Ingram JL, Stodgell CJ, Hyman SL, Figlewicz DA, Weitkamp LR,
Discovery of allelic variants of HOXA1 and
HOXB1: genetic susceptibility to autism spectrum disorders.
BACKGROUND: Family studies have demonstrated that the
autism spectrum disorders (ASDs) have a major genetic etiologic component, but
expression and penetrance of the phenotype are variable. Mice with null mutations
of Hoxa1 or Hoxb1, two genes critical to hindbrain development, have phenotypic
features frequently observed in autism, but no naturally occurring variants of
either gene have been identified in mammals. METHODS: By sequencing regions of
genomic DNA of patients with autism spectrum disorders, we detected a substitution
variant at HOXA1 and an insertion variant at HOXB1, both in coding regions of
the genes. Fifty-seven individuals ascertained for a diagnosis of an ASD, along
with 166 of their relatives, were typed for these variants. Two non-ASD populations
were typed, and the frequency of the newly identified alleles was determined in
all groups. The genotypes of the ASD families were tested for conformation to
Hardy-Weinberg proportions and Mendelian expectations for gene transmission. RESULTS:
The frequency of the variants was 10-25% in persons of European or African origin.
In the ASD families, there was a significant deviation from the HOXA1 genotype
ratios expected from Hardy-Weinberg proportions (P = 0.005). Among affected offspring,
a significant deviation from Mendelian expectation in gene transmission (P = 0.011)
was observed. No statistically significant effects were detected when the same
analyses were applied to the HOXB1 locus, but there was evidence of an interaction
between HOXA1, HOXB1, and gender in susceptibility to ASDs. CONCLUSIONS: The results
support a role for HOXA1 in susceptibility to autism, and add to the existing
body of evidence implicating early brain stem injury in the etiology of ASDs.
L, Hawi Z, Kearney G, Fitzgerald M, Gill M
between allelic variants of HOXA1/HOXB1 and autism.
J Med Genet. 2004 Jan 1;124B(1):64-7.
Two recent studies have reported conflicting
findings of association of a variant in the HOXA1 gene and autism. To try to resolve
the conflict in findings, we conducted an association study in 78 Irish families
of the reported DNA variants. We did not find statistically significant association
between the variants and autism. Similarly there was no evidence of preferential
transmission of variants from parent of either sex to affected offspring. We also
report negative findings for HOXB1 variants. We conclude that the HOXA1/B1 are
unlikely to be the susceptibility genes for autism in our sample. [Abstract]
JS, Schroer RJ, Bird J, Michaelis RC
The HOXA1 A218G
polymorphism and autism: lack of association in white and black patients from
the South Carolina Autism Project.
J Autism Dev Disord.
A recent study has suggested that the A218G polymorphism
in the homeobox A1 (HOXA1) gene may influence susceptibility to autism. We have
determined the frequencies of the A and G alleles of the HOXA1 A218G polymorphism
in both white and black patients from the South Carolina Autism Project (SCAP)
and controls. Marked differences were found in allele frequencies between the
races, but no deviations from Hardy-Weinberg equilibrium were seen in either white
or black SCAP family members. More direct tests, comparing genotype frequencies
between probands and controls and tracking transmission of the A versus G alleles
to affected offspring, did not support the contention that allele status for the
HOXA1 A218G polymorphism influences one's susceptibility to autism. [Abstract]
Z, Bittel DC, Miles JH, Takahashi N, Wang CH, Kibiryeva N, Butler MG
association between HOXA1 and HOXB1 genes and autism spectrum disorders (ASD).
Med Genet. 2002 Nov;39(11):e70. [Abstract]
B, Bennett P, Cook EH, Dawson G, Gonen D, Grigorenko EL, McMahon W, Pauls D, Smith
M, Spence MA, Schellenberg GD
No evidence for linkage
of liability to autism to HOXA1 in a sample from the CPEA network.
J Med Genet. 2002 Aug 8;114(6):667-72.
A recent study by Ingram et al. [2000b:
Teratology 62:393-405] suggests a (His)73(Arg) polymorphism (A:G) in HOXA1 contributes
substantially to a liability for autism. Using 68 individuals diagnosed with Autism
Spectrum Disorders, they found a significant dearth of G homozygotes and biased
transmission of G alleles from parents to affected offspring, especially from
mothers. Because the connection between HOXA1 and liability to autism is compelling,
we attempted to replicate their finding using a larger, independent sample from
the Collaborative Programs of Excellence in Autism (CPEA) network. In our data,
genotype frequencies conform to Hardy-Weinberg equilibrium; allele transmissions
meet Mendelian expectations; and there is no obvious sex-biased allele transmission.
Based on our sample size, calculations suggest that we would have at least 95%
power to detect linkage and association even if the A:G polymorphism were to account
for only 1% of the heritability of autism. Therefore, although we cannot exclude
the possibility that the samples in the two studies are intrinsically different,
our data from our sample argue against a major role for HOXA1 (His)73(Arg) in
liability to autism. [Abstract]
J, Tabor HK, Nguyen L, Gleason C, Lotspeich LJ, Spiker D, Risch N, Myers RM
of association between HoxA1 and HoxB1 gene variants and autism in 110 multiplex
Am J Med Genet. 2002 Jan 8;114(1):24-30.
recent report suggested that the HoxA1 and/or HoxB1 genes play a role in susceptibility
to autism. To determine whether these findings could be confirmed, we screened
these genes for DNA polymorphisms by sequencing all exons in 24 individuals with
autism. We identified the same sequence variants in the genes that appeared in
this report, which include one single-base substitution variant in HoxA1 and a
common haplotype in HoxB1. We performed an association study by applying the transmission
disequilibrium test to detect possible association of these variants to autism
in 110 multiplex families. Our results demonstrated no deviation from the null
hypothesis of no association. We have also separately examined transmissions within
individual mating types, for paternal versus maternal alleles, to affected versus
unaffected children, and for transmission to affected boys versus girls. None
of these subsets revealed significant deviation from the null expectation. Our
interpretation of these findings is that it is unlikely that HoxA1 and HoxB1 play
a significant role in the genetic predisposition to autism. [Abstract]
M, Stodgell CJ, Hyman SL, O'Bara M, Militerni R, Bravaccio C, Trillo S, Montecchi
F, Schneider C, Melmed R, Elia M, Crawford L, Spence SJ, Muscarella L, Guarnieri
V, D'Agruma L, Quattrone A, Zelante L, Rabinowitz D, Pascucci T, Puglisi-Allegra
S, Reichelt KL, Rodier PM, Persico AM
between the HOXA1 A218G polymorphism and increased head circumference in patients
Biol Psychiatry. 2004 Feb 15;55(4):413-9.
The HOXA1 gene plays a major role in brainstem and cranial morphogenesis. The
G allele of the HOXA1 A218G polymorphism has been previously found associated
with autism. METHODS: We performed case-control and family-based association analyses,
contrasting 127 autistic patients with 174 ethnically matched controls, and assessing
for allelic transmission disequilibrium in 189 complete trios. RESULTS: A, and
not G, alleles were associated with autism using both case-control (chi(2) = 8.96
and 5.71, 1 df, p <.005 and <.025 for genotypes and alleles, respectively),
and family-based (transmission/disequilibrium test chi(2) = 8.80, 1 df, p <.005)
association analyses. The head circumference of 31 patients carrying one or two
copies of the G allele displayed significantly larger median values (95.0th vs.
82.5th percentile, p <.05) and dramatically reduced interindividual variability
(p <.0001), compared with 166 patients carrying the A/A genotype. CONCLUSIONS:
The HOXA1 A218G polymorphism explains approximately 5% of the variance in the
head circumference of autistic patients and represents to our knowledge the first
known gene variant providing sizable contributions to cranial morphology. The
disease specificity of this finding is currently being investigated. Nonreplications
in genetic linkage/association studies could partly stem from the dyshomogeneous
distribution of an endophenotype morphologically defined by cranial circumference.
PM, Chen QL, Lai KY, Wong CK, Pang CP
CGG repeat interruptions
in the FMR1 gene in patients with infantile autism.
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]
K, Saijo T, Mori K, Kuroda Y
polymorphism analysis of the FMR1 gene in autistic and mentally retarded children
J Med Invest. 2004 Feb;51(1-2):52-8.
X syndrome is one of the most common causes of mental retardation in males, and
patients with fragile X syndrome occasionally develop autism. It is usually caused
by an expansion of the trinucleotide repeat in the 5'-untranslated region of the
FMR1 gene, but in a small number of patients deletions and point mutations have
been identified. We screened all 17 exons of the FMR1 gene for mutations in 90
autistic or mentally retarded children using polymerase chain reaction (PCR)-single
strand conformation polymorphism (SSCP) analysis. No mutations were found in 76
male patients. However, one female patient was heterozygous for a normal allele
and a mutant allele with an A to C substitution at nucleotide 879 in exon 9. This
mutation was not found in 50 controls. Reverse transcription-PCR revealed that
a large proportion of the mutant transcripts were spliced aberrantly, causing
premature termination of the protein synthesis. Although uncommon, point mutations
in the FMR1 gene may be a cause of autism and mental retardation in Japanese patients.
JB, Konecki DS, Munstermann E, Bolton P, Poustka A, Poustka F, Gurling HM
mutation analysis of the FMR-1 gene in autism.
Psychiatry. 1996 Jul;1(3):227-31.
We have analysed all 17 exons of the human
FMR-1 gene for mutations in autistic individuals using single-stranded conformational
polymorphism (SSCP) analysis. We have identified three new polymorphisms. SSCP
DNA fragment shifts were found for exons, 5, 10 and 11 in autistic individuals
and in normal controls. Sequence analysis showed the exon 10 and 11 polymorphisms
to result from base substitutions within introns, 14 and 73 bp downstream from
the splice site respectively. In exon 5, a G to A base substitution at codon 138
has no effect on amino acid sequence. The intronic polymorphism adjacent to exon
10 was analysed amongst two groups of unrelated autistic individuals-one from
the UK and one from Germany- and amongst a control population. Comparison of allele
frequencies between Caucasian autism cases and Caucasian controls show a significant
increase in the presence of the polymorphic intronic sequence 3' to exon 10 (Fisher's
exact test, P = 0.01). The base change is at a position where it is unlikely to
affect splicing of the FMR-1 transcript and is most likely a neutral variant that
has only a spurious false positive association with autism. However further linkage
disequilibrium analyses are justifiable. The positive association with autism
should be explored in further samples to determine whether it has any validity
as a genetic marker for autism. [Abstract]
JB, Thevarkunnel S, Kolozsvari D, Paterson AD, Roberts W, Scherer SW
and transmission analysis of the FMR1 IVS10 + 14C-T variant in autism.
