--derived from a principal-component factor analysis using data on 221 patients with AutD from the repetitive behaviors/stereotyped patterns domain in the Autism Diagnostic Interview-Revised--was used as a covariate in OSA. Analysis of families sharing high scores on the IS factor increased linkage evidence for the 15q11-q13 region, at the GABRB3 locus, from a LOD score of 1.45 to a LOD score of 4.71. These results narrow our region of interest on chromosome 15 to an area surrounding the gamma-aminobutyric acid-receptor subunit genes, in AutD, and support the hypothesis that the analysis of phenotypic homogeneous subtypes may be a powerful tool for the mapping of disease-susceptibility genes in complex traits. [Abstract]

Menold MM, Shao Y, Wolpert CM, Donnelly SL, Raiford KL, Martin ER, Ravan SA, Abramson RK, Wright HH, Delong GR, Cuccaro ML, Pericak-Vance MA, Gilbert JR
Association analysis of chromosome 15 gabaa receptor subunit genes in autistic disorder.
J Neurogenet. 2001;15(3-4):245-59.
Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, acting via the GABAA receptors. The GABAA receptors are comprised of several different homologous subunits, forming a group of receptors that are both structurally and functionally diverse. Three of the GABAA receptor subunit genes (GABRB3, GABRA5 and GABRG3) form a cluster on chromosome 15q11-q13, in a region that has been genetically associated with autistic disorder (AutD). Based on these data, we examined 16 single nucleotide polymorphisms (SNPs) located within GABRB3, GABRA5 and GABRG3 for linkage disequilibrium (LD) in 226 AutD families (AutD patients and parents). Genotyping was performed using either OLA (oligonucleotide ligation assay), or SSCP (single strand conformation polymorphism) followed by DNA sequencing. We tested for LD using the Pedigree Disequilibrium Test (PDT). PDT results gave significant evidence that AutD is associated with two SNPs located within the GABRG3 gene (exon5_539T/C, p=0.02 and intron5_687T/C, p=0.03), suggesting that the GABRG3 gene or a gene nearby contributes to genetic risk in AutD. [Abstract]

Buxbaum JD, Silverman JM, Smith CJ, Greenberg DA, Kilifarski M, Reichert J, Cook EH, Fang Y, Song CY, Vitale R
Association between a GABRB3 polymorphism and autism.
Mol Psychiatry. 2002;7(3):311-6.
Autistic disorder (OMIM 209850) is a disease with a significant genetic component of a complex nature.(1) Cytogenetic abnormalities in the Prader-Willi/Angelman syndrome critical region (15q11-13) have been described in several individuals with autism.(1) For this reason, markers across this region have been screened for evidence of linkage and association, and a marker (155CA-2) in the gamma-aminobutyric acid type-A receptor beta3 subunit gene (GABRB3) has been associated in one study(2) but not others.(3-5) We completed an association analysis with 155CA-2 using the transmission disequilibrium test (TDT) in a set of 80 autism families (59 multiplex and 21 trios). We also used four additional markers (69CA, 155CA-1, 85CA, and A55CA-1) localized within 150 kb of 155CA-2. The use of multi-allelic TDT (MTDT) (P < 0.002), as well as the TDT (P < 0.004), demonstrated an association between autistic disorder and 155CA-2 in these families. Meiotic segregation distortion could be excluded as a possible cause for these results since no disequilibrium was observed in unaffected siblings. These findings support a role for genetic variants within the GABA receptor gene complex in 15q11-13 in autistic disorder. [Abstract]

Cook EH, Courchesne RY, Cox NJ, Lord C, Gonen D, Guter SJ, Lincoln A, Nix K, Haas R, Leventhal BL, Courchesne E
Linkage-disequilibrium mapping of autistic disorder, with 15q11-13 markers.
Am J Hum Genet. 1998 May;62(5):1077-83.
Autistic disorder is a complex genetic disease. Because of previous reports of individuals with autistic disorder with duplications of the Prader-Willi/Angelman syndrome critical region, we screened several markers across the 15q11-13 region, for linkage disequilibrium. One hundred forty families, consisting predominantly of a child with autistic disorder and both parents, were studied. Genotyping was performed by use of multiplex PCR and capillary electrophoresis. Two children were identified who had interstitial chromosome 15 duplications and were excluded from further linkage-disequilibrium analysis. Use of the multiallelic transmission-disequilibrium test (MTDT), for nine loci on 15q11-13, revealed linkage disequilibrium between autistic disorder and a marker in the gamma-aminobutyric acidA receptor subunit gene, GABRB3 155CA-2 (MTDT 28.63, 10 df, P=.0014). No evidence was found for parent-of-origin effects on allelic transmission. The convergence of GABRB3 as a positional and functional candidate along with the linkage-disequilibrium data suggests the need for further investigation of the role of GABRB3 or adjacent genes in autistic disorder. [Abstract]

Nurmi EL, Dowd M, Tadevosyan-Leyfer O, Haines JL, Folstein SE, Sutcliffe JS
Exploratory subsetting of autism families based on savant skills improves evidence of genetic linkage to 15q11-q13.
J Am Acad Child Adolesc Psychiatry. 2003 Jul;42(7):856-63.
OBJECTIVE: Autism displays a remarkably high heritability but a complex genetic etiology. One approach to identifying susceptibility loci under these conditions is to define more homogeneous subsets of families on the basis of genetically relevant phenotypic or biological characteristics that vary from case to case. METHOD: The authors performed a principal components analysis, using items from the Autism Diagnostic Interview, which resulted in six clusters of variables, five of which showed significant sib-sib correlation. The utility of these phenotypic subsets was tested in an exploratory genetic analysis of the autism candidate region on chromosome 15q11-q13. RESULTS: When the Collaborative Linkage Study of Autism sample was divided, on the basis of mean proband score for the "savant skills" cluster, the heterogeneity logarithm of the odds under a recessive model at D15S511, within the GABRB3 gene, increased from 0.6 to 2.6 in the subset of families in which probands had greater savant skills. CONCLUSIONS: These data are consistent with the genetic contribution of a 15q locus to autism susceptibility in a subset of affected individuals exhibiting savant skills. Similar types of skills have been noted in individuals with Prader-Willi syndrome, which results from deletions of this chromosomal region. [Abstract]

Bass MP, Menold MM, Wolpert CM, Donnelly SL, Ravan SA, Hauser ER, Maddox LO, Vance JM, Abramson RK, Wright HH, Gilbert JR, Cuccaro ML, DeLong GR, Pericak-Vance MA
Genetic studies in autistic disorder and chromosome 15.
Neurogenetics. 2000 Mar;2(4):219-26.
Autistic disorder (AD) is a developmental disorder affecting social interactions, communication, and behavior. AD is a disease of complex genetic architecture. It is postulated that several genes contribute to the underlying etiology of AD. Chromosome 15 is of particular interest due to numerous reports of AD in the presence of chromosomal abnormalities, located mainly in the 15q11-q13 region. There are also a number of plausible candidate genes in this area, including the gamma-aminobutyric acidA (GABA(A)) receptor gene complex. We have undertaken a study of this region of chromosome 15 in a data set of 63 multiplex families (with 2 or more AD affected individuals per family). We found evidence in support of linkage to the 15q11-q13 region, as well as evidence of increased recombination in this region. These findings provide further support for the involvement of chromosome 15q11-q13 in the genetic etiology of AD. [Abstract]

Martin ER, Menold MM, Wolpert CM, Bass MP, Donnelly SL, Ravan SA, Zimmerman A, Gilbert JR, Vance JM, Maddox LO, Wright HH, Abramson RK, DeLong GR, Cuccaro ML, Pericak-Vance MA
Analysis of linkage disequilibrium in gamma-aminobutyric acid receptor subunit genes in autistic disorder.
Am J Med Genet. 2000 Feb 7;96(1):43-8.
Autistic disorder (AD) is a neurodevelopmental disorder characterized by abnormalities in behavior, communication, and social interactions and functioning. Recently, Cook et al. reported significant linkage disequilibrium with an AD susceptibility locus and a marker, GABRB3 155CA-2, in the gamma-aminobutyric acid(A) (GABA(A)) receptor beta3-subunit gene on chromosome 15q11-q13. This linkage disequilibrium was detected using a multiallelic version of the transmission/disequilibrium test (TDT) in a sample of nuclear families having at least one child with autistic disorder. In an attempt to replicate this finding we tested for linkage disequilibrium with this marker, as well as with three additional markers in and around the GABA(A) receptor beta3-subunit gene, in an independent, clinically comparable set of AD families. Unlike Cook et al., we failed to detect significant linkage disequilibrium between GABRB3 155CA-2 and AD in our sample. We did, however, find suggestive evidence for linkage disequilibrium with a marker, GABRB3, approximately 60 kb beyond the 3' end of beta3-subunit gene. This finding lends support for previous reports implicating the involvement of genes in this region with AD. [Abstract]

Salmon B, Hallmayer J, Rogers T, Kalaydjieva L, Petersen PB, Nicholas P, Pingree C, McMahon W, Spiker D, Lotspeich L, Kraemer H, McCague P, Dimiceli S, Nouri N, Pitts T, Yang J, Hinds D, Myers RM, Risch N
Absence of linkage and linkage disequilibrium to chromosome 15q11-q13 markers in 139 multiplex families with autism.
Am J Med Genet. 1999 Oct 15;88(5):551-6.
Chromosomal region 15q11-q13 has been implicated to harbor a susceptibility gene or genes underlying autism. Evidence has been derived from the existence of cytogenetic anomalies in this region associated with autism, and the report of linkage in a modest collection of multiplex families. Most recently, linkage disequilibrium with the marker GABRB3-155CA2 in the candidate locus GABRB3, located in this region, has been reported. We searched for linkage using eight microsatellite markers located in this region of chromosome 15 in 147 affected sib-pairs from 139 multiplex autism families. We also tested for linkage disequilibrium in the same set of families with the same markers. We found no evidence for excess allele sharing (linkage) for the markers in this region. Also, we found no evidence of linkage disequilibrium, including for the locus GABRB3-155CA2. Thus, it appears that the role of this region of chromosome 15 is minor, at best, in the majority of individuals with autism. [Abstract]