J Med Genet. 2004 Feb 15;125B(1):54-6.
Evidence from the high male to female
ratio of individuals with autism as well as suggestive linkage data have implicated
the possible involvement of X chromosomal loci in the aetiology of autism. Studies
of the FMR1 gene on Xq27 have shown that occasionally individuals, and particularly
females, with the [CGG] repeat expansion and methylation mutation may present
with autistic symptoms. However, molecular studies suggest that such mutations
are not a major cause of autism. Previously, we have screened autism probands
for mutations in regions of the FMR1 gene downstream of the [CGG] repeat and identified
an intronic variant in the FMR1 gene, IVS10 + 14C-T, which was present at a significantly
higher frequency in autistic individuals compared to controls individuals. We
have now investigated this variant in a further 136 autism families and 186 control
individuals. We have established that the variant is significantly more frequent
among East Asian individuals within our affected and control groups (P < 0.0001)
and although we observed a trend of higher transmission frequency of the rare
allele to affected individuals, there was no significant evidence in either family-based
or case/control association studies for this variant in autism (P > 0.05).
SM, Münstermann E, Bieber-Martig B, Rühl D, Lisch S, Schmötzer G, Poustka A, Poustka
Molecular genetic analysis of the FMR-1 gene in
a large collection of autistic patients.
A genetic etiology in autism is now strongly supported
by family and twin studies. A 3:1 ratio of affected males to females suggests
the involvement of at least one X-linked locus in the disease. Several reports
have indicated an association of the fragile X chromosomal anomaly at Xq27.3 (FRAXA)
with autism, whereas others have not supported this finding. We have so far collected
blood from 105 simplex and 18 multiplex families and have assessed 141 patients
by using the Autism Diagnostic Interview-Revised (ADI-R), the Autism Diagnostic
Observation Scale, and psychometric tests. All four ADI-R algorithm criteria were
met by 131 patients (93%), whereas 10 patients (7%) showed a broader phenotype
of autism. Southern blot analysis was performed with three different enzymes,
and filters were hybridized to an FMR-1-specific probe to detect amplification
of the CCG repeat at FRAXA, to the complete FMR-1 cDNA probe, and to additional
probes from the neighborhood of the gene. No significant changes were found in
139 patients (99%) from 122 families, other than the normal variations in the
population. In the case of one multiplex family with three children showing no
dysmorphic features of the fragile X syndrome (one male meeting 3 out of 4 ADI-algorithm
criteria, one normal male with slight learning disability but negative ADI-R testing,
and one fully autistic female), the FRAXA full-mutation-specific CCG-repeat expansion
in the genotype was not correlated with the autism phenotype. Further analysis
revealed a mosaic pattern of methylation at the FMR-1 gene locus in the two sons
of the family, indicating at least a partly functional gene. Therefore, we conclude
that the association of autism with fragile X at Xq27.3 is non-existent and exclude
this location as a candidate gene region for autism. [Abstract]
JJ, Wing M, Chalifoux M, Julien-Inalsingh C, Schutz C, Robinson P, Szatmari P,
Lack of expansion of triplet repeats in the
FMR1, FRAXE, and FRAXF loci in male multiplex families with autism and pervasive
Am J Med Genet. 1996 Aug
Sib, twin, and family studies have shown that a genetic cause
exists in many cases of autism, with a portion of cases associated with a fragile
X chromosome. Three folate-sensitive fragile sites in the Xq27-->Xq28 region
have been cloned and found to have polymorphic trinucleotide repeats at the respective
sites; these repeats are amplified and methylated in individuals who are positive
for the different fragile sites. We have tested affected boys and their mothers
from 19 families with two autistic/PDD boys for amplification and/or instability
of the triplet repeats at these loci and concordance of inheritance of alleles
by affected brothers. In all cases, the triplet repeat numbers were within the
normal range, with no individuals having expanded or premutation-size alleles.
For each locus, there was no evidence for an increased frequency of concordance,
indicating that mutations within these genes are unlikely to be responsible for
the autistic/PDD phenotypes in the affected boys. Thus, we think it is important
to retest those autistic individuals who were cytogenetically positive for a fragile
X chromosome, particularly cases where there is no family history of the fragile
X syndrome, using the more accurate DNA-based testing procedures. [Abstract]
J, Pintado E, Lotspeich L, Spiker D, McMahon W, Petersen PB, Nicholas P, Pingree
C, Kraemer HC, Wong DL
Molecular analysis and test
of linkage between the FMR-1 gene and infantile autism in multiplex families.
J Hum Genet. 1994 Nov;55(5):951-9.
Approximately 2%-5% of autistic children
show cytogenetic evidence of the fragile X syndrome. This report tests whether
infantile autism in multiplex autism families arises from an unusual manifestion
of the fragile X syndrome. This could arise either by expansion of the (CGG)n
trinucleotide repeat in FMR-1 or from a mutation elsewhere in the gene. We studied
35 families that met stringent criteria for multiplex autism. Amplification of
the trinucleotide repeat and analysis of methylation status were performed in
79 autistic children and in 31 of their unaffected siblings, by Southern blot
analysis. No examples of amplified repeats were seen in the autistic or control
children or in their parents or grandparents. We next examined the hypothesis
that there was a mutation elsewhere in the FMR-1 gene, by linkage analysis in
32 of these families. We tested four different dominant models and a recessive
model. Linkage to FMR-1 could be excluded (lod score between -24 and -62) in all
models by using probes DXS548, FRAXAC1, and FRAXAC2 and the CGG repeat itself.
Tests for heterogeneity in this sample were negative, and the occurrence of positive
lod scores in this data set could be attributed to chance. Analysis of the data
by the affected-sib method also did not show evidence for linkage of any marker
to autism. These results enable us to reject the hypothesis that multiplex autism
arises from expansion of the (CGG)n trinucleotide repeat in FMR-1. [Abstract]
GA, Blum NJ, Hitchcock W, Fortina P
Absence of the
fragile X CGG trinucleotide repeat expansion in girls diagnosed with a pervasive
J Pediatr. 1998 Sep;133(3):363-5.
purpose of this study was to determine the prevalence of the fragile X (FRAX)
CGG trinucleotide expansion in a population of young girls (n = 45) diagnosed
with pervasive developmental disorder (PDD). Their mean age was 43.7 months (range,
25 to 132 months). Diagnoses included autistic disorder (n = 20), PDD (n = 23),
and Asperger's syndrome (n = 2). Molecular FRAX testing was performed on all patients
by using the Southern gene blot technique. Genomic DNA was digested with both
EcoRI and EagI, fractionated on agarose gel, and blotted and probed with the radiolabeled
StB12.3 FMR-1 probe. None of the subjects were found to have an expansion of CGG
in either the 2.8 kb or 5.2 kb fragments. A 95% CI, for the prevalence of the
FRAX mutation in female subjects with PDD, has an upper bound of 2.9%. We conclude
that the prevalence of FRAX positivity in girls with PDD is lower than previously
reported. This raises the question of whether any association between FRAX and
PDD in female subjects is specific to PDD or is related rather to the presence
of mental retardation. [Abstract]
JB, Steele MW, Wenger SL, Minshew NJ
The fragile X
marker and autism in perspective.
J Am Acad Child
Adolesc Psychiatry. 1989 May;28(3):417-21.
Recent reports link the fragile
X chromosome abnormality to autism, with the association ranging from 0 to 53%,
but the diagnostic criteria for autism were unclear in some of the studies. The
need for fragile X chromosome studies in larger populations of autistic children
and adults was recognized. In this study, chromosome analyses were performed on
85 carefully diagnosed autistic males, yielding a 2.4% incidence of the fragile
X abnormality. It is concluded that the incidence of the fragile X chromosome
abnormality in autistic individuals is likely the same as that in the mentally
retarded male population and therefore does not increase the risk for autism above
that of mental retardation itself. [Abstract]
A, Bolton P, Butler L, Le Couteur A, Murphy M, Scott S, Webb T, Rutter M
of the fragile X anomaly amongst autistic twins and singletons.
Child Psychol Psychiatry. 1993 Jul;34(5):673-88.
Early screening studies of
autistic individuals suggested that up to one-quarter of cases were associated
with the Fragile X anomaly. Recent studies find that the usual behavioural phenotype
of the Fragile X anomaly is distinct from autism as usually defined, and that
a variety of methodological factors contribute to the variability of the prevalence
estimates. We report the prevalence of the Fragile X anomaly, using strict cytogenetic
criteria, in a large sample of autistic individuals whose diagnosis was confirmed
using a standardised diagnostic instrument. The anomaly was detected in 1.6% of
tested autistic individuals from a combined sample of: autistic twins; clinic
attenders; and, individuals from families multiplex for autism or related cognitive
phenotypes. The anomaly was not detected in greater than 2.5% of any of the constituent
samples and accounted for only a small proportion of the genetic influences amongst
concordant twins and multiplex families. The anomaly was detected in 5% of the
40 tested autistic females, confirming reports that the prevalence of the anomaly
is similar amongst autistic individuals of both sexes. [Abstract]
HM, Bolton PF, Vincent J, Melmer G, Rutter M
and cytogenetic investigations of the fragile X region including the Frax A and
Frax E CGG trinucleotide repeat sequences in families multiplex for autism and
Hum Hered. 1997 Sep-Oct;47(5):254-62.
undertook molecular and cytogenetic analyses in 25 families multiplex for autism
and related disorders. Three of the multiplex families exhibited fragile X, and
the affected offspring all exhibited CGG triplet repeat insertion mutations in
the FMR-1 gene. One of these families contained an affected pair of monozygotic
female twins. Both had similar-sized CGG triplet repeat expansions, but different
phenotypic manifestations. One suffered from autism and the other from mild mental
retardation and marked social anxiety. PCR and Southern hybridization analysis
of the CGG repeat sequences characterizing fragile X A (Frax A) and E and the
methylation status of FMR-1 showed no evidence of abnormal CGG repeat expansion
or FMR-1 hypermethylation in the remaining 22 multiplex families. Moreover, there
was no correlation between the Frax A or E (CGG)n repeat length with affected
status, nor any association with the low-level (< 3 %) expression of cytogenetic
fragility at Xq27 previously reported in these families. Our findings indicate
that most instances of recurrence in families multiplex for autism and related
disorders are not accounted for by Frax A and E. They also indicate that the phenotypic
manifestations of Frax A may be influenced by stochastic, environmental and other
biological factors. [Abstract]
D, Dyer-Friedman J, Glaser B, Wisbeck J, Barajas RG, Taylor A, Reiss AL
influence of environmental and genetic factors on behavior problems and autistic
symptoms in boys and girls with fragile X syndrome.
OBJECTIVE: Fragile X syndrome, caused by mutations in
a single gene of the X chromosome (FMR1), is associated with neurobehavioral characteristics
including social deficits with peers, social withdrawal, gaze aversion, inattention,
hyperactivity, anxiety, depression, and autistic behavior. However, there is considerable
variability in the behavioral and psychiatric problems among children with this
condition. The purpose of this study was to measure genetic and environmental
factors influencing behavior problems and autistic symptoms in children with fragile
X syndrome. DESIGN: We conducted an in-home evaluation of 120 children (80 boys
and 40 girls) with the fragile X full mutation and their unaffected siblings,
including measurements of the FMR1 protein (FMRP), quality of the home environment,
maternal and paternal psychopathology, effectiveness of educational and therapeutic
services, and child behavior problems. RESULTS: Results of multiple regression
analyses showed that for boys with fragile X, effectiveness of educational and
therapeutic services and parental psychological problems predicted internalizing
and externalizing types of problems, while the quality of the home environment
predicted autistic behavior. For girls with fragile X, the results emphasized
significant effects of FMRP on behavior, in particular social withdrawal and anxious/depressed
behavior. CONCLUSIONS: These findings are among the first to link FMRP expression
to behavior. They also emphasize the significance of home- and school-based environmental
variables in the neurobehavioral phenotype and help to lay the foundation for
studies designed to identify specific interventions for reducing problem behavior
in children with fragile X syndrome. [Abstract]
V, Cohen IL, Silverman W, Wolf-Schein EG
analyses of males with fragile X, Down syndrome, and autism: comparison of the
emergence of deviant language.
Am J Ment Retard.
Deviant, repetitive language of 33 males (9 with Down
syndrome, 12 with fragile X (fra[X]) syndrome, and 12 with autism) was analyzed
within three conversational contexts: direct responses, initiation of new material,
and topic maintenance. Results indicated that males with fra(X) manifest deviant,
repetitive language that is distinct from males with either Down syndrome or autism.
Thus, the deviant repetitive language of males with fra(X) cannot be accounted
for by either their level of adaptive functioning or autistic-like behaviors per
se. Possible explanations for this etiologically specific language deviance were
S, Molony H, Hall W
Autism is not associated with
the fragile X syndrome.
Am J Med Genet. 1989 Oct;34(2):187-93.
provided a controlled test of the hypothesis that individuals with the Martin-Bell
or Fragile X [fra(x)] syndrome are more autistic than mentally retarded control
individuals. A sample of fra(x) individuals was obtained from the register of
a clinical genetics unit and compared with mentally retarded control individuals
selected from an assessment centre who were individually matched for age, sex,
and IQ. A comparison of 45 pairs of fra(x) cases and control individuals on the
DSM-III (R) criteria for autism and two standardized "instruments" for
the assessment of autism (ABC and ADC) failed to find a higher prevalence of autism
among fra(x) individuals. There was no statistically significant difference between
fra(x) individuals and control individuals, and the mean differences on both the
ABC and ADC scales were in the direction contrary to the hypothesis. An analysis
of the study's statistical power suggested that it is unlikely the investigation
failed to detect a large to medium difference between fra(x) individuals and control
individuals in autistic behaviour. Subsidiary analyses of case-control differences
showed that two autistic-like behaviours occurred at a higher rate among fra(x)
individuals than other mentally retarded children, namely, gaze avoidance and
hand flapping. These abnormalities may have misled clinicians into thinking that
autism and fra(x) are associated. [Abstract]
IL, Vietze PM, Sudhalter V, Jenkins EC, Brown WT
dyadic gaze patterns in fragile X males and in non-fragile X males with autistic
J Child Psychol Psychiatry. 1989 Nov;30(6):845-56.
dyadic gaze patterns were examined in fragile X [fra(X)] males and in non-fra(X)
autistic males across three age groups--early childhood, middle childhood and
adolescence. Absolute probabilities of social gaze did not significantly differ
across diagnostic groups. Event lag sequential analyses indicated that fra(X)
males were sensitive to social gaze initiation by their parents but found eye
contact aversive. Non-fra(X) autistic males, by contrast, were insensitive to
parent-initiated social gaze, and did not find eye contact aversive. Implications
for research on the social characteristics of fra(X) and autistic children are
IL, Fisch GS, Sudhalter V, Wolf-Schein EG, Hanson D, Hagerman R, Jenkins EC, Brown
Social gaze, social avoidance, and repetitive behavior
in fragile X males: a controlled study.
Am J Ment
Retard. 1988 Mar;92(5):436-46.
Preference for social gaze as well as the percentage
occurrence of social gaze, nonverbal social avoidance, and nonverbal repetitive
behaviors were examined in autistic and nonautistic prepubertal males with the
fragile X syndrome (fra[X]) during social interaction with a parent or stranger.
Comparison groups were nonhandicapped, Down syndrome, atypical pervasive developmental
disorder, and autistic males. The subjects with fra(X) and the nonhandicapped
and Down syndrome control subjects discriminated parent from stranger as evidenced
by their avoidance behavior. The overall percentage of avoidance was higher, however,
for both parent and stranger, among the males with fra(X). Autistic and atypical
groups without fra(X) failed to discriminate parent from stranger in their avoidance
behavior. Possible explanations for these group differences in terms of language
level or degree of language demand were ruled out. Implications for research concerning
the relations among fra(X), autism, and mental retardation were discussed. [Abstract]
DB, Hatton DD, Skinner M, Mesibov G
FMR1 protein, and developmental trajectories in young males with fragile X syndrome.
Autism Dev Disord. 2001 Apr;31(2):165-74.
In the context of a longitudinal
study, we assessed the relationship between ratings of autistic behavior, FMR1
protein expression (FMRP), and the developmental trajectories of 55 young males
with fragile X syndrome. Autistic behavior, as measured by the Childhood Autism
Rating Scale, was not related to FMRP expression. However, autistic behavior was
a significant predictor of both developmental status and developmental change.
Boys with both autistic behavior and fragile X syndrome functioned at significantly
lower levels of development and grew at significantly slower rates than those
without autistic behavior. FMRP expression accounted for less variance in developmental
level than did autistic behavior, and was not significantly related to slope (developmental
change over time). No autistic behavior x FMRP interaction was found. [Abstract]
VC, Lam ST
Fragile X positivity in Chinese children
with autistic spectrum disorder.
Chromosome analysis was performed in 105 Chinese children
(96 boys, 9 girls) with autistic spectrum disorder to assess fragile X positivity.
Seventy percent of these autistic children were mentally retarded. None of the
children in the infantile autism group (N = 75) had fragile X positivity. Two
boys in the autistic condition group (N = 30) had clinical features and chromosomal
positivity for fragile X syndrome. The low (2%) prevalence rate of fragile X positivity
in children with different degrees of expressivity of autistic features may be
related to other factors rather than to pure autistic characteristics per se.
H, Ohdo S, Sonoda T, Ohba K, Tanaka H, Hayakawa K
autism and the fragile X syndrome in Japanese children.
Paediatr Jpn. 1989 Apr;31(2):163-5.
A total of 97 children with infantile autism,
85 boys and 12 girls, were screened for the fragile X chromosome. They ranged
in age from 2 to 14 years with an average of 5 5/12 years. There were two fra(X)
positive boys and no such girls. [Abstract]
T, Shiotsuki Y, Niikawa N, Katafuchi Y, Otaki E, Ando H, Yamashita Y, Horikawa
M, Urabe F, Kuriya N
Fragile X syndrome in Japanese
patients with infantile autism.
Pediatr Neurol. 1987
Forty-seven patients (39 boys and 8 girls) with infantile
autism whose clinical symptoms had matched the diagnostic criteria of DSM III
were studied cytogenetically for the occurrence of fragile X [fra(X)] syndrome.
The existence of fra(X) chromosome in these patients was screened first by culturing
peripheral blood lymphocytes in a medium in which folic acid was absent; the fra(X)
chromosome then was confirmed by reculturing in another medium to which 5-fluoro-2'-deoxyuridine
was added for the last 24 hours of culture. Fra(X) chromosome was found in 2 of
39 male patients, but in none of the female patients; the 2 patients are siblings.
Thus, fra(X) syndrome occurs in 2.6% (1/38) in this study population of male autistic
children. The frequencies of fra(X) expression in the older brother with mild
mental retardation, in the more severely retarded younger brother, and in their
mother were 3-5%, 17-20%, and 9-3%, respectively. Of the two methods used in the
present study, the method employing 5-fluoro-2'-deoxyuridine tended to be more
sensitive to fra(X) chromosome detection, especially for a suspected carrier.
J, Gillberg C, Gustavson KH, Holmgren G
autism and the fragile X. A Swedish multicenter study.
J Med Genet. 1986 Jan-Feb;23(1-2):403-8.