Silva AE, Vayego-Lourenco SA, Fett-Conte AC, Goloni-Bertollo EM, Varella-Garcia M
Tetrasomy 15q11-q13 identified by fluorescence in situ hybridization in a patient with autistic disorder.
Arq Neuropsiquiatr. 2002 Jun;60(2-A):290-4.
We report a female child with tetrasomy of the 15q11-q13 chromosomal region, and autistic disorder associated with mental retardation, developmental problems and behavioral disorders. Combining classical and molecular cytogenetic approaches by fluorescence in situ hybridization technique, the karyotype was demonstrated as 47,XX,+mar.ish der(15)(D15Z1++,D15S11++,GABRB3++,PML-). Duplication of the 15q proximal segment represents the most consistent chromosomal abnormality reported in association with autism. The contribution of the GABA receptor subunit genes, and other genes mapped to this region, to the clinical symptoms of the disease is discussed. [Abstract]

Bolton PF, Dennis NR, Browne CE, Thomas NS, Veltman MW, Thompson RJ, Jacobs P
The phenotypic manifestations of interstitial duplications of proximal 15q with special reference to the autistic spectrum disorders.
Am J Med Genet. 2001 Dec 8;105(8):675-85.
This study investigated the phenotypic manifestations of interstitial duplications of chromosome 15 that involve the Prader-Willi/Angelman syndrome critical region (PWACR). Twenty-one affected individuals from six families were evaluated in detail, using standardized and semi-standardized measures of intelligence, psychopathology, and physical anomalies. Special attention was placed on determining the prevalence of autism spectrum disorders as well as the relationship between the parental origin of the duplication and the phenotypic effects. Assessments of the affected individuals were compared with evaluations of the unaffected relatives from the same families. Results indicated that duplications in the region were associated with variable degrees of intellectual impairments and motor coordination problems. Four of the subjects received a diagnosis of pervasive developmental disorder. Three of these cases were probands and only one met criteria for classic autism. There was very little evidence of the duplication cosegregating with autism spectrum disorder diagnosis. Paternally inherited duplications were significantly less likely to give rise to phenotypic effects. The findings indicate that duplications in the PWACR give rise to developmental delay but not necessarily autism spectrum disorders. They also suggest that phenotypic expression is dependent on the parental origin of the duplication and implicate maternally active genes in the pathogenesis of the developmental impairments. Further research will be required to clarify the range and basis of the phenotypic manifestations. [Abstract]

Cook EH, Lindgren V, Leventhal BL, Courchesne R, Lincoln A, Shulman C, Lord C, Courchesne E
Autism or atypical autism in maternally but not paternally derived proximal 15q duplication.
Am J Hum Genet. 1997 Apr;60(4):928-34.
Duplications of proximal 15q have been found in individuals with autistic disorder (AD) and varying degrees of mental retardation. Often these abnormalities take the form of a supernumerary inverted duplicated chromosome 15, more properly described as an isodicentric chromosome 15, or idic(15). However, intrachromosomal duplications also have been reported. In a few cases, unaffected mothers, as well as their affected children, carry the same duplications. During the course of the genotyping of trios of affected probands with AD and their parents, at the positional candidate locus D15S122, an intrachromosomal duplication of proximal 15q was detected by microsatellite analysis in a phenotypically normal mother. Microsatellite and methylation analyses of the pedigree in the following report show that, among three children, the two with autism or atypical autism have maternal inheritance of a 15q11-q13 duplication whereas the third child, who is unaffected, did not inherit this duplication. Their mother's 15q11-q13 duplication arose de novo from her father's chromosomes 15. This finding documents, for the first time, the significance of parental origin for duplications of 15q11-q13. In this family, paternal inheritance leads to a normal phenotype, and maternal inheritance leads to autism or atypical autism. [Abstract]

Martinsson T, Johannesson T, Vujic M, Sjöstedt A, Steffenburg S, Gillberg C, Wahlström J
Maternal origin of inv dup(15) chromosomes in infantile autism.
Eur Child Adolesc Psychiatry. 1996 Dec;5(4):185-92.
Six male patients with infantile autism and an extra inverted duplicated chromosome 15[inv dup(15)] were reported in a previous study. These patients had four copies of the chromosome region 15pter-q13, or an inv dup(15)(pter-->q13; q13-->pter). In this new study, DNA from the families of four of the patients were analysed using Southern based RFLPs and microsatellite polymorphisms from the region. In all four cases the inv dup(15) chromosome was of maternal origin. Furthermore, the data suggests that it originated in the maternal meiotic process rather than in an early mitosis in the developmental process of the embryo. The extra chromosome contained material from both of the maternally derived 15-chromosomes. Based on the molecular data presented here, a model for the origin of chromosome markers of this type is proposed. [Abstract]

Flejter WL, Bennett-Baker PE, Ghaziuddin M, McDonald M, Sheldon S, Gorski JL
Cytogenetic and molecular analysis of inv dup(15) chromosomes observed in two patients with autistic disorder and mental retardation.
Am J Med Genet. 1996 Jan 11;61(2):182-7.
A variety of distinct phenotypes has been associated with supernumerary inv dup(15) chromosomes. Although different cytogenetic rearrangements have been associated with distinguishable clinical syndromes, precise genotype-phenotype correlations have not been determined. However, the availability of chromosome 15 DNA markers provides a means to characterize inv dup(15) chromosomes in detail to facilitate the determination of specific genotype-phenotype associations. We describe 2 patients with an autistic disorder, mental retardation, developmental delay, seizures, and supernumerary inv dup(15) chromosomes. Conventional and molecular cytogenetic studies confirmed the chromosomal origin of the supernumerary chromosomes and showed that the duplicated region extended to at least band 15q13. An analysis of chromosome 15 microsatellite CA polymorphisms suggested a maternal origin of the inv dup(15) chromosomes and biparental inheritance of the two intact chromosome 15 homologs. The results of this study add to the existing literature which suggests that the clinical phenotype of patients with a supernumerary inv dup(15) chromosome is determined not only by the extent of the duplicated region, but by the dosage of genes located within band 15q13 and the origin of the normal chromosomes 15. [Abstract]

Bundey S, Hardy C, Vickers S, Kilpatrick MW, Corbett JA
Duplication of the 15q11-13 region in a patient with autism, epilepsy and ataxia.
Dev Med Child Neurol. 1994 Aug;36(8):736-42.
Various developmental abnormalities can give rise to the clinical syndrome of autism, and some are due to chromosomal anomalies. One syndrome has been identified in which behavioural disorder is associated with the clinical features of epilepsy and ataxia, and with the chromosomal anomaly of an extra marker chromosome containing a duplication of 15q11-13. The authors report a boy with autism, epilepsy, ataxia and an interstitial duplication of 15q, in whom molecular analysis reveals duplication of the GABRA5 and GABRB3 genes on the maternally derived chromosome. [Abstract]

Boyar FZ, Whitney MM, Lossie AC, Gray BA, Keller KL, Stalker HJ, Zori RT, Geffken G, Mutch J, Edge PJ, Voeller KS, Williams CA, Driscoll DJ
A family with a grand-maternally derived interstitial duplication of proximal 15q.
Clin Genet. 2001 Dec;60(6):421-30.
About 1% of individuals with autism or types of pervasive developmental disorder have a duplication of the 15q11-q13 region. These abnormalities can be detected by routine G-banded chromosome study, showing an extra marker chromosome, or demonstrated by fluorescence in situ hybridization (FISH) analysis, revealing an interstitial duplication. We report here the molecular, cytogenetic, clinical and neuropsychiatric evaluations of a family in whom 3 of 4 siblings inherited an interstitial duplication of 15q11-q13. This duplication was inherited from their mother who also had a maternally derived duplication. Affected family members had apraxia of speech, phonological awareness deficits, developmental language disorder, dyslexia, as well as limb apraxia but did not have any dysmorphic clinical features. The observations in this family suggest that the phenotypic manifestations of proximal 15q duplications may also involve language-based learning disabilities. [Abstract]

Fantes JA, Mewborn SK, Lese CM, Hedrick J, Brown RL, Dyomin V, Chaganti RS, Christian SL, Ledbetter DH
Organisation of the pericentromeric region of chromosome 15: at least four partial gene copies are amplified in patients with a proximal duplication of 15q.
J Med Genet. 2002 Mar;39(3):170-7.
Clinical cytogenetic laboratories frequently identify an apparent duplication of proximal 15q that does not involve probes within the PWS/AS critical region and is not associated with any consistent phenotype. Previous mapping data placed several pseudogenes, NF1, IgH D/V, and GABRA5 in the pericentromeric region of proximal 15q. Recent studies have shown that these pseudogene sequences have increased copy numbers in subjects with apparent duplications of proximal 15q. To determine the extent of variation in a control population, we analysed NF1 and IgH D pseudogene copy number in interphase nuclei from 20 cytogenetically normal subjects by FISH. Both loci are polymorphic in controls, ranging from 1-4 signals for NF1 and 1-3 signals for IgH D. Eight subjects with apparent duplications, examined by the same method, showed significantly increased NF1 copy number (5-10 signals). IgH D copy number was also increased in 6/8 of these patients (4-9 signals). We identified a fourth pseudogene, BCL8A, which maps to the pericentromeric region and is coamplified along with the NF1 sequences. Interphase FISH ordering experiments show that IgH D lies closest to the centromere, while BCL8A is the most distal locus in this pseudogene array; the total size of the amplicon is estimated at approximately 1 Mb. The duplicated chromosome was inherited from either sex parent, indicating no parent of origin effect, and no consistent phenotype was present. FISH analysis with one or more of these probes is therefore useful in discriminating polymorphic amplification of proximal pseudogene sequences from clinically significant duplications of 15q. [Abstract]