In a Swedish multicenter study of
122 cases of infantile autism, 16 boys (13%) were found to be fragile (X) (q27)
positive. None of the 21 girls studied were fragile (X) positive. [Abstract]
SY, Chen YC, Lai TJ, Hsu CY, Wang YC
cytogenetic analyses of autism in Taiwan.
Karyotypic and DNA analyses were both performed on 104
autistic children referred from Taichung Autism Education Academy and Tainan Autism
Association in Taiwan. The frequency of fragile sites of the autistic patients
did not differ significantly from that of the normal individuals. Of the 12 autistic
children with chromosomal abnormalities, 8 had the fragile X, 2 had Down syndrome,
and the remaining had other aneuploid constitutions. The results of this study
illustrate the contribution of chromosomal abnormalities or variants to the pathogenesis
of infantile autism. [Abstract]
GS, Cohen IL, Jenkins EC, Brown WT
disabled male populations for fragile X: the effect of sample size.
J Med Genet. 1988 May-Jun;30(1-2):655-63.
The fra(X) or Martin-Bell syndrome
is the most common cause of inherited mental retardation (MR) in males. It is
also associated with a variety of unusual behavioral and developmental disorders.
Recent studies found great variability in the estimated strength of association
between "autism" and the fra(X) syndrome, but not between MR and fra(X).
We examined 31 studies which investigated the association of fra(X) syndrome with
either MR or "autism" and found that the conclusion of those researchers
could be significantly affected by sample size. Different behavioral and cytogenetic
protocols will also influence the strength of association between fra(X) and autism.
E, Bacchelli E, Levy ER, Blasi F, Marlow A, Monaco AP, Maestrini E
screening and imprinting analysis of four candidate genes for autism in the 7q32
Mol Psychiatry. 2002;7(3):289-301.
studies indicate that chromosome 7q is likely to contain an autism susceptibility
locus (AUTS1). We have followed a positional candidate gene approach to identify
the relevant gene and report the analysis of four adjacent genes localised to
a 800 kb region in 7q32 that contains an imprinted domain: PEG1/MEST, COPG2, CPA1
and CPA5-a previously uncharacterised member of the carboxypeptidase gene family.
Screening these genes for DNA changes and association analysis using intragenic
single nucleotide polymorphisms (SNPs) provided no evidence for an etiological
role in IMGSAC families. We also searched for imprinting mutations potentially
implicated in autism: analysis of both DNA methylation and replication timing
indicated a normal imprinting regulation of the PEG1/COPG2 domain in blood lymphocytes
of all patients tested. The analysis of these four genes strongly suggests that
they do not play a major role in autism aetiology, and delineates our strategy
to screen additional candidate genes in the AUTS1 locus. [Abstract]
JB, Petek E, Thevarkunnel S, Kolozsvari D, Cheung J, Patel M, Scherer SW
RAY1/ST7 tumor-suppressor locus on chromosome 7q31 represents a complex multi-transcript
Genomics. 2002 Sep;80(3):283-94.
identified a novel gene, RAY1 (FAM4A1), which spans a translocation breakpoint
at 7q31 in a patient with autism. This gene has more recently been reported to
be a suppressor of tumorigenicity, ST7, although controversy surrounds this observation
because subsequent reports have failed to corroborate these findings. Our further
analysis of this locus reveals that it is composed of a multigene system that
includes two noncoding sense strand genes (ST7OT3 and ST7OT4) that overlap with
many alternative forms of the coding RAY1/ST7 transcript, and two noncoding genes
on the antisense strand (ST7OT1 and ST7OT2). RAY1/ST7 was determined to have at
least three different 5' exons with alternative start codons, one of which seems
to be used almost exclusively in the brain. We have also identified a third alternative
3' end of RAY1/ST7 that uses exons from ST7OT3. ST7OT3 spans from intron 10 to
exon 14 of RAY1/ST7 and includes several exons. ST7OT4 has at least seven exons
and is transcribed on the sense strand between RAY1/ST7 exon 1 and a tropomyosin-like
sequence, TPM3L2. ST7OT1 overlaps with the RAY1/ST7 exon 1 and promoter. ST7OT2
spans from RAY1/ST7 intron 9 to intron 1, and has multiple isoforms. We screened
the exons of RAY1/ST7 and ST7OT1-3 for sequence variants in 90 unrelated autism
probands and identified several rare variants, including a Ile361Val substitution.
Although these variants were not observed in a control population, it is unclear
whether they contribute to the autistic phenotype. We postulate that the apparent
noncoding genes at the RAY1/ST7 locus may be regulatory RNAs. The RAY1/ST7 may
generate at least 18 possible isoforms, with many more arising if other sense-strand
exons from ST7OT3 and ST7 OT4 are used in a selective and possibly tissue-specific
JB, Herbrick JA, Gurling HM, Bolton PF, Roberts W, Scherer SW
of a novel gene on chromosome 7q31 that is interrupted by a translocation breakpoint
in an autistic individual.
Am J Hum Genet. 2000 Aug;67(2):510-4.
results of genetic linkage studies for autism have suggested that a susceptibility
locus for the disease is located on the long arm of chromosome 7 (7q). An autistic
individual carrying a translocation, t(7;13)(q31.3;q21), with the chromosome 7
breakpoint located in the region of 7q implicated by genetic studies was identified.
A novel gene known as "RAY1" (or "FAM4A1") was found to be
directly interrupted by the translocation breakpoint. The gene, which was found
to be encoded by 16 exons with evidence of alternative splicing, spanned >
or =220 kb of DNA at 7q31.3. Mutation screening of the entire coding region in
a set of 27 unrelated autistic individuals failed to identify phenotype-specific
variants, suggesting that coding region mutations are unlikely to be involved
in the etiology of autism. Apparent homologues of RAY1 have also been identified
in mouse, rat, pig, chicken, fruit fly, and nematode. The human and mouse genes
share similar splicing patterns, and their predicted protein products are 98%
KS, Klauck SM, Benner A, Poustka F, Poustka A
studies of the HOPA dodecamer duplication variant in different subtypes of autism.
J Med Genet. 2002 Jan 8;114(1):110-5.
The HOPA gene in Xq13 is coding for a
protein involved in a nuclear thyroid receptor complex. Previous studies suggested
association of the dodecamer duplication in the OPA-repeat region in exon 43 (according
to the genomic database sequence) with autism, mental retardation, and schizophrenia/hypothyroidism.
We determined the frequency of this 12 bp duplication variant in a sample of 155
patients divided in different subtypes of autism, 278 parents of those patients,
and 157 control individuals. The allele frequency of the duplication variant was
not significantly different between autistic patients, their parents, and the
control group. Therefore, it is unlikely that this 12 bp duplication variant of
the HOPA gene has major relevance to the susceptibility to different subtypes
of autism at least in this German patient sample. In addition, we identified a
third variant with a 15 bp deletion in the OPA-repeat region, recently described
by another group, in one autistic patient. This third allele was also present
in the patient's nonautistic mother and sister, who are heterozygous for this
variant, but could not be detected in any other individual genotyped in this study.
Expression analysis revealed transcription of all three allelic variants in lymphoblastoid
cell lines. Furthermore, we identified a new splice variant that utilizes an additional
9 bp of the 3' intron subsequent to exon 39. Both alternative transcripts are
coexpressed in all fetal and adult tissues examined. [Abstract]
RC, Copeland-Yates SA, Sossey-Alaoui K, Skinner C, Friez MJ, Longshore JW, Simensen
RJ, Schroer RJ, Stevenson RE
The HOPA gene dodecamer
duplication is not a significant etiological factor in autism.
Autism Dev Disord. 2000 Aug;30(4):355-8.
A recent study has suggested that
a dodecamer duplication in the HOPA gene in Xq13 may occur in a significant portion
of male patients with autism. We have determined the incidence of this duplication
in 202 patients from the South Carolina Autism Study. The incidence of the duplication
was not significantly different between patients and controls. Three of the female
patients inherited the duplication from nonautistic fathers. In addition, there
was no systematic skewing of X inactivation in the female patients with the duplication,
or in nonautistic mothers and sisters with the duplication. These findings suggest
that the dodecamer duplication in the HOPA gene does not play a significant role
in the etiology of autism. [Abstract]
H, Liu X, Zhang C, Mundo E, Macciardi F, Grayson DR, Guidotti AR, Holden JJ
gene alleles and susceptibility to autism spectrum disorders.
A polymorphic trinucleotide repeat (CGG/GCC)
within the human Reelin gene (RELN) was examined as a candidate gene for autism
spectrum disorders (ASDs). This gene encodes a large extracellular matrix protein
that orchestrates neuronal positioning during corticogenesis. The CGG-repeat within
the 5' untranslated region of RELN exon 1 was examined in 126 multiple-incidence
families. The number of CGG repeats varied from three to 16 in affected individuals
and controls, with no expansion or contraction observed during maternal (n = 291)
or paternal (n = 287) transmissions in families with autistic probands. Although
the frequencies of the RELN alleles and genotypes in affected children were not
different from those in the comparison group, a family-based association test
(FBAT) showed that the larger RELN alleles (> or = 11 repeats) were transmitted
more often than expected to affected children (S = 43, E(S) = 34.5, P = 0.035);
this was particularly the case for the 13-repeat RELN allele (S = 22, E(S) = 16,
P = 0.034). Affected sib-pair (ASP) analysis found no evidence of excess sharing
of RELN alleles in affected siblings. The impact of genotypes with large alleles
(> or = 11 repeats) on the phenotypes in individuals with ASD was analyzed
by ANOVA in a subset of the families for which results of the Autism Diagnostic
Interview-Revised were available. Children with large RELN alleles did not show
any difference in scores for questions related to the core symptoms of autistic
disorder, but there was a tendency for children with at least one large RELN allele
to have an earlier age at first phrase (chi(2) = 3.538, P = 0.06). Thus, although
the case-control and affected sib-pair findings did not support a role for RELN
in susceptibility to ASD, the more powerful family-based association study demonstrated
that RELN alleles with larger numbers of CGG repeats may play a role in the etiology
of some cases of ASD, especially in children without delayed phrase speech. [Abstract]
AM, D'Agruma L, Maiorano N, Totaro A, Militerni R, Bravaccio C, Wassink TH, Schneider
C, Melmed R, Trillo S, Montecchi F, Palermo M, Pascucci T, Puglisi-Allegra S,
Reichelt KL, Conciatori M, Marino R, Quattrocchi CC, Baldi A, Zelante L, Gasparini
P, Keller F
Reelin gene alleles and haplotypes as
a factor predisposing to autistic disorder.
Autistic disorder (MIM 209850) is currently viewed as
a neurodevelopmental disease. Reelin plays a pivotal role in the development of
laminar structures including the cerebral cortex, hippocampus, cerebellum and
of several brainstem nuclei. Neuroanatomical evidence is consistent with Reelin
involvement in autistic disorder. In this study, we describe several polymorphisms
identified using RNA-SSCP and DNA sequencing. Association and linkage were assessed
comparing 95 Italian patients to 186 ethnically-matched controls, and using the
transmission/disequilibrium test and haplotype-based haplotype relative risk in
172 complete trios from 165 families collected in Italy and in the USA. Both case-control
and family-based analyses yield a significant association between autistic disorder
and a polymorphic GGC repeat located immediately 5' of the reelin gene (RELN)
ATG initiator codon, as well as with specific haplotypes formed by this polymorphism
with two single-base substitutions located in a splice junction in exon 6 and
within exon 50. Triplet repeats located in 5' untranslated regions (5'UTRs) are
indicative of strong transcriptional regulation. Our findings suggest that longer
triplet repeats in the 5'UTR of the RELN gene confer vulnerability to autistic
J, Nguyen L, Gleason C, Lotspeich L, Spiker D, Risch N, Myers RM
of evidence for an association between WNT2 and RELN polymorphisms and autism.
J Med Genet. 2004 Apr 1;126B(1):51-7.
Autism is a pervasive neurodevelopmental
disorder characterized by deficits in language development and social interaction,
as well as stereotypical, repetitive behaviors. The etiology of autism is largely
unknown. Family and twin studies have provided compelling evidence for a strong
genetic component in most idiopathic cases. Several recent candidate gene studies
have suggested that alleles of WNT2 and the reelin gene (RELN), two genes involved
in distinct aspects of neurodevelopment, confer greater susceptibility to autism.
We screened WNT2 for DNA polymorphisms by sequencing all exons and adjacent intronic
regions in 24 autistic patients, and identified not only the WNT2 variants reported
previously (two common single-nucleotide polymorphisms (SNPs) in the 5' upstream
region and the 3' untranslated region (UTR), respectively), but also two new SNPs
in its 3' UTR. We genotyped all four WNT2 polymorphisms and a polymorphic trinucleotide
repeat in the 5' UTR of RELN in 107 families with multiple autistic children,
and evaluated evidence for association between these variants and autism by the
transmission disequilibrium test (TDT). Our results revealed no deviation from
the null hypothesis of no association. Our interpretation of these findings is
that it is unlikely that DNA variations in RELN and WNT2 play a significant role
in the genetic predisposition to autism. [Abstract]
PA, Shao Y, Wolpert CM, Donnelly SL, Ashley-Koch A, Abel HL, Ravan SA, Abramson
RK, Wright HH, DeLong GR, Cuccaro ML, Gilbert JR, Pericak-Vance MA
association between the WNT2 gene and autistic disorder.
J Med Genet. 2002 Jan 8;114(1):106-9.
Autistic disorder is a pervasive neurodevelopmental
disorder characterized by deficits in language and social communication, as well
as stereotyped patterns of behavior. Peak LOD scores from several genomic screening
efforts indicate the presence of an autistic disorder susceptibility locus within
the distal long arm of human chromosome 7 (7q31-q35). Wassink et al. [2001: Am
J Med Genet 105:406-413] reported that WNT2, located at 7q31, influences genetic
risk in autistic disorder. These findings were enhanced when examined in a subset
of families with severe language impairment. WNT genes encode secreted growth
factor-like proteins that participate in growth regulation, differentiation, and
tumorigenesis. We tested for genetic association of two WNT2 variants in an independent
data set of 135 singleton and 82 multiplex families. No significant association
was found between autistic disorder and the WNT2 genotypes in either the overall
data set or in the language-impaired subset of families. However, differences
in allele frequencies of the 3' UTR single nucleotide polymorphism between the
present population and that of Wassink et al. may account for the inability to
detect association between WNT2 and autistic disorder in the present data set.
We also screened the two reported autistic disorder mutations previously detected
by Wassink et al. We did not identify any activating mutation in the coding region
of the WNT2 gene. Thus, we conclude that activating mutations of the WNT2 gene
are not a major contributor to the development of autistic disorder in these data.
TH, Piven J, Vieland VJ, Huang J, Swiderski RE, Pietila J, Braun T, Beck G, Folstein
SE, Haines JL, Sheffield VC
Evidence supporting WNT2
as an autism susceptibility gene.
Am J Med Genet.
2001 Jul 8;105(5):406-13.
We examined WNT2 as a candidate disease gene for
autism for the following reasons. First, the WNT family of genes influences the
development of numerous organs and systems, including the central nervous system.
Second, WNT2 is located in the region of chromosome 7q31-33 linked to autism and
is adjacent to a chromosomal breakpoint in an individual with autism. Third, a
mouse knockout of Dvl1, a member of a gene family essential for the function of
the WNT pathway, exhibits a behavioral phenotype characterized primarily by diminished
social interaction. We screened the WNT2 coding sequence for mutations in a large
number of autistic probands and found two families containing nonconservative
coding sequence variants that segregated with autism in those families. We also
identified linkage disequilibrium (LD) between a WNT2 3'UTR SNP and our sample
of autism-affected sibling pair (ASP) families and trios. The LD arose almost
exclusively from a subgroup of our ASP families defined by the presence of severe
language abnormalities and was also found to be associated with the evidence for
linkage to 7q from our previously published genomewide linkage screen. Furthermore,
expression analysis demonstrated WNT2 expression in the human thalamus. Based
on these findings, we hypothesize that rare mutations occur in the WNT2 gene that
significantly increase susceptibility to autism even when present in single copies,
while a more common WNT2 allele (or alleles) not yet identified may exist that
contributes to the disorder to a lesser degree. [Abstract]
B, Bennett P, Dawson G, Figlewicz DA, Grigorenko EL, McMahon W, Minshew N, Pauls
D, Smith M, Spence MA, Rodier PM, Stodgell C, Schellenberg GD
of a reelin CGG repeat do not convey liability to autism in a sample from the
Am J Med Genet. 2004 Apr 1;126B(1):46-50.
recent study by Persico et al. [2001: Mol Psychiatry 6:150-159] suggests alleles
of a CGG polymorphism, just 5' of the reelin gene (RELN) initiator codon, confer
liability for autism, especially alleles bearing 11 or more CGG repeats (long
alleles). The association is consistent across both a case-control and family-based
sample. We attempted to replicate their finding using a larger, independent family-based
sample from the NIH Collaborative Programs of Excellence in Autism (CPEA) Network.
In our data, allele transmissions to individuals with autism versus unaffected
individuals are unbiased, both when alleles are classified by repeat length and
when they are classified into long/short categories. Because of the apparent linkage
of autism to chromosome 7q, particularly related to the development of language,
we also evaluate the relationship between Reelin alleles and the age at which
autism subjects use their first word or first phrase. Neither is significantly
associated with Reelin alleles. Our results are not consistent with a major role
for Reelin alleles in liability to autism. [Abstract]
E, Beyer KS, Lamb JA, Parr JR, Klauck SM, Benner A, Paolucci M, Abbott A, Ragoussis
I, Poustka A, Bailey AJ, Monaco AP
Analysis of reelin
as a candidate gene for autism.
Mol Psychiatry. 2003
Genetic studies indicate that chromosome 7q is likely to
contain an autism susceptibility locus (AUTS1). We have followed a positional
candidate gene approach to identify relevant gene(s) and report here the analysis
of reelin (RELN), a gene located under our peak of linkage. Screening RELN for
DNA changes identified novel missense variants absent in a large control group;
however, the low frequency of these mutations does not explain the relatively
strong linkage results on 7q. Furthermore, analysis of a previously reported triplet
repeat polymorphism and intragenic single nucleotide polymorphisms, using the
transmission disequilibrium test, provided no evidence for association with autism
in IMGSAC and German singleton families. The analysis of RELN suggests that it
probably does not play a major role in autism aetiology, although further analysis
of several missense mutations is warranted in additional affected individuals.
MO, Betancur C, Leroy S, Bourdel MC, Gillberg C, Leboyer M
of association between a polymorphic GGC repeat in the 5' untranslated region
of the reelin gene and autism.
Mol Psychiatry. 2002;7(7):801-4.
is a complex neurodevelopmental disorder with severe cognitive and communication
disabilities, that has a strong genetic predisposition. Reelin, a protein involved
in neuronal migration during development, is encoded by a gene located on 7q22,
within the candidate region on 7q showing increased allele sharing in previous
genome scans. A case/control and family-based association study recently reported
a positive association between a trinucleotide repeat polymorphism (GGC) located
in the 5' untranslated region (UTR) of the reelin gene and autism. We performed
a transmission disequilibrium test (TDT) analysis of the 5'UTR polymorphism in
167 families including 218 affected subjects (117 trios and 50 affected sib pairs)
and found no evidence of linkage/association. Our results do not support previous
findings and suggest that this GGC polymorphism of the reelin gene is unlikely
to be a major susceptibility factor in autism and/or genetic heterogeneity. [Abstract]
Tordjman S, Gutknecht L, Carlier M, Spitz E, Antoine
C, Slama F, Carsalade V, Cohen DJ, Ferrari P, Roubertoux PL, Anderson GM
of the serotonin transporter gene in the behavioral expression of autism.
Psychiatry. 2001 Jul;6(4):434-9.
The promoter polymorphism of the serotonin
transporter gene (HTT, locus SLC6A4) is of special interest in autism given the
well-replicated platelet hyperserotonemia of autism, treatment effects of serotonin
reuptake inhibitors, and the role of serotonin in limbic functioning and neurodevelopment.