Wolpert CM, Menold MM, Bass MP, Qumsiyeh MB, Donnelly SL, Ravan SA, Vance JM, Gilbert JR, Abramson RK, Wright HH, Cuccaro ML, Pericak-Vance MA
Three probands with autistic disorder and isodicentric chromosome 15.
Am J Med Genet. 2000 Jun 12;96(3):365-72.
We have identified three unrelated probands with autistic disorder (AD) and isodicentric chromosomes that encompass the proximal region of 15q11.2. All three probands met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition [DSM-IV; American Psychiatric Association, 1994], and International Classification of Diseases ( ICD-10) diagnostic criteria for AD, confirmed with the Autism Diagnostic Interview -Revised (ADI-R). Chromosome analysis revealed the following karyotypes: 47,XX,+idic(15)(q11.2), 47,XX, +idic(15) (q11.2), and 47,XY,+idic(15)(q11.2). Haplotype analysis of genotypic maker data in the probands and their parents showed that marker chromosomes in all three instances were of maternal origin. Comparison of the clinical findings of the three AD probands with case reports in the published literature (N = 20) reveals a clustering of physical and developmental features. Specifically, these three probands and the majority of reported probands in the literature exhibited hypotonia (n = 13), seizures (n = 13), and delayed gross motor development (n = 13). In addition, clustering of the following clinical signs was seen with respect to exhibited speech delay (n = 13), lack of social reciprocity (n = 11), and stereotyped behaviors (n = 12). Collectively, these data provide further evidence for the involvement of chromosome 15 in AD as well as present preliminary data suggesting a clustering of clinical features in AD probands with proximal 15q anomalies. [Abstract]

Rineer S, Finucane B, Simon EW
Autistic symptoms among children and young adults with isodicentric chromosome 15.
Am J Med Genet. 1998 Sep 7;81(5):428-33.
A standardized assessment of autistic symptomatology was completed for 29 children and young adults with a supernumerary isodicentric chromosome 15 (formerly known as inverted duplication 15). Although there was variability in severity, 20 individuals with an isodicentric chromosome 15 [idic(15)] had a high probability of being autistic. Eight of the 9 remaining children were under age 5 years and were more sociable than the rest of the cohort. Group characteristics such as gender and seizure presence could not explain the observed difference between older and younger individuals in our study. The natural history of isodicentric 15 syndrome remains to be shown through longitudinal work and may include an age-related risk for developing autism. [Abstract]

Wolpert C, Pericak-Vance MA, Abramson RK, Wright HH, Cuccaro ML
Autistic symptoms among children and young adults with isodicentric chromosome 15.
Am J Med Genet. 2000 Feb 7;96(1):128-9. [Abstract]

Nurmi EL, Amin T, Olson LM, Jacobs MM, McCauley JL, Lam AY, Organ EL, Folstein SE, Haines JL, Sutcliffe JS
Dense linkage disequilibrium mapping in the 15q11-q13 maternal expression domain yields evidence for association in autism.
Mol Psychiatry. 2003 Jun;8(6):624-34, 570.
Autism [MIM 209850] is a neurodevelopmental disorder exhibiting a complex genetic etiology with clinical and locus heterogeneity. Chromosome 15q11-q13 has been proposed to harbor a gene for autism susceptibility based on (1) maternal-specific chromosomal duplications seen in autism and (2) positive evidence for linkage disequilibrium (LD) at 15q markers in chromosomally normal autism families. To investigate and localize a potential susceptibility variant, we developed a dense single nucleotide polymorphism (SNP) map of the maternal expression domain in proximal 15q. We analyzed 29 SNPs spanning the two known imprinted, maternally expressed genes in the interval (UBE3A and ATP10C) and putative imprinting control regions. With a marker coverage of 1/10 kb in coding regions and 1/15 kb in large 5' introns, this map was employed to thoroughly dissect LD in autism families. Two SNPs within ATP10C demonstrated evidence for preferential allelic transmission to affected offspring. The signal detected at these SNPs was stronger in singleton families, and an adjacent SNP demonstrated transmission distortion in this subset. All SNPs showing allelic association lie within islands of sequence homology between human and mouse genomes that may be part of an ancestral haplotype containing a functional susceptibility allele. The region was further explored for recombination hot spots and haplotype blocks to evaluate haplotype transmission. Five haplotype blocks were defined within this region. One haplotype within ATP10C displayed suggestive evidence for preferential transmission. Interpretation of these data will require replication across data sets, evaluation of potential functional effects of associated alleles, and a thorough assessment of haplotype transmission within ATP10C and neighboring genes. Nevertheless, these findings are consistent with the presence of an autism susceptibility locus in 15q11-q13. [Abstract]

Nurmi EL, Bradford Y, Chen Y, Hall J, Arnone B, Gardiner MB, Hutcheson HB, Gilbert JR, Pericak-Vance MA, Copeland-Yates SA, Michaelis RC, Wassink TH, Santangelo SL, Sheffield VC, Piven J, Folstein SE, Haines JL, Sutcliffe JS
Linkage disequilibrium at the Angelman syndrome gene UBE3A in autism families.
Genomics. 2001 Sep;77(1-2):105-13.
Autistic disorder is a neurodevelopmental disorder with a complex genetic etiology. Observations of maternal duplications affecting chromosome 15q11-q13 in patients with autism and evidence for linkage and linkage disequilibrium to markers in this region in chromosomally normal autism families indicate the existence of a susceptibility locus. We have screened the families of the Collaborative Linkage Study of Autism for several markers spanning a candidate region covering approximately 2 Mb and including the Angelman syndrome gene (UBE3A) and a cluster of gamma-aminobutyric acid (GABA(A)) receptor subunit genes (GABRB3, GABRA5, and GABRG3). We found significant evidence for linkage disequilibrium at marker D15S122, located at the 5' end of UBE3A. This is the first report, to our knowledge, of linkage disequilibrium at UBE3A in autism families. Characterization of null alleles detected at D15S822 in the course of genetic studies of this region showed a small (approximately 5-kb) genomic deletion, which was present at somewhat higher frequencies in autism families than in controls. [Abstract]

Kim SJ, Herzing LB, Veenstra-VanderWeele J, Lord C, Courchesne R, Leventhal BL, Ledbetter DH, Courchesne E, Cook EH
Mutation screening and transmission disequilibrium study of ATP10C in autism.
Am J Med Genet. 2002 Mar 8;114(2):137-43.
Autism is a complex genetic disorder. Chromosome 15 is of particular interest in this disorder, because of previous reports of individuals with autism with chromosomal abnormalities in the 15q11-q13 region. Transmission disequilibrium between polymorphisms in this region and autism has been also been reported in some, but not all studies. Recently, a novel maternally expressed gene, ATP10C, was characterized and mapped to the chromosome 15q11-q13 region, 200 kb distal to UBE3A. It encodes a putative aminophospholipid translocase likely to be involved in the asymmetric distribution of proteins in the cell membrane. Preferential maternal expression has been demonstrated in fibroblasts and brain. Because of its physical location and imprinting pattern, ATP10C was considered to be a candidate gene for chromosome 15-associated autism. In an effort to find the genes responsible for autism in this chromosomal region, 1.5 kb of the 5' flanking region, as well as the coding and splicing regions of ATP10C, were screened for sequence variants. Several polymorphic markers including five nonsynonymous SNPs were identified. To investigate transmission disequilibrium between ATP10C and autism, a family-based association study was conducted for 14 markers in 115 autism trios. No significant transmission disequilibrium was found, suggesting ATP10C is unlikely to contribute strongly to susceptibility to autism in these families. However, due to limited power to detect genes of modest effect, the possible functional role of the nonsynonymous SNPs and the functional implications of the SNPs identified from 5' flanking region and intron 2 splicing region may be evaluated in further studies. [Abstract]

Bolton PF, Veltman MW, Weisblatt E, Holmes JR, Thomas NS, Youings SA, Thompson RJ, Roberts SE, Dennis NR, Browne CE, Goodson S, Moore V, Brown J
Chromosome 15q11-13 abnormalities and other medical conditions in individuals with autism spectrum disorders.
Psychiatr Genet. 2004 Sep;14(3):131-137.
OBJECTIVES: The frequency of abnormalities of 15q11-q13 and other possibly causal medical disorders including karyotypic abnormalities was investigated in an unselected series of children who were referred to one of two autism assessment centres. METHODS: Two hundred and twenty-one cases were assessed using the Autism Diagnostic Interview and Observation Schedule and, where appropriate, standardized tests of intelligence and language abilities. Medical histories and notes were reviewed, and molecular and cytogenetic investigations used to detect chromosomal abnormalities. RESULTS: One hundred and eighty-one cases were diagnosed according to International Classification of Diseases ? version 10 criteria as having an autism spectrum disorder (autistic-like Pervasive Developmental Disorder) and 40 cases as having other disorders. Twenty-one (11.6%) of the children with autism spectrum disorders had a possibly causal condition compared with six (15%) of the children with other diagnoses. One child with an autism spectrum disorder had a paternally inherited familial duplication of 15q11-13. The pattern of genotype?phenotype correlation within the family indicated that this form of abnormality might carry a risk for developmental difficulties, although the risk did not appear to be specific for autism spectrum disorders. CONCLUSION: The overall rate of possibly causal medical and cytogenetic conditions in children with autism spectrum disorders was low and no different from the rate of disorder in children with other developmental/neuropsychiatric disorders that attended the same clinics. Further research is required to determine whether paternal duplication of 15q11-13 gives rise to adverse developmental outcomes. [Abstract]

Thomas JA, Johnson J, Peterson Kraai TL, Wilson R, Tartaglia N, LeRoux J, Beischel L, McGavran L, Hagerman RJ
Genetic and clinical characterization of patients with an interstitial duplication 15q11-q13, emphasizing behavioral phenotype and response to treatment.
Am J Med Genet. 2003 Jun 1;119A(2):111-20.
The clinical significance of an interstitial duplication of (15)(q11-q13) remains unclear and controversial. The reported phenotypes vary widely and appear to be influenced by the parent of origin of the duplication. Aside from cases of dup(15) reported with autism, the behavioral phenotype of individuals with dup(15) has not been described. We present three families, two with intrachromosomal duplication (15)(q11-q13) ascertained because of developmental delay in a relative. Two families show clear evidence of multigenerational maternal inheritance. The individuals discussed in this paper have minor anomalies and developmental delays. In addition, we describe a behavioral phenotype which often includes attention deficit hyperactivity disorder (ADHD) and autistic spectrum disorder. Responses to medications used to manage these behaviors are also described, including a positive response to methylphenidate and a poor response to fluoxetine. The duplication in each presenting individual, and available family members, was investigated utilizing cytogenetic and molecular techniques including high resolution cytogenetics, fluorescence in situ hybridization (FISH), DNA methylation studies, and quantitative fluorescence PCR. High resolution cytogenetic techniques alone missed some cases, demonstrating the need to confirm results with other methods. [Abstract]