Parent-offspring transmission of the long (l) and short (s) alleles of the deletion/insertion
polymorphism in the HTT promoter region was examined in families of 71 children
with autism using the transmission test for linkage disequilibrium (TDT). Transmission
of HTT promoter alleles did not differ between probands with autism and their
unaffected siblings. However, allelic transmission in probands was dependent upon
severity of impairments in the social and communication domains, with greater
s allele transmission in severely impaired individuals and greater l transmission
in mild/moderately impaired individuals. This relationship between HTT promoter
alleles and severity of autistic impairment was also seen when ratings of social
and communication behaviors were compared across genotypes. The data indicate
that HTT promoter alleles by themselves do not convey risk for autism, but, rather,
modify the severity of autistic behaviors in the social and communication domains.
The results require replication and, given the size of the groups and subgroups
examined, must be considered still preliminary. The results suggest that future
research on the genetics of autism should carefully assess each of the major behavioral
domains and seriously consider the possible role of modifying loci. [Abstract]
J, Meally E, Kearney G, Fitzgerald M, Gill M, Gallagher L
transporter gene and autism: a haplotype analysis in an Irish autistic population.
Psychiatry. 2004 Jun;9(6):587-93.
The role of the serotonin transporter (5-HTT)
in the development of neuropsychiatric disorders has been widely investigated.
Two polymorphisms, an insertion/deletion in the promoter region and a 12 repeat
allele in a variable nucleotide tandem repeat (VNTR) in intron 2, drive higher
expression of the 5-HTT gene. Four studies have shown nominally significant excess
transmission of alleles of the 5-HTT gene in autism, while three studies have
reported no excess transmission. This present study investigates the role of 5-HTT
in the genetically homogenous Irish population. In all, 84 families were genotyped
for five polymorphisms (three SNPs, a VNTR and an in/del). The analysis of allele
transmissions using the transmission disequilibrium test (TDT) was undertaken
and indicated preferential transmission of the short promoter allele (TDT P-value=0.0334).
Linkage disequilibrium between markers was calculated and haplotypes were assessed
for excess transmission and odds ratios (ORs) to affected children. A number of
haplotypes, especially those involving and surrounding SNP10, showed evidence
of association. The ORs ranged from 1.2 to 2.4. The most significant haplotype
associated with transmission to affected probands was the SNP10-VNTR-SNP18 haplotype
(chi(2)=7.3023, P=0.0069, odds ratio=1.8). This haplotype included the 12 repeat
allele of the VNTR, which is associated with increased expression and may play
a subtle role in the early development of the brain in affected probands. [Abstract]
SJ, Cox N, Courchesne R, Lord C, Corsello C, Akshoomoff N, Guter S, Leventhal
BL, Courchesne E, Cook EH
mapping at the serotonin transporter gene (SLC6A4) region in autistic disorder.
The serotonin transporter gene (SLC6A4, MIM 182138)
is a candidate gene in autistic disorder based on neurochemical, neuroendocrine
studies and the efficacy of potent serotonin transporter inhibitors in reducing
ritualistic behaviors and related aggression. An insertion/deletion polymorphism
(5-HTTLPR) in the promoter region and a variable number of tandem repeat polymorphism
(VNTR) in the second intron, were previously identified and suggested to modulate
transcription. Six previous family-based association studies of SLC6A4 in autistic
disorder have been conducted, with four studies showing nominally significant
transmission disequilibrium and two studies with no evidence of nominally significant
transmission disequilibrium. In the present study, TDT was conducted in 81 new
trios. A previous finding of transmission disequilibrium between a haplotype consisting
of the 5-HTTLPR and intron 2 VNTR was replicated in this study, but not preferential
transmission of 5-HTTLPR as an independent marker. Because of inconsistent transmission
of 5-HTTLPR across studies, SLC6A4 and its flanking regions were sequenced in
10 probands, followed by typing of 20 single nucleotide polymorphisms (SNPs) and
seven simple sequence repeat (SSR) polymorphisms in 115 autism trios. When individual
markers were analyzed by TDT, seven SNP markers and four SSR markers (six SNPs,
5-HTTLPR and the second intron VNTR from promoter 1A through intron 2 of SLC6A4,
one SSR from intron 7 of SLC6A4, one SNP from the bleomycin hydrolase gene (BLMH,
MIM 602403) and one SSR telomeric to BLMH) showed nominally significant evidence
of transmission disequilibrium. Four markers showed stronger evidence of transmission
disequilibrium (TDT(max) P = 0.0005) than 5-HTTLPR. [Abstract]
C, Corbex M, Spielewoy C, Philippe A, Laplanche JL, Launay JM, Gillberg C, Mouren-Siméoni
MC, Hamon M, Giros B, Nosten-Bertrand M, Leboyer M
transporter gene polymorphisms and hyperserotonemia in autistic disorder.
Previous studies have provided conflicting evidence
regarding the association of the serotonin transporter (5-HTT) gene with autism.
Two polymorphisms have been identified in the human 5-HTT gene, a VNTR in intron
2 and a functional deletion/insertion in the promoter region (5-HTTLPR) with short
and long variants. Positive associations of the 5-HTTLPR polymorphism with autism
have been reported by two family-based studies, but one found preferential transmission
of the short allele and the other of the long allele. Two subsequent studies failed
to find evidence of transmission disequilibrium at the 5-HTTLPR locus. These conflicting
results could be due to heterogeneity of clinical samples with regard to serotonin
(5-HT) blood levels, which have been found to be elevated in some autistic subjects.
Thus, we examined the association of the 5-HTTLPR and VNTR polymorphisms of the
5-HTT gene with autism, and we investigated the relationship between 5-HTT variants
and whole-blood 5-HT. The transmission/disequilibrium test (TDT) revealed no linkage
disequilibrium at either loci in a sample of 96 families comprising 43 trios and
53 sib pairs. Furthermore, no significant relationship between 5-HT blood levels
and 5-HTT gene polymorphisms was found. Our results suggest that the 5-HTT gene
is unlikely to play a major role as a susceptibility factor in autism. [Abstract]
AM, Oliveira G, Morgadinho T, Fesel C, Macedo TR, Bento C, Marques C, Ataíde A,
Miguel T, Borges L, Vicente AM
Variants of the serotonin
transporter gene (SLC6A4) significantly contribute to hyperserotonemia in autism.
Psychiatry. 2004 Mar;9(3):264-71.
The role of the serotonin system in the etiology
and pathogenesis of autism spectrum disorders (ASD) is not clearly defined. High
levels of platelet serotonin (5-HT) have been consistently found in a proportion
of patients, and it is known that specific 5-HT transporter gene (SLC6A4) variants
modulate transporter reuptake function, therefore possibly influencing the occurrence
of hyperserotonemia in a subset of autistic patients. We have examined the association
of platelet serotonin levels with two SLC6A4 polymorphisms, 5-HTT gene-linked
polymorphic region (HTTLPR) in the promoter and intron 2 variable number of tandem
repeats (VNTR), in a sample of 105 ASD patients, their parents, and 52 control
children. Quantitative transmission disequilibrium test (QTDT) results showed
a significant effect on 5-HT levels of each SLC6A4 marker (P=0.017 for HTTLPR;
P=0.047 for intron 2 VNTR) and of haplotypes of the two markers (P=0.017), with
a major contribution of the L.Stin2.10 haplotype (P=0.0013). A 5-HT mean value
in the range of hyperserotonemia was associated with the homozygous L.Stin2.10
haplotype (H (1,N=97)=7.76, P=0.0054), which occurred in 33% of hyperserotonemic
patients against 6% of patients with normal 5-HT levels (Fisher's exact test:
P=0.013, OR=8). Allele interaction at the HTTLPR locus was found, with a significant
dominance variance effect on 5-HT levels. We found no transmission disequilibrium
of any of the SLC6A4 variants in ASD. Our results show that the SLC6A4 gene is
a significant factor in the determination of 5-HT levels, and that specific SLC6A4
variants are associated with an increased risk for hyperserotonemia in our sample
of autistic patients. The biological mechanism, however, is unlikely to involve
the SLC6A4 gene solely. The associated SLC6A4 alleles likely interact with other
genes or environmental factors to produce the abnormally high 5-HT levels observed
in this subset of autistic patients, who possibly represent a separate etiological
AM, Pascucci T, Puglisi-Allegra S, Militerni R, Bravaccio C, Schneider C, Melmed
R, Trillo S, Montecchi F, Palermo M, Rabinowitz D, Reichelt KL, Conciatori M,
Marino R, Keller F
Serotonin transporter gene promoter
variants do not explain the hyperserotoninemia in autistic children.
Autism is a biologically-heterogeneous disease.
Distinct subgroups of autistic patients may be marked by intermediate phenotypes,
such as elevated serotonin (5-HT) blood levels, potentially associated with different
underlying disease mechanisms. This could lead to inconsistent genetic association
results, such as those of prior studies on serotonin transporter (5-HTT) gene
promoter variants and autistic disorder. Contributions of 5-HTT gene promoter
alleles to 5-HT blood levels were thus investigated in 134 autistic patients and
291 first-degree relatives. Mean 5-HT blood levels are 11% higher in autistic
patients carrying the L/L genotype, compared to patients with the S/S or S/L genotype;
this trend is not observed in first-degree relatives. The probability of inheriting
L or S alleles is significantly enhanced in patients with 5-HT blood levels above
or below the mean, respectively (P < 0.05), but quantitative TDT analyses
yield a non-significant trend (P = 0.10), as this polymorphism explains only 2.5%
of the variance in 5-HT blood levels of autistic patients. In conclusion, 5-HTT
gene promoter variants seemingly exert a small effect on 5-HT blood levels in
autistic children, which largely does not account for hyperserotoninemia. Nonetheless,
the inconsistent outcome of prior association studies could partly stem from a
selection bias of hyper- or hypo-serotoninemic probands. [Abstract]
GM, Gutknecht L, Cohen DJ, Brailly-Tabard S, Cohen JH, Ferrari P, Roubertoux PL,
Serotonin transporter promoter variants
in autism: functional effects and relationship to platelet hyperserotonemia.