Repetto GM, White LM, Bader PJ, Johnson D, Knoll JH
Interstitial duplications of chromosome region 15q11q13: clinical and molecular characterization.
Am J Med Genet. 1998 Sep 1;79(2):82-9.
Duplications of chromosome region 15q11q13 often occur as a supernumerary chromosome 15. Less frequently they occur as interstitial duplications [dup(15)]. We describe the clinical and molecular characteristics of three patients with de novo dup(15). The patients, two males and one female (ages 3-21 years), had nonspecific findings that included autistic behavior, hypotonia, and variable degrees of mental retardation. The extent, orientation, and parental origin of the duplications were assessed by fluorescent in situ hybridization, microsatellite analyses, and methylation status at D15S63. Two patients had large direct duplications of 15q11q13 [dir dup(15)(q11q13)] that extended through the entire Angelman syndrome/Prader-Willi syndrome (AS/PWS) chromosomal region. Their proximal and distal breaks, at D15S541 or D15S9 and between D15S12 and D15S24, respectively, were comparable to those found in the common AS/PWS deletions. This suggests that duplications and deletions may be the reciprocal product of an unequal recombination event. These two duplications were maternally derived, but the origin of the chromatids involved in the unequal crossing over in meiosis differs. In one patient, the duplication originated from two different maternal chromosomes, while in the other patient it arose from the same maternal chromosome. The third patient had a much smaller duplication that involved only D15S11 and parental origin could not be determined. There was no obvious correlation between phenotype and extent of the duplication in these patients. [Abstract]

Borgatti R, Piccinelli P, Passoni D, Dalprà L, Miozzo M, Micheli R, Gagliardi C, Balottin U
Relationship between clinical and genetic features in "inverted duplicated chromosome 15" patients.
Pediatr Neurol. 2001 Feb;24(2):111-6.
Inverted duplicated chromosome 15 (Inv dup [15]) syndrome is a genetic disorder characterized by psychologic or intellectual language delay; neurologic signs, such as hypotonia, ataxia, and epilepsy; mental retardation ranging from mild to severe; and facial dysmorphisms. All patients present with a psychopathologic impairment that is highly variable in severity but always classifiable as pervasive developmental disorder (PDD). Many genetic mechanisms have been hypothesized to explain the clinical variability. This article describes the neurologic and psychopathologic features of six Inv dup(15) patients, one male and five females, between 8 and 14 years of age, all with a maternal marker chromosome. Four patients were diagnosed with PDD not otherwise specified, whereas two patients received a diagnosis of autism. Epilepsy was present in three patients (two generalized symptomatic and one focal symptomatic), and a correlation between the severity of the disease and its outcome was not always observed. Nevertheless, the influence of gene content of the marker chromosome, particularly the three gamma-aminobutyric acid-A receptor subunit genes, may represent the link between epilepsy, mental retardation, and PDD. [Abstract]

Schroer RJ, Phelan MC, Michaelis RC, Crawford EC, Skinner SA, Cuccaro M, Simensen RJ, Bishop J, Skinner C, Fender D, Stevenson RE
Autism and maternally derived aberrations of chromosome 15q.
Am J Med Genet. 1998 Apr 1;76(4):327-36.
Of the chronic mental disabilities of childhood, autism is causally least well understood. The former view that autism was rooted in exposure to humorless and perfectionistic parenting has given way to the notion that genetic influences are dominant underlying factors. Still, identification of specific heritable factors has been slow with causes identified in only a few cases in unselected series. A broad search for genetic and environmental influences that cause or predispose to autism is the major thrust of the South Carolina Autism Project. Among the first 100 cases enrolled in the project, abnormalities of chromosome 15 have emerged as the single most common cause. The four abnormalities identified include deletions and duplications of proximal 15q. Other chromosome aberrations seen in single cases include a balanced 13;16 translocation, a pericentric inversion 12, a deletion of 20p, and a ring 7. Candidate genes involved in the 15q region affected by duplication and deletion include the ubiquitin-protein ligase (UBE3A) gene responsible for Angelman syndrome and genes for three GABA(A) receptor subunits. In all cases, the deletions or duplications occurred on the chromosome inherited from the mother. [Abstract]

Veltman MW, Thompson RJ, Roberts SE, Thomas NS, Whittington J, Bolton PF
Prader-Willi syndrome--a study comparing deletion and uniparental disomy cases with reference to autism spectrum disorders.
Eur Child Adolesc Psychiatry. 2004 Feb;13(1):42-50.
Prader Willi Syndrome (PWS) is a neuro-genetic disorder. It has been reported that cases due to paternal deletion 15q11-13 (Del) behave differently to cases due to uniparental disomy (UPD). Comparison of the two forms of PWS has, to date, not included the frequency of autistic behaviours, even though there are reports of an association between maternal duplications of 15q11-13 and autism spectrum disorders (ASD). It was predicted that maternal UPD PWS cases would be more prone to ASD than Del PWS cases due to their duplicated maternally expressed genes. A preliminary test of the hypothesis was conducted using postal and telephone surveys of matched, genetically verified, UPD and Del cases using the Autism Screening Questionnaire (ASQ) and the Vineland Adaptive Behaviour Scales (VABS). As predicted, UPD cases were reported as exhibiting significantly more autistic symptomatology. They also were born to older mothers and were reported on the VABS to have more deficits in motor control problems and fewer adaptive skills in the Daily Living Skills domain. Del cases were reportedly more skilled at jigsaw puzzles. The results lend further support to the notion that abnormality in the expression of maternal imprinted 15q11-13 genes may confer a susceptibility to ASD. They also suggest that there may be cognitive differences between the groups in processing visuo-spatial information. [Abstract]

Smith M, Filipek PA, Wu C, Bocian M, Hakim S, Modahl C, Spence MA
Analysis of a 1-megabase deletion in 15q22-q23 in an autistic patient: identification of candidate genes for autism and of homologous DNA segments in 15q22-q23 and 15q11-q13.
Am J Med Genet. 2000 Dec 4;96(6):765-70.
We have identified a one megabase deletion in the 15q22-15q23 region in a patient with autism, developmental delay, and mild dysmorphism. Genes that map within the deletion region and genes that are interrupted or rearranged at the deletion breakpoints are candidate genes for autism. Fluroescence in situ hybridization studies in this patient revealed that part or all of the PML gene is absent from one chromosome 15 and a BAC clone containing the D15S124 gene locus hybridizes to only one chromosome 15. BAC clones containing the PTPN9, and SLP-1[hUNC24] genes showed markedly reduced hybridization in the 15q22-q23 region on one chromosome 15 in the patient. These BACs also hybridize to the 15q11-q13 region in close proximity to SNRPN and HERC2, and in this region there is equal intensity of signal on the normal and on the deleted chromosome. There are previous reports of deletions and duplications of the 15q11-q13 region in patients with autism. Our patient represents the first report of a 15q22-q23 deletion. Hybridization of the PTPN9 and Slp-1 Bac clones to the 15q11-q13 and the 15q22-q23 regions of chromosome 15 may be due to the presence of PTPN9 or SLP-1 gene sequences or to the presence of other gene sequences or to non-coding homologous DNA sequences. The PTPN9 gene encodes a non-receptor protein tyrosine phosphatase. The Slp-1 [hUNC24] gene is expressed mainly in the brain. [Abstract]

Filipek PA, Juranek J, Smith M, Mays LZ, Ramos ER, Bocian M, Masser-Frye D, Laulhere TM, Modahl C, Spence MA, Gargus JJ
Mitochondrial dysfunction in autistic patients with 15q inverted duplication.
Ann Neurol. 2003 Jun;53(6):801-4.
Two autistic children with a chromosome 15q11-q13 inverted duplication are presented. Both had uneventful perinatal courses, normal electroencephalogram and magnetic resonance imaging scans, moderate motor delay, lethargy, severe hypotonia, and modest lactic acidosis. Both had muscle mitochondrial enzyme assays that showed a pronounced mitochondrial hyperproliferation and a partial respiratory chain block most parsimoniously placed at the level of complex III, suggesting candidate gene loci for autism within the critical region may affect pathways influencing mitochondrial function. [Abstract]

Graf WD, Marin-Garcia J, Gao HG, Pizzo S, Naviaux RK, Markusic D, Barshop BA, Courchesne E, Haas RH
Autism associated with the mitochondrial DNA G8363A transfer RNA(Lys) mutation.
J Child Neurol. 2000 Jun;15(6):357-61.
We report a family with a heterogeneous group of neurologic disorders associated with the mitochondrial DNA G8363A transfer ribonucleic acid (RNA)Lys mutation. The phenotype of one child in the family was consistent with autism. During his second year of life, he lost previously acquired language skills and developed marked hyperactivity with toe-walking, abnormal reciprocal social interaction, stereotyped mannerisms, restricted interests, self-injurious behavior, and seizures. Brain magnetic resonance imaging (MRI) and repeated serum lactate studies were normal. His older sister developed signs of Leigh syndrome with progressive ataxia, myoclonus, seizures, and cognitive regression. Her laboratory studies revealed increased MRI T2-weighted signal in the putamen and posterior medulla, elevated lactate in serum and cerebrospinal fluid, and absence of cytochrome c oxidase staining in muscle histochemistry. Molecular analysis in her revealed the G8363A mutation of the mitochondrial transfer RNA(Lys) gene in blood (82% mutant mitochondrial DNA) and muscle (86%). The proportions of mutant mitochondrial DNA from her brother with autism were lower (blood 60%, muscle 61%). It is likely that the origin of his autism phenotype is the pathogenic G8363A mitochondrial DNA mutation. This observation suggests that certain mitochondrial point mutations could be the basis for autism in some individuals. [Abstract]

Barrett S, Beck JC, Bernier R, Bisson E, Braun TA, Casavant TL, Childress D, Folstein SE, Garcia M, Gardiner MB, Gilman S, Haines JL, Hopkins K, Landa R, Meyer NH, Mullane JA, Nishimura DY, Palmer P, Piven J, Purdy J, Santangelo SL, Searby C, Sheffield V, Singleton J, Slager S, et al.
An autosomal genomic screen for autism. Collaborative linkage study of autism.
Am J Med Genet. 1999 Dec 15;88(6):609-15.
Autism is a severe neurodevelopmental disorder defined by social and communication deficits and ritualistic-repetitive behaviors that are detectable in early childhood. The etiology of idiopathic autism is strongly genetic, and oligogenic transmission is likely. The first stage of a two-stage genomic screen for autism was carried out by the Collaborative Linkage Study of Autism on individuals affected with autism from 75 families ascertained through an affected sib-pair. The strongest multipoint results were for regions on chromosomes 13 and 7. The highest maximum multipoint heterogeneity LOD (MMLS/het) score is 3.0 at D13S800 (approximately 55 cM from the telomere) under the recessive model, with an estimated 35% of families linked to this locus. The next highest peak is an MMLS/het score of 2.3 at 19 cM, between D13S217 and D13S1229. Our third highest MMLS/het score of 2.2 is on chromosome 7 and is consistent with the International Molecular Genetic Study of Autism Consortium report of a possible susceptibility locus somewhere within 7q31-33. These regions and others will be followed up in the second stage of our study by typing additional markers in both the original and a second set of identically ascertained autism families, which are currently being collected. By comparing results across a number of studies, we expect to be able to narrow our search for autism susceptibility genes to a small number of genomic regions. [Abstract]

Shao Y, Wolpert CM, Raiford KL, Menold MM, Donnelly SL, Ravan SA, Bass MP, McClain C, von Wendt L, Vance JM, Abramson RH, Wright HH, Ashley-Koch A, Gilbert JR, DeLong RG, Cuccaro ML, Pericak-Vance MA
Genomic screen and follow-up analysis for autistic disorder.
Am J Med Genet. 2002 Jan 8;114(1):99-105.
Autistic disorder (AutD) is a neurodevelopmental disorder characterized by significant impairment in social, communicative, and behavioral functioning. A genetic basis for AutD is well established with as many as 10 genes postulated to contribute to its underlying etiology. We have completed a genomic screen and follow-up analysis to identify potential AutD susceptibility loci. In stage one of the genome screen, 52 multiplex families (two or more AutD affected individuals/family) were genotyped with 352 genetic markers to yield an approximately 10 centimorgan (cM) grid, inclusive of the X chromosome. The selection criterion for follow-up of interesting regions was a maximum heterogeneity lod score (MLOD) or a maximum nonparametric sib pair lod score (MLS) of at least 1.0. Eight promising regions were identified on chromosomes 2, 3, 7, 15, 18, 19, and X. In the stage two follow-up study we analyzed an additional 47 multiplex families (total=99 families). Regions on chromosomes 2, 3, 7, 15, 19, and X remained interesting (MLOD> or =1.0) in stage two analysis. The peak lod score regions on chromosomes 2, 7, 15, 19, and X overlap previously reported peak linkage areas. The region on chromosome 3 is unique. [Abstract]

Buxbaum JD, Silverman J, Keddache M, Smith CJ, Hollander E, Ramoz N, Reichert JG
Linkage analysis for autism in a subset families with obsessive-compulsive behaviors: evidence for an autism susceptibility gene on chromosome 1 and further support for susceptibility genes on chromosome 6 and 19.
Mol Psychiatry. 2004 Feb;9(2):144-50.
Although there is considerable evidence for a strong genetic component to idiopathic autism, several genome-wide screens for susceptibility genes have been carried out with limited concordance of linked loci, reflecting numerous genes of weak effect and/or sample heterogeneity. In the current study, linkage analysis was carried out in a sample of 62 autism-affected relative pairs with more severe obsessive-compulsive behaviors, selected from a larger (n=115) set of autism-affected relative pairs as a means of reducing sample heterogeneity. Obsessive-compulsive behaviors were assessed using the Autism Diagnostic Interview-Revised (ADI-R). In the sample with more severe obsessive-compulsive behaviors, multipoint NPL scores above 2 were observed on chromosomes 1, 4, 5, 6, 10, 11 and 19, with the strongest evidence for linkage on chromosome 1 at the marker D1S1656, where the multipoint NPL score was 3.06, and the two-point NPL score was 3.21. In follow-up analyses, analyzing the subset of families (n=35) where the patients had the most severe obsessive-compulsive behaviors generated a multipoint NPL score of 2.76, and a two-point NPL score of 2.79, indicating that the bulk of evidence for linkage was derived from the families most severely affected with obsessive-compulsive behaviors. The data suggest that there is an autism susceptibility gene on chromosome 1 and provide further support for the presence of autism susceptibility genes on chromosomes 6 and 19. [Abstract]

Yonan AL, Alarcón M, Cheng R, Magnusson PK, Spence SJ, Palmer AA, Grunn A, Juo SH, Terwilliger JD, Liu J, Cantor RM, Geschwind DH, Gilliam TC
A genomewide screen of 345 families for autism-susceptibility loci.
Am J Hum Genet. 2003 Oct;73(4):886-97.
We previously reported a genomewide scan to identify autism-susceptibility loci in 110 multiplex families, showing suggestive evidence (P <.01) for linkage to autism-spectrum disorders (ASD) on chromosomes 5, 8, 16, 19, and X and showing nominal evidence (P <.05) on several additional chromosomes (2, 3, 4, 10, 11, 12, 15, 18, and 20). In this follow-up analysis we have increased the sample size threefold, while holding the study design constant, so that we now report 345 multiplex families, each with at least two siblings affected with autism or ASD phenotype. Along with 235 new multiplex families, 73 new microsatellite markers were also added in 10 regions, thereby increasing the marker density at these strategic locations from 10 cM to approximately 2 cM and bringing the total number of markers to 408 over the entire genome. Multipoint maximum LOD scores (MLS) obtained from affected-sib-pair analysis of all 345 families yielded suggestive evidence for linkage on chromosomes 17, 5, 11, 4, and 8 (listed in order by MLS) (P <.01). The most significant findings were an MLS of 2.83 (P =.00029) on chromosome 17q, near the serotonin transporter (5-hydroxytryptamine transporter [5-HTT]), and an MLS of 2.54 (P =.00059) on 5p. The present follow-up genome scan, which used a consistent research design across studies and examined the largest ASD sample collection reported to date, gave either equivalent or marginally increased evidence for linkage at several chromosomal regions implicated in our previous scan but eliminated evidence for linkage at other regions. [Abstract]

International Molecular Genetic Study of Autism Consortium (IMGSAC).
A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p.
Am J Hum Genet. 2001 Sep;69(3):570-81.
Autism is characterized by impairments in reciprocal communication and social interaction and by repetitive and stereotyped patterns of activities and interests. Evidence for a strong underlying genetic predisposition comes from twin and family studies, although susceptibility genes have not yet been identified. A whole-genome screen for linkage, using 83 sib pairs with autism, has been completed, and 119 markers have been genotyped in 13 candidate regions in a further 69 sib pairs. The addition of new families and markers provides further support for previous reports of linkages on chromosomes 7q and 16p. Two new regions of linkage have also been identified on chromosomes 2q and 17q. The most significant finding was a multipoint maximum LOD score (MLS) of 3.74 at marker D2S2188 on chromosome 2; this MLS increased to 4.80 when only sib pairs fulfilling strict diagnostic criteria were included. The susceptibility region on chromosome 7 was the next most significant, generating a multipoint MLS of 3.20 at marker D7S477. Chromosome 16 generated a multipoint MLS of 2.93 at D16S3102, whereas chromosome 17 generated a multipoint MLS of 2.34 at HTTINT2. With the addition of new families, there was no increased allele sharing at a number of other loci originally showing some evidence of linkage. These results support the continuing collection of multiplex sib-pair families to identify autism-susceptibility genes. [Abstract]

Auranen M, Nieminen T, Majuri S, Vanhala R, Peltonen L, Järvelä I
Analysis of autism susceptibility gene loci on chromosomes 1p, 4p, 6q, 7q, 13q, 15q, 16p, 17q, 19q and 22q in Finnish multiplex families.
Mol Psychiatry. 2000 May;5(3):320-2.
The role of genetic factors in the etiology of the autistic spectrum of disorders has clearly been demonstrated. Ten chromosomal regions, on chromosomes 1p, 4p, 6q, 7q, 13q, 15q, 16p, 17q, 19q and 22q have potentially been linked to autism.1-8 We have analyzed these chromosomal regions in a total of 17 multiplex families with autism originating from the isolated Finnish population by pairwise linkage analysis and sib-pair analysis. Mild evidence for putative contribution was found only with the 1p chromosomal region in the susceptibility to autism. Our data suggest that additional gene loci exist for autism which will be detectable in and even restricted to the isolated Finnish population. [Abstract]

Risch N, Spiker D, Lotspeich L, Nouri N, Hinds D, Hallmayer J, Kalaydjieva L, McCague P, Dimiceli S, Pitts T, Nguyen L, Yang J, Harper C, Thorpe D, Vermeer S, Young H, Hebert J, Lin A, Ferguson J, Chiotti C, Wiese-Slater S, Rogers T, Salmon B, Nicholas P, Myers RM
A genomic screen of autism: evidence for a multilocus etiology.
Am J Hum Genet. 1999 Aug;65(2):493-507.
We have conducted a genome screen of autism, by linkage analysis in an initial set of 90 multiplex sibships, with parents, containing 97 independent affected sib pairs (ASPs), with follow-up in 49 additional multiplex sibships, containing 50 ASPs. In total, 519 markers were genotyped, including 362 for the initial screen, and an additional 157 were genotyped in the follow-up. As a control, we also included in the analysis unaffected sibs, which provided 51 discordant sib pairs (DSPs) for the initial screen and 29 for the follow-up. In the initial phase of the work, we observed increased identity by descent (IBD) in the ASPs (sharing of 51.6%) compared with the DSPs (sharing of 50.8%). The excess sharing in the ASPs could not be attributed to the effect of a small number of loci but, rather, was due to the modest increase in the entire distribution of IBD. These results are most compatible with a model specifying a large number of loci (perhaps >/=15) and are less compatible with models specifying </=10 loci. The largest LOD score obtained in the initial scan was for a marker on chromosome 1p; this region also showed positive sharing in the replication family set, giving a maximum multipoint LOD score of 2.15 for both sets combined. Thus, there may exist a gene of moderate effect in this region. We had only modestly positive or negative linkage evidence in candidate regions identified in other studies. Our results suggest that positional cloning of susceptibility loci by linkage analysis may be a formidable task and that other approaches may be necessary. [Abstract]