The well-replicated platelet hyperserotonemia
of autism has stimulated interest in serotonin (5-HT) in autism. We have examined
the effects of the serotonin transporter gene (5-HTT, locus SLC6A4) promoter polymorphism
(5-HTTLPR) on platelet 5-HT physiology in autism. Platelet 5-HT uptake rates and
affinities (V(max) and K(m)), uptake site densities (B(max)) and 5-HT levels were
examined in 31 French individuals with autism genotyped with respect to the 5-HTTLPR.
Platelet 5-HT uptake and 5-HT levels were measured using HPLC; uptake sites were
determined by radioligand binding. A 1.5-fold increased rate (V(max)) of platelet
5-HT uptake was observed in ll genotype individuals compared to those with ls
and ss genotypes (Mann- Whitney U-test, P = 0.022). However, no significant relationship
was observed between genotype and uptake site density (U-test, P = 0.51). Although
median levels of platelet 5-HT in platelet-rich plasma were higher in the ll group,
only trend level significance was observed (U-test, P= 0.069); platelet 5-HT content
measured in whole blood was similar across genotypes. Uptake rates were well correlated
with B(max) values (r = 0.66, P = 0.002); correlations between uptake and platelet
5-HT levels and between B(max) values and 5-HT levels were somewhat lower. While
5-HTTLPR alleles had an appreciable effect on platelet 5-HT uptake rates, effects
on 5-HT levels and uptake site density were smaller or absent. Based on these
preliminary data and prior studies of allele frequencies, we conclude that the
5-HTTLPR is not a major determinant of the group mean platelet serotonin elevation
seen in autism. However, a role for increased uptake in the hyperserotonemia of
autism can not be ruled out. In addition, it appears that studies of platelet
5-HT measures in autism and other disorders should take account of the effects
of 5-HTTLPR genotype on 5-HT uptake [Abstract]
N, Pilowsky T, Nemanov L, Arbelle S, Feinsilver T, Fried I, Ebstein RP
for an association with the serotonin transporter promoter region polymorphism
Am J Med Genet. 2001 May 8;105(4):381-6.
have examined three functional polymorphisms, serotonin transporter promoter region
polymorphism (5-HTTLPR), dopamine D4 exon III repeat region (DRD4), and catechol-O-methyltransferase
(COMT), in a small family-based design toward identifying candidate genes that
confer risk for autism. A significant excess of the long/long 5-HTTLPR genotype
was observed (likelihood ratio = 7.18; P = 0.027; 2 df; n = 33 families) as well
as preferential transmission of the long allele of the 5-HTTLPR (TDT chi-square
= 5.44; P<0.025; 1 df). No association was observed between the COMT and DRD4
polymorphisms and autism in this sample. Some previous studies have observed linkage
between autism and the 5-HTTLPR polymorphism and the current results are similar
to those first reported by Klauck et al. [1997: Hum Genet 100:224-229; 1997: Hum
Mol Genet 6:2233-2238]. Additionally, elevated serotonin levels have been consistently
found in 30%-50% of autistic patients and may represent a marker for familial
autism. Hyperserotonemia in autism appears to be due to enhanced 5-HT uptake,
as free 5-HT levels are normal and the current report of an excess of the long/long
5-HTTLPR genotype in autism could provide a partial molecular explanation for
high platelet serotonin content in autism. [Abstract]
N, Ye L, Ju W, Brown WT, Tsiouris J, Cohen I
variants not associated with autistic spectrum disorders.
To determine whether there is an association of polymorphic
variants of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR)
and autistic spectrum disorders, we analyzed the 5-HTTLPR genotypes of 72 autistic
subjects, 11 fragile X syndrome patients with autistic behavior, 43 normal subjects,
and 49 fragile X syndrome non-autistic subjects. The distribution frequency of
5-HTTLPR long allele (L) and the short allele (S) variants showed no differences
between subjects. Our findings do not support the hypothesis that polymorphic
5-HTTLPR variants are a susceptibility factor for autistic disorders. [Abstract]
EH, Courchesne R, Lord C, Cox NJ, Yan S, Lincoln A, Haas R, Courchesne E, Leventhal
Evidence of linkage between the serotonin transporter
and autistic disorder.
Mol Psychiatry. 1997 May;2(3):247-50.
serotonin transporter gene (HTT) is a primary candidate in autistic disorder based
on efficacy of potent serotonin transporter inhibitors in reducing rituals and
routines. We initiated a candidate gene study of HTT in trios consisting of probands
with autistic disorder and both parents. Preliminary transmission/disequilibrium
test (TDT) analysis with 86 families revealed no evidence for linkage or linkage
disequilibrium between autistic disorder and a polymorphism in the second intron
of HTT. However, preferential transmission of a short variant of the HTT promoter
was found in the same 86 trios (TDT chi 2 = 4.69, 1 d.f., P = 0.030). In further
analyses, we considered haplotypes of the HTT promoter variant and second intron
locus as alleles in a multiallelic TDT. Results confirmed the significance of
the effect of this region (TDT chi 2 = 11.85, 4 d.f., P = 0.018). This provides
preliminary evidence of linkage and association between HTT and autistic disorder.
AM, Militerni R, Bravaccio C, Schneider C, Melmed R, Conciatori M, Damiani V,
Baldi A, Keller F
Lack of association between serotonin
transporter gene promoter variants and autistic disorder in two ethnically distinct
Am J Med Genet. 2000 Feb 7;96(1):123-7.
studies performed to date provide conflicting evidence of linkage/association
between autistic disorder and either the "short" [Cook et al., 1997:
Mol Psychiatry 2:247-250] or the "long" [Klauck et al., 1997: Hum Mol
Genet 6:2233-2238] allele of a polymorphic repeat located in the serotonin transporter
(5-HTT) gene promoter region, affecting 5-HTT gene expression [Lesch et al., 1996:
Science 274:1527-1531]. The present study was designed to assess linkage and linkage
disequilibrium in two new ethnically distinct samples of families with primary
autistic probands. The 5-HTT promoter repeat was genotyped in 54 singleton families
collected in Italy and in 32 singleton and 5 multiplex families collected in the
U.S.A., yielding a total sample of 98 trios. Linkage/association between 5-HTT
gene promoter alleles and autistic disorder was assessed using the transmission/disequilibrium
test (TDT) and the haplotype-based haplotype relative risk (HHRR). Both the Italian
and the American samples, either singly or combined, displayed no evidence of
linkage/association between 5-HTT gene promoter alleles and autistic disorder.
Our findings do not support prominent contributions of 5-HTT gene variants to
the pathogenesis of idiopathic infantile autism. Heterogeneity in pathogenetic
mechanisms underlying the disease may require that linkage/association studies
be targeted toward patient subgroups isolated on the basis of specific biochemical
markers, such as serotonin (5-HT) blood levels. [Abstract]
E, Lai C, Marlow A, Matthews N, Wallace S, Bailey A, Cook EH, Weeks DE, Monaco
Serotonin transporter (5-HTT) and gamma-aminobutyric
acid receptor subunit beta3 (GABRB3) gene polymorphisms are not associated with
autism in the IMGSA families. The International Molecular Genetic Study of Autism
Am J Med Genet. 1999 Oct 15;88(5):492-6.
studies have suggested that the serotonin transporter (5-HTT) gene and the gamma-aminobutyric
acid receptor subunit beta3 (GABRB3) gene, or other genes in the 15q11-q13 region,
are possibly involved in susceptibility to autism. To test this hypothesis we
performed an association study on the collection of families from the International
Molecular Genetic Study of Autism (IMGSA) Consortium, using the transmission disequilibrium
test. Two polymorphisms in the 5-HTT gene (a functional insertion-deletion polymorphism
in the promoter and a variable number tandem repeat in the second intron) were
examined in 90 families comprising 174 affected individuals. Furthermore, seven
microsatellite markers spanning the 15q11-q13 region were studied in 94 families
with 182 affected individuals. No significant evidence of association or linkage
was found at any of the markers tested, indicating that the 5-HTT and the GABRB3
genes are unlikely to play a major role in the aetiology of autism in our family
data set. [Abstract]
SM, Poustka F, Benner A, Lesch KP, Poustka A
transporter (5-HTT) gene variants associated with autism?
Mol Genet. 1997 Dec;6(13):2233-8.
An association study was performed to elucidate
the role of the serotonin transporter (5-HTT) gene as a susceptibility factor
for autism as treatment of patients with antidepressant drugs which selectively
target 5-HTT reduced autistic or concomitant symptoms, such as repetitive behavior
and aggression, and ameliorate language use. Using the transmission/disequilibrium
test (TDT) an analysis was done for a common polymorphism in the upstream regulatory
region (5-HTTLPR), a VNTR in intron 2 of the gene and a haplotype of both loci
in 52 trios fulfilling stringent criteria for autism and an extended group of
65 trios including patients showing no language delay in their first 3 years of
life. A higher frequency and preferential transmission of the long allele of the
5-HTTLPR was observed, but the TDT gave a statistically significant value ( P
= 0. 032) only for the extended patient group. This result is in contrast to a
recent study by a US group presenting preliminary evidence for preferential transmission
of the short allele of 5-HTTLPR in 86 trios. Both studies failed to reveal significant
linkage disequilibrium between the VNTR in intron 2 of the gene and autism. In
our study haplotype analysis of the 5-HTTLPR and the VNTR in intron 2 supplied
evidence for an association of 5-HTT and autism in the stringent ( P = 0.069)
and extended patient group ( P = 0.049). Overall, we were not able to replicate
the findings of the first study on 5-HTT and autism and instead observed a tendency
for association of the opposite genetic variant of the gene with the disorder.
The implications for genetic variants of the serotonin transporter in the etiology
of autism and possible subgroups of patients, therefore, needs clarification in
further studies with other and larger patient samples. [Abstract]
JL, Olson LM, Dowd M, Amin T, Steele A, Blakely RD, Folstein SE, Haines JL, Sutcliffe
Linkage and association analysis at the serotonin
transporter (SLC6A4) locus in a rigid-compulsive subset of autism.