Keller K, Williams C, Wharton P, Paulk M, Bent-Williams A, Gray B, Ward A, Stalker H, Wallace M, Carter R, Zori R
Routine cytogenetic and FISH studies for 17p11/15q11 duplications and subtelomeric rearrangement studies in children with autism spectrum disorders.
Am J Med Genet. 2003 Mar 1;117A(2):105-11.
To assess the frequency of cytogenetic abnormalities in children with autism spectrum disorders (ASDs), routine G-banded cytogenetic analyses and FISH studies to rule out 15q11.2 and 17p11.2 duplications were performed on 49 children with ASDs. Blood samples were further studied using a complete set of subtelomeric FISH probes. Routine chromosome study showed that one child had a small duplication of chromosome 5: 46,XY,dup(5)(p?14.2p?15.1). Another child had an interstitial duplication of the Prader-Willi and Angelman syndrome critical region of chromosome 15, detected by FISH analysis. The detection of these two cases underscores the importance of obtaining routine chromosome and 15q11-q13 FISH analyses in children with ASDs. No instance of 17p11.2 duplication was observed. Subtelomeric analysis did not reveal abnormalities in any of the subjects. [Abstract]

Shaffer LG, McCaskill C, Hersh JH, Greenberg F, Lupski JR
A clinical and molecular study of mosaicism for trisomy 17.
Hum Genet. 1996 Jan;97(1):69-72.
Trisomy 17 has never been reported in a live birth. We present a case of mosaic trisomy 17 in a male presenting with mental retardation, seizures, attention deficit hyperactivity and autistic disorders, hearing loss, growth retardation, microcephaly, and minor anomalies. Although peripheral blood lymphocyte chromosomes were normal, trisomy 17 was present in the skin fibroblasts. The percentage of abnormal cells appears to have increased from 18% in an initial skin biopsy at age 3 years 8 months to 80% at age 8 years 8 months. Molecular analysis using 13 highly polymorphic markers spanning the length of chromosome 17 demonstrated the extra chromosome 17 in the skin to be of paternal origin. Three alleles were never seen in the trisomic cell line, suggesting that the extra chromosome arose through a mitotic duplication error after conception. Uniparental disomy was excluded in the euploid blood sample. Although Smith-Magenis syndrome involves a deletion of proximal 17p, some of the clinical features of this mosaic trisomy 17 patient, such as decreased REM sleep and increased tolerance to pain, are suggestive of phenotypic features observed in Smith-Magenis syndrome. We speculate that there are dosage-sensitive genes located in 17p11.2 that produce these phenotypes for either deficiencies or over-expression of their gene products. [Abstract]

Vostanis P, Harrington R, Prendergast M, Farndon P
Case reports of autism with interstitial deletion of chromosome 17 (p11.2 p11.2) and monosomy of chromosome 5 (5pter-->5p15.3).
Psychiatr Genet. 1994 Summer;4(2):109-11.
Two cases of autism and autosomal chromosome abnormalities are reported: a 14-year-old boy with interstitial deletion of chromosome 17 and a 19-year-old man with an unbalanced translocation of chromosome 5, resulting in monosomy for part of the short arm (5pter-->5p15.3). The possible implications for research into the aetiology of autism are discussed. [Abstract]

Geerts M, Steyaert J, Fryns JP
The XYY syndrome: a follow-up study on 38 boys.
Genet Couns. 2003;14(3):267-79.
In the last decade there has been a significant increase in the proportion of XYY males detected prenatally, mostly as a fortuitous finding. It is of utmost importance to obtain a clear idea of the developmental profile of boys with karyotype 47,XYY and of possible problem areas during further development in order to inform the parents correctly during pregnancy and to provide an adequate surveillance later on. In this study we observed 38 XYY males, of which 12 were diagnosed prenatally. We found that these patients are at considerably increased risk for delayed language--and/or motor development. From birth on, weight, height and head circumference are above average values. The majority attends kindergarten in the normal education circuit although in 50% of the cases psychosocial problems are documented. From primary school age on, there is an increased risk for child psychiatric disorders such as autism. Moreover, although normally intelligent, many of these boys are referred to special education programmes. [Abstract]

Nicolson R, Bhalerao S, Sloman L
47,XYY karyotypes and pervasive developmental disorders.
Can J Psychiatry. 1998 Aug;43(6):619-22.
OBJECTIVE: The presence of a 47, XYY karyotype in boys with pervasive developmental disorders (PDDs) has rarely been described in the past. Herein, 2 boys with PDDs and a supernumerary Y chromosome are presented. METHODS: The case histories of the 2 patients are described along with the results of associated testing. The literature on psychosocial development as well as brain morphology and physiology in males with 47, XYY karyotypes is reviewed. RESULTS: Both boys had presentations typical of PDDs, one with autistic disorder and the other with PDD not otherwise specified. CONCLUSION: The finding that, in a clinic for children with developmental disorders, 2 of 40 male referrals had 47, XYY karyotypes suggests that the rate of this sex chromosome anomaly may be increased in PDDs. An extra Y chromosome may be related to abnormal brain development, which may, in turn, predispose vulnerable males to PDDs. [Abstract]

Gillberg C, Winnergård I, Wahlström J
The sex chromosomes--one key to autism? An XYY case of infantile autism.
Appl Res Ment Retard. 1984;5(3):353-60.
Genetic/chromosomal factors have recently been proposed as being of importance in many children presenting with the behavioral syndrome of infantile autism. There are several single case studies in the literature of childhood psychosis in connection with the XYY syndrome. A further case of this combination is described. It is suggested that the sex chromosomes may be of major importance in the genesis of some cases of autism. [Abstract]

Weidmer-Mikhail E, Sheldon S, Ghaziuddin M
Chromosomes in autism and related pervasive developmental disorders: a cytogenetic study.
J Intellect Disabil Res. 1998 Feb;42 ( Pt 1)8-12.
Few studies have examined the occurrence of chromosome abnormalities in a large sample of patients with autism and related pervasive developmental disorders (PDDs). In the present report, the authors examined a consecutive series of 92 children with PDDs (DSM-III-R; 75 males and 17 females). A cytogenetic examination, including growth in folate deficient medium, was performed in all cases. Three patients (3.2%) (two females and one male) showed chromosome abnormalities: deletion of the long arm of chromosome 8; tetrasomy of chromosome 15; and XYY syndrome. Only the subject who had tetrasomy 15 met the criteria for autistic disorder, while the other were diagnosed as suffering from a PDD not otherwise specified (PDDNOS). Another patient showed an abnormal fragile site at Xq27 in three out of 100 cells. However, subsequent molecular studies did not confirm the presence of fragile-X syndrome. These results suggest that chromosome abnormalities are uncommon in traditional autism and may be relatively more common in people with PDDNOS. [Abstract]

Blackman JA, Selzer SC, Patil S, Van Dyke DC
Autistic disorder associated with an iso-dicentric Y chromosome.
Dev Med Child Neurol. 1991 Feb;33(2):162-6.
The relationship between a fragile site on the X chromosome and autism has been well documented. The authors report a three-year-old child with partial duplication of the short arm of chromosome Y, who had an autistic disorder. He was microcephalic, but otherwise had a normal phenotype. There was a history of preterm birth and maternal diabetes. This is the sixth case of sex chromosome Y aneuploidy associated with autism, but the first with an isodicentric Y. In well-substantiated cases of autism, clinicians should now consider abnormalities of the Y as well as the X chromosome. [Abstract]

Manning MA, Cassidy SB, Clericuzio C, Cherry AM, Schwartz S, Hudgins L, Enns GM, Hoyme HE
Terminal 22q deletion syndrome: a newly recognized cause of speech and language disability in the autism spectrum.
Pediatrics. 2004 Aug;114(2):451-7.
OBJECTIVE: Cryptic subtelomeric chromosome rearrangements account for 6% to 10% of idiopathic mental retardation. As cytogenetic and molecular techniques have become more sophisticated, the number of genetic syndromes attributed to these microdeletions has increased. To date, 64 patients have been described in the literature with a more recently recognized microdeletion syndrome, del 22q13.3. The purpose of this study is to present 11 new cases of this recently described syndrome to delineate further the phenotype and to alert the clinician to another genetic condition that should be considered in the differential diagnosis of early hypotonia, delayed speech acquisition, and autistic behavior. METHODS: Eleven patients were evaluated in 3 academic institutions. Clinical features and results of cytogenetic testing were recorded and tabulated. Reasons for referral for genetic evaluation included developmental delay, severe expressive speech and language delay, and dysmorphic features. RESULTS: Age of presentation ranged from 5 months to 46 years. There were 10 female patients and 1 male patient. All of the patients exhibited delayed motor development, some degree of hypotonia, and severe expressive speech and language delay. Dysmorphic facial features included epicanthal folds, large cupped ears, underdeveloped philtrum, loss of cupid's bow, and full supraorbital ridges. Six patients exhibited autistic-like behaviors. Microscopically visible chromosome deletions were observed in 6 patients. In the remainder, the deletion was detected with the use of fluorescence in situ hybridization. CONCLUSIONS: Hypotonia and developmental delay are nonspecific findings observed in many malformation and genetic syndromes. However, in association with severe speech and language delay and autistic-like behavior, this phenotype may be a significant indication to consider the 22q13 deletion syndrome as a potential cause. [Abstract]

Goizet C, Excoffier E, Taine L, Taupiac E, El Moneim AA, Arveiler B, Bouvard M, Lacombe D
Case with autistic syndrome and chromosome 22q13.3 deletion detected by FISH.
Am J Med Genet. 2000 Dec 4;96(6):839-44.
Autism is a rare neurodevelopmental disorder with a strong genetic component. Co-occurrence of autism and chromosomal abnormalities is useful to localize candidate regions that may include gene(s) implicated in autism determinism. Several candidate chromosomal regions are known, but association of chromosome 22 abnormalities with autism is unusual. We report a child with autistic syndrome and a de novo 22q13.3 cryptic deletion detected by FISH. Previously described cases with 22q13.3 deletions shared characteristic developmental and speech delay, but autism was not specifically reported. This case emphasizes a new candidate region that may bear a gene involved in autism etiopathogenesis. Abstract]

Ogilvie CM, Moore J, Daker M, Palferman S, Docherty Z
Chromosome 22q11 deletions are not found in autistic patients identified using strict diagnostic criteria. IMGSAC. International Molecular Genetics Study of Autism Consortium.
Am J Med Genet. 2000 Feb 7;96(1):15-7.
A group of 103 subjects with a strict diagnosis of autism were tested for deletion of band q11.2 on the long arm of chromosome 22. No deletions were found, indicating that when a patient has been diagnosed with autism using strict and consistent criteria, in the absence of other indications, it is unlikely that this individual will have a 22q11 deletion. Testing for 22q11 deletions is therefore unlikely to be necessary in these patients. [Abstract]

Carratalá F, Galán F, Moya M, Estivill X, Pritchard MA, Llevadot R, Nadal M, Gratacòs M
A patient with autistic disorder and a 20/22 chromosomal translocation.
Dev Med Child Neurol. 1998 Jul;40(7):492-5.
The case history of a 3-year-old boy without speech and who met 10 criteria of an autistic condition (DSM-IV) (American Psychiatric Association 1994) is reported. Psychometric evaluation, excluding the verbal scale, resulted in an IQ score of 56. The cytogenetic study showed a 20/22 translocation and an interstitial deletion within the region 22q11: 45,XY, -22, +der(20), t(20;22) (q13.3;q11.2), which was confirmed by fluorescence in situ hybridisation (FISH). Although deletions at 22q11 are responsible for the DiGeorge syndrome; clinical, metabolic, and neurological image studies of the patient were inconsistent with this syndrome. In the clinical examination the patient presented with a mildly dysmorphic facies, pectus excavatum, and a short thumb. A 99mTc HMPAO brain perfusion SPECT showed a hypoperfusion of the left temporoparietal cortex. As there have been no previous reports of autistic patients with abnormalities involving both chromosomes 20 and 22, these findings merit some discussion either as a possible cause of autism or as accompanying factors. [Abstract]

Sultana R, Yu CE, Yu J, Munson J, Chen D, Hua W, Estes A, Cortes F, de la Barra F, Yu D, Haider ST, Trask BJ, Green ED, Raskind WH, Disteche CM, Wijsman E, Dawson G, Storm DR, Schellenberg GD, Villacres EC
Identification of a novel gene on chromosome 7q11.2 interrupted by a translocation breakpoint in a pair of autistic twins.
Genomics. 2002 Aug;80(2):129-34.
We report here the identification and characterization of a novel gene (AUTS2) that spans the 7q11.2 breakpoint in a monozygotic twin pair concordant for autism and a t(7;20) (q11.2; p11.2) translocation. AUTS2 is 1.2 Mb and has 19 exons. The predicted protein is 1295 amino acids and does not correspond to any known protein. DNA sequence analysis of autism subjects and controls revealed 22 biallelic polymorphic sites. For all sites, both alleles were observed in both cases and controls. Thus no autism-specific mutation was observed. Association analysis with two exonic polymorphic sites and linkage analysis of four dinucleotide repeat markers, two within and two flanking AUTS2, was negative. Thus, although it is unlikely that AUTS2 is an autism susceptibility gene for idiopathic autism, it may be the gene responsible for the disorder in the twins studied here. [Abstract]

Michaelis RC, Skinner SA, Deason R, Skinner C, Moore CL, Phelan MC
Intersitial deletion of 20p: new candidate region for Hirschsprung disease and autism?
Am J Med Genet. 1997 Aug 22;71(3):298-304.
We describe a patient with Hirschsprung disease and autism. High-resolution karyotyping indicated that the patient has an interstitial deletion of 20p11.22-p11.23. Microsatellite analysis showed a deletion involving a 5-6 cM region from the maternally derived chromosome 20. The deleted region is proximal to, and does not overlap, the recently characterized Alagille syndrome region. This region of 20p has not yet been implicated in Hirschsprung disease or autism. However, this region contains several genes that could plausibly contribute to any phenotype that includes abnormal neural development. [Abstract]

Pescucci C, Meloni I, Bruttini M, Ariani F, Longo I, Mari F, Canitano R, Hayek G, Zappella M, Renieri A
Chromosome 2 deletion encompassing the MAP2 gene in a patient with autism and Rett-like features.
Clin Genet. 2003 Dec;64(6):497-501.
We present here a unique case of a 14-year-old female with autism and some features similar to Rett syndrome (RTT). Genetic analysis demonstrated a large deletion of chromosome 2q instead of a MECP2 mutation. Like a Rett patient, she is dyspraxic and shows frequent hand-washing stereotypic activities, hyperpnea, and bruxism. Like a preserved speech variant (PSV) of RTT, she is obese, able to speak in second and third persons, frequently echolalic, and has final normal head circumference and autistic behavior. In addition, she has dysmorphic features such as down-slanting palpebral fissures, low set ears without lobuli, bilateral flat feet, and bilateral syndactyly of the second and third toes, which do not belong to the Rett spectrum. She has a de novo chromosomal deletion in 2q34 of paternal origin. Gene content analysis of the deleted region showed the presence of 47 genes (14 putative and 33 known genes). This region contains some interesting genes such as ADAM23/MDC3, CREB1, KLF7, and MAP2. Because alteration of neuronal maturation, dendritic anomalies, and a decrease in MAP2 immunoreactivity in white matter neurons are well documented in RTT patients, we propose MAP2 gene as a good candidate for the generation of PSV phenotype in this case. [Abstract]

Borg I, Squire M, Menzel C, Stout K, Morgan D, Willatt L, O'Brien PC, Ferguson-Smith MA, Ropers HH, Tommerup N, Kalscheuer VM, Sargan DR
A cryptic deletion of 2q35 including part of the PAX3 gene detected by breakpoint mapping in a child with autism and a de novo 2;8 translocation.
J Med Genet. 2002 Jun;39(6):391-9.
We report a de novo, apparently balanced (2;8)(q35;q21.2) translocation in a boy with developmental delay and autism. Cross species (colour) paint (Rx) and SKY FISH, forward and reverse chromosome painting, and FISH with subtelomeric probes were used to examine the patient's karyotype, but further rearrangements were not detected. FISH with region specific clones mapping near 2q35 and 8q21.2 breakpoints and STS mapping performed on the isolated derivative chromosomes were used to refine the location of the breakpoints further. A cryptic deletion of between 4.23 and 4.41 Mb in extent and involving at least 13 complete genes or transcription units was found at the breakpoint on 2q35. The deletion includes the promoter and 5' untranslated region of the paired box 3 (PAX3) gene. The child has very mild dystopia canthorum which may be associated with the PAX3 haploinsufficiency. The 8q21.2 breakpoint is within MMP16 which encodes matrix metalloproteinase 16. We postulate that the cryptic deletion and rearrangement are responsible for the patient's phenotype and that a gene (or genes) responsible for autism lies at 2q35 or 8q21.2. The results present a step towards identifying genes predisposing to autism. [Abstract]

Gallagher L, Becker K, Kearney G, Dunlop A, Stallings R, Green A, Fitzgerald M, Gill M
Brief report: A case of autism associated with del(2)(q32.1q32.2) or (q32.2q32.3).
J Autism Dev Disord. 2003 Feb;33(1):105-8.
Autism is a neurodevelopmental disorder presenting in the first 3 years of life. Deficits occur in the three core areas of communication, social interaction, and behavior. The causes of autism are unknown, but clinical genetic studies show strong evidence in favor of a genetic etiology. Molecular genetic studies report some association with candidate genes, and candidate regions have emerged from several genome-wide linkage studies. Here we report a clinical case of autism with a deletion on chromosome 2 in a young male with high-functioning autism. The deletion seems to correspond with regions emerging from linkage studies. We propose this as a possible candidate region in the search for autism genes. [Abstract]

Burd L, Martsolf JT, Kerbeshian J, Jalal SM
Partial 6p trisomy associated with infantile autism.
Clin Genet. 1988 May;33(5):356-9.
Partial trisomy 6p with duplications ranging from 6p21 to 6p25-pter is emerging as an established syndrome. We report a case of duplication of 6p (6p23-pter) and deletion of 2q37-qter. Features characteristic of 6p partial trisomy present in the patient are low birthweight, and mental and developmental retardation. Major facial features include prominent forehead, flat occiput, multiple ocular abnormalities, low-set ears, prominent nasal bridge, long philtrum and small pointed mouth. Repeated examinations of the patient from birth to the age of over 5 years revealed that he has infantile autism. Since autistic children are generally not associated with chromosome anomalies, in view of the present case, it is suggested that karyotypic analysis be considered for such children. Where possible, extended study for autism in 6p trisomic children may also be desirable. [Abstract]

Smith M, Escamilla JR, Filipek P, Bocian ME, Modahl C, Flodman P, Spence MA
Molecular genetic delineation of 2q37.3 deletion in autism and osteodystrophy: report of a case and of new markers for deletion screening by PCR.
Cytogenet Cell Genet. 2001;94(1-2):15-22.
We recently studied a patient who meets criteria for autistic disorder and has a 2q37 deletion. Molecular cytogenetic studies were carried out using DNA isolated from 22 different 2q37 mapped BACs to more precisely define the extent of the chromosome deletion. We also analyzed 2q37 mapped polymorphic markers. In addition DNA sequences of BACs in the deletion region were scanned to identify microsatellite repeats. We describe four new polymorphic microsatellite repeat markers in the 2q37.3 region. These markers enabled us to determine the parental origin of the deletion in our patient. DNA from 8-13 unrelated individuals was used to determine heterozygosity estimates for these markers. We review four genes deleted in our patient - genes whose known functions and sites of expression in the brain and/or bone make them candidates for involvement in autism and/or the osteodystrophy observed in patients with 2q37.3 deletions. [Abstract]

Ghaziuddin M, Burmeister M
Deletion of chromosome 2q37 and autism: a distinct subtype?
J Autism Dev Disord. 1999 Jun;29(3):259-63.
Several reports have described the occurrence of chromosome abnormalities in autism, a neuro-developmental disorder characterized by social deficits, communication impairment, and a restricted range of interests. These include the fragile X abnormality and 15q duplications. In this report, we describe two cases of chromosome 2q37 and review the literature on this topic. We propose that deletion of the distal portion of the long arm of chromosome 2 (2q37) may be associated with some cases of autism and with a distinct phenotype. Increased awareness of the dysmorphic features associated with 2q37 deletions may aid in the molecular genetic analysis of this chromosome anomaly and clarify its relationship with autism. [Abstract]

Konstantareas MM, Homatidis S
Chromosomal abnormalities in a series of children with autistic disorder.
J Autism Dev Disord. 1999 Aug;29(4):275-85.
In a series of 127 children diagnosed with autistic disorder the karyotypes of 8, on whom data were available, showed the following chromosomal abnormalities: breakage, a 47 XY pattern, trisomy 13, inversion-duplication of chromosome 15, 47 XY, +der (15) (pter q15: p11 pter), 47 XXY and 46 XY, inv (2) (p11:q13pat, 3q+). Compared to those who were not karyotyped or had normal karyotypes, the children with abnormalities, although cognitively more delayed, were not rated as more severely autistic. Facial dysmorphias and minor physical anomalies tended to be more frequent in the chromosomally deviant subgroup. No differences in demographic characteristics or parental ages were evident. Results are consistent with the view of variability of expression of marker chromosome deviations and a greater severity of retardation and symptoms of autism in those affected. The relevance of the findings to a multimodal genetic etiology of autistic disorder is discussed. [Abstract]

Sauter S, von Beust G, Burfeind P, Weise A, Starke H, Liehr T, Zoll B
Autistic disorder and chromosomal mosaicism 46,XY[123]/46,XY,del(20)(pter --> p12.2)[10].
Am J Med Genet. 2003 Aug 1;120A(4):533-6.
We report on a 3-year-old boy with a moderate to severe mental retardation, autistic behavior patterns, and myoclonic epilepsy of early childhood. The cytogenetic analysis of blood lymphocytes revealed a deletion of chromosome 20pter --> p12.2 occurring as mosaicism in 8% of the analyzed metaphases: 46,XY[123]/46,XY,del(20)(pter --> p12.2)[10]. The deletion was confirmed by the recently developed multicolor banding approach and additionally by region specific fluorescence in situ hybridization (FISH) probes. To the best of our knowledge, this is the first report on a patient with autistic behavior with terminal 20p deletion mosaicism reported up to present. [Abstract]

Oliveira G, Matoso E, Vicente A, Ribeiro P, Marques C, Ataíde A, Miguel T, Saraiva J, Carreira I
Partial tetrasomy of chromosome 3q and mosaicism in a child with autism.
J Autism Dev Disord. 2003 Apr;33(2):177-85.
In this report we describe the case of an 11-year-old male with autism and mental retardation, presenting a tetrasomy of chromosome 3q. Cytogenetic analysis showed a mosaic for an unbalanced karyotype consisting of mos46,XY,add(12)(p13.3)(56)/46,XY(45). FISH using WCP and subtelomeric probes identified the extra material on 12p to be an inverted duplication of the distal segment of chromosome 3q. Anomalies in chromosome 3q have not been previously described in association with autism, although association with psychomotor delays and behavior problems has been frequently reported and are here further discussed. This chromosomal 3q segment is therefore likely to include genes involved in specific neurodevelopment pathways, and further analysis of the region is warranted for the identification of the molecular alterations that lead to the autistic features described. [Abstract]

Sabaratnam M, Turk J, Vroegop P
Case report: autistic disorder and chromosomal abnormality 46, XX duplication (4) p12-p13.
Eur Child Adolesc Psychiatry. 2000 Dec;9(4):307-11.
We report an 18-year-old female with a diagnosis of DSM-IV Autistic Disorder and moderate to severe mental retardation who was discovered to have a previously undescribed chromosomal abnormality 46, XX, duplication (4) p12-p13. We discuss her history and diagnosis, noting that the co-occurrence of her diagnoses have not previously been documented. The report adds to the literature supporting the argument that individuals with autistic spectrum disorders should be re-examined for chromosomal abnormalities. [Abstract]

Wolpert CM, Donnelly SL, Cuccaro ML, Hedges DJ, Poole CP, Wright HH, Gilbert JR, Pericak-Vance MA
De novo partial duplication of chromosome 7p in a male with autistic disorder.
Am J Med Genet. 2001 Apr 8;105(3):222-5.
We describe a de novo partial duplication of 7p in a 25-year-old male with autistic disorder (AD). High-resolution chromosome analysis revealed an extra segment added to the proximal short arm of chromosome 7. The G-band pattern was consistent with an inverted duplication of 7p11.2-p14.1. Fluorescent in situ hybridization (FISH), using a whole chromosome 7 DNA probe (Cytocell, Inc., UK), confirmed that the extra chromosome material is derived from chromosome 7, indicating that the patient is partially trisomic for a region of the short arm of chromosome 7. Partial duplication of the short arm of chromosome 7 is uncommon with little more than 30 cases in the literature. This is the first report of an individual with a 7p duplication who also has AD. [Abstract]

Nasr A, Roy M
Association of a balanced chromosomal translocation (4; 12)(q21.3; q15), affective disorder and autism.
J Intellect Disabil Res. 2000 Apr;44 ( Pt 2)170-4.
This case report describes a set of monozygotic twins with severe intellectual disability, autism and affective disorder with a balanced translocation between chromosomes 4 and 12. Their mother, who carries the same balanced translocation, had severe postnatal depression. The association between autism affective disorder and these chromosome break points has not been reported previously. The implications are discussed. [Abstract]

Arrieta I, Núñez T, Martínez B, Pérez A, Télez M, Criado B, Gainza I, Lostao CM
Chromosomal fragility in a behavioral disorder.
Behav Genet. 2002 Nov;32(6):397-412.
Numerous studies have shown there is consistent evidence implicating genetic factors in the etiology of autism. In some cases chromosomal abnormalities have been identified. One type of these abnormalities is gaps and breaks nonrandomly located in chromosomes, denominated fragile sites (FS). We cytogenetically analyzed a group of autistic individuals and a normal population, and we examined the FS found in both samples with the aim of (1) comparing their FS expression, (2) ascertaining whether any FS could be associated with our autistic sample, and (3) examining if there are differences between individual and pooled-data analyses. Different statistical methods were used to analyse the FS of pooled and individual data. Our results show that there are statistically significant differences in the spontaneous expression of breakages between patients and controls, with a minimal sex difference. Using the method for pooled data, eight autosomal FS have preferential expression in patients and five patients were found to be positive at FS Xq27.3. With the method per-individual analysis, four FS emerged as specific in our autistic sample. Inferences of FS from pooled data were different from those of individual data. The findings suggest that although analysis of pooled data is necessitated by the problem of sparse data, analysis of single individuals is essential to know the significance of FS in autism. [Abstract]

MacLean JE, Teshima IE, Szatmari P, Nowaczyk MJ
Ring chromosome 22 and autism: report and review.
Am J Med Genet. 2000 Feb 28;90(5):382-5.
Ring chromosome 22 has been described in over 50 cases. A characteristic phenotype has not been fully delineated; however, long face, thick eyebrows, 2-3 toe syndactyly, mental retardation, adequate somatic growth and the absence of major malformations are noted in many cases. An 11-year-old boy with ring chromosome 22 and 46,XY,r(22)(p11.31-q13.31 approximately q13.33) karyotype presented with global developmental delay, autistic disorder, and dolichocephaly, apparently low-set and large ears, midface hypoplasia, and 2-3 toe syndactyly. This is the second report of a ring chromosome 22 with autistic disorder. There appears to be an association between abnormalities of chromosome 22, including r(22), and autistic disorder; however, this occurrence may be a result of the association of autistic disorder with mental retardation rather than specifically due to r(22). The physical findings in this case also suggest that ring chromosome 22 causes a subtle but distinct phenotype which has previously been proposed. [Abstract]

Assumpcão Júnior FB
Brief report: a case of chromosome 22 alteration associated with autistic syndrome.
J Autism Dev Disord. 1998 Jun;28(3):253-6.
The author described a male patient, age 13 years and 5 months, with behavioral profile meeting the criteria of the autistic syndrome by the DSM-III-R (APA, 1989) and DSM-IV (APA, 1995). After clinical and laboratory examinations, it was found that he had an abnormal karyotype, 46 XY, R(22). The need for clinical and laboratory case studies of autism is of great importance to develop data for defining an etiological basis for diagnosis. [Abstract]

Ghaziuddin M, Sheldon S, Tsai LY, Alessi N
Abnormalities of chromosome 18 in a girl with mental retardation and autistic disorder.
J Intellect Disabil Res. 1993 Jun;37 ( Pt 3)313-7.
Structural autosome defects have rarely been described in autism. In this report, the authors describe the association of autism and mental retardation in a girl with mosaicism for a duplication of the long arm of chromosome 18 and a deletion of the short arm of chromosome 18. [Abstract]

Seshadri K, Wallerstein R, Burack G
18q- chromosomal abnormality in a phenotypically normal 2 1/2-year-old male with autism.
Dev Med Child Neurol. 1992 Nov;34(11):1005-9.
The authors report the case of a 2 1/2-year-old male with autism, with an 18q- chromosomal abnormality in the absence of phenotypical features of the 18q- syndrome. It is suggested that clinicians evaluating children with autistic disorders consider obtaining chromosome analysis, even in the absence of phenotypical abnormalities. [Abstract]

Fryns JP, Kleczkowska A
Autism and ring chromosome 18 mosaicism.
Clin Genet. 1992 Jul;42(1):55. [Abstract]