J Med Genet. 2004 May 15;127B(1):104-12.
Autism is a complex genetic neurodevelopmental
disorder in which affected individuals display deficits in language, social relationships,
and patterns of compulsive and stereotyped behaviors and rigidity. Linkage analysis
in our dataset of 57 New England and 80 AGRE multiplex autism families reveals
a multipoint heterogeneity LOD (HLOD) score of 2.74 at D17S1871 in 17q11.2. Analysis
of phenotypic subsets shows an increased HLOD of 3.62 in families with compulsive
behaviors and rigidity. The serotonin transporter locus (SLC6A4) maps nearby and
is considered a functional candidate gene in autism and obsessive-compulsive disorder.
We genotyped an insertion/deletion polymorphism in the promoter (5-HTTLPR), and
seven single nucleotide polymorphisms (SNPs) across the 38-kb transcriptional
unit. Transmission disequilibrium (TD) analysis reveals nominal association at
a SNP in intron 5 (P = 0.02) as well as 5-HTTLPR (P = 0.01), corresponding to
over-transmission of the short allele. TD analysis in the rigid-compulsive subset
shows no evidence for association. Intermarker linkage disequilibrium was determined.
All SNPs define a single haplotype block, while 5-HTTLPR lies 5' to this block.
Three SNPs are sufficient to detect all common alleles (> or =5%) in this >
26-kb block. Analysis of haplotypes for these markers demonstrates no evidence
for association to autism. These data indicate that a common allele within the
coding region of SLC6A4 is not responsible for the observed linkage. However,
the presence of heterogeneous disease variants within the block or the existence
of a common disease-associated allele either upstream or downstream of this block
is possible. In fact, such variants may well account for linkage to 17q11.2 in
our families. [Abstract]
Y, Sugie H, Fukuda T, Ito M, Ohzeki T
the adverse effects of fluvoxamine treatment in children with autistic disorder:
correlation with genetic polymorphism in serotonin related genes]
To Hattatsu. 2003 May;35(3):233-7.
Selective serotonin re-uptake inhibitors
(SSRIs) have recently been applied to the children with autistic disorder. To
create better treatment, we studied here clinical adverse effects of fluvoxamine
and correlated them with genetic polymorphism of two genes, the promoter region
of serotonin transporter gene (5-HTTLPR) and serotonin 2A receptor gene (5-HT2AR).
Twenty-eight subjects, consisting of 23 boys and 5 girls, aged from 3 to 18 years
old diagnosed as having autistic disorder were analyzed during fluvoxamine administration.
The dosages and duration of fluvoxamine treatment are 1.5 to 3 mg/kg/day and 2
weeks to 17 months (mean 7.9 months), respectively. There were several clinical
adverse effects such as sleep disturbance in 9 cases, climb up to high places
in 8, gastrointestinal symptoms in 6, hyperactivities in 5, excitement in 4, general
fatigability in 2 and urticaria in 1. Medication was discontinued in 2 patients
with fatigability and 1 with sleep disturbance, diarrhea and poor appetite. There
was no significant correlation between genetic polymorphism in 5-HTTLPR and the
occurrence of clinical adverse effects of fluvoxamine. However hyperactivity was
significantly more frequent in the subjects with 102T/102T polymorphism of 5-HT2AR,
and patients with sleep disturbance were significantly less frequent in the subjects
with 102C/102C polymorphism. We conclude that the clinical adverse effects such
as climb up to high places and hyperactivity during fluvoxamine treatment may
be relatively specific in children, and that genetic polymorphism of 5-HT2AR may
be related to the appearance of clinical adverse effects. [Abstract]
J, Kim SJ, Lord C, Courchesne R, Akshoomoff N, Leventhal BL, Courchesne E, Cook
Transmission disequilibrium studies of the serotonin
5-HT2A receptor gene (HTR2A) in autism.
Am J Med
Genet. 2002 Apr 8;114(3):277-83.
Hyperserotonemia in autism is one of the longest-standing
biochemical findings in a psychiatric disorder. This well-replicated finding and
subsequent studies of platelet serotonin receptors in autism indicate that the
serotonin 2A receptor gene (HTR2A) on chromosome 13q is a primary candidate gene
in autism. Converging data from recent genome screens also implicates the genomic
region containing HTR2A. Based on these lines of evidence, the transmission/disequilibrium
test (TDT) was used to assess transmission disequilibrium between autism and haplotypes
of three polymorphisms, including the promoter -1438 G/A single nucleotide polymorphism
(SNP) in perfect linkage disequilibrium with the 102 T/C SNP in previous studies,
a newly identified SNP in intron 1 near exon 2, and the SNP responsible for the
His452Tyr amino acid change in exon 3. Because expression studies have shown HTR2A
to be polymorphically imprinted in the brain, secondary analyses were split into
maternal and paternal transmissions. No evidence was found for unequal transmission
of haplotypes; however, power analysis reveals low power to detect a parent-of-origin
effect in this sample size. [Abstract]
J, Petit E, Martineau J, Cherpi C, Perrot A, Barthélémy C, Lelord G, Müh JP
and autism: biochemical and molecular biology features.
Res. 1996 Nov 1;65(1):33-43.
Whole blood and urinary levels of serotonin (5-hydroxytryptamine;
5-HT) and the derivative urinary 5-hydroxyindoleacetic acid (5-HIAA) were measured
in normal and autistic subjects. An association was tested between autism and
a marker coding for the 5-HT2A serotonergic receptor gene. Significant group (high
urinary 5-HT and low whole blood 5-HT in autism) and age effects (urinary 5-HT
decrease with age) were found. Moreover, whole blood 5-HT levels were correlated
with clinical state. No differences in allele and genotype frequencies for the
5-HT2A receptor marker were found in this autistic population compared with age-matched
healthy students. [Abstract]
JP, Vachirasomtoon K, Hartzell K, Leventhal M, Courchesne E, Courchesne R, Lord
C, Leventhal BL, Cook EH
Physical mapping of the serotonin
5-HT(7) receptor gene (HTR7) to chromosome 10 and pseudogene (HTR7P) to chromosome
12, and testing of linkage disequilibrium between HTR7 and autistic disorder.
J Med Genet. 1999 Oct 15;88(5):472-5.
The gene encoding the serotonin 5-HT(7)
receptor (HTR7) has been considered as a candidate locus in several neuropsychiatric
disorders, based on pharmacological evidence and ligand-binding studies. After
determining over 3 kb of previously unpublished sequence from introns 1 and 2
of HTR7, a single base (C/T) polymorphism in the second intron of HTR7 was found.
Allele-specific PCR was used to genotype the HTR7 marker in 53 trios consisting
of subjects with autistic disorder and both parents. Using the transmission disequilibrium
test (TDT), no evidence of preferential transmission of either allele was found
(TDT chi(2) = 0.252, p = 0.602). Sequence data obtained from both intron 1 and
intron 2 of HTR7, and from the 5-HT(7) pseudogene (HTR7P), was used to confirm
localization of HTR7 to 10q23 and HTR7P to 12p13 using radiation hybrid analyses.
A, Guilloud-Bataille M, Martinez M, Gillberg C, Råstam M, Sponheim E, Coleman
M, Zappella M, Aschauer H, Penet C, Feingold J, Brice A, Leboyer M
of ten candidate genes in autism by association and linkage.
J Med Genet. 2002 Mar 8;114(2):125-8.
We studied the possible involvement of
ten candidate genes in autism: proenkephalin, prodynorphin, and proprotein convertase
subtilisin/kexin type 2 (opioid metabolism); tyrosine hydroxylase, dopamine receptors
D2 and D5, monoamine oxidases A and B (monoaminergic system); brain-derived neurotrophic
factor, and neural cell adhesion molecule (involved in neurodevelopment). Thirty-eight
families with two affected siblings and one family with two affected half-siblings,
recruited by the Paris Autism Research International Sibpair Study (PARIS), were
tested using the transmission disequilibrium test and two-point affected sib-pair
linkage analysis. We found no evidence for association or linkage with intragenic
or linked markers. Our family sample has good power for detecting a linkage disequilibrium
of 0.80. Thus, these genes are unlikely to play a major role in the families studied,
but further studies in a much larger sample would be needed to highlight weaker
genetic effects. [Abstract]
DE, Gade R, Muhleman D, Sverd J
No association of
a tyrosine hydroxylase gene tetranucleotide repeat polymorphism in autism, Tourette
syndrome, or ADHD.
Biol Psychiatry. 1995 Apr 1;37(7):484-6.
J, Hérault J, Petit E, Guérin P, Hameury L, Perrot A, Mallet J, Sauvage D, Lelord
G, Müh JP
Catecholaminergic metabolism and autism.
Med Child Neurol. 1994 Aug;36(8):688-97.
The authors determined levels of dopamine
(DA) and its derivatives homovanillic acid (HVA), 3-4 dihydroxyphenylacetic acid
(DOPAC), 3 methoxytyramine and norepinephrine + epinephrine (NE + E) in the urine,
and DA, E and NE in the whole blood of 50 autistic children aged between 1 year
11 months and 16 years. An association was tested for between markers coding for
the enzymes and D3 dopaminergic receptor genes implicated in the monoaminergic
pathway and autism, using restriction fragment-length polymorphism. There were
significant modifications of catecholamine metabolites, but no difference for
allele frequencies of the genes coding for tyrosine hydroxylase, dopamine beta
hydroxylase and DRD3 in this population compared with a healthy school population
matched for chronological age. However, some of the data encourage a more complete
study of chromosome 11. [Abstract]
MB, Børglum AD, Betancur C, Philippe A, Kruse TA, Leboyer M, Ewald H
of two variants in the DOPA decarboxylase gene in patients with autism.
J Med Genet. 2002 May 8;114(4):466-70.
Though genetic risk factors are important
for the development of autism, no specific risk alleles have yet been identified.
DOPA decarboxylase (DDC) is involved in both the catecholaminergic and serotonergic
pathways and may be considered a functional candidate gene for autism. The present
study is the first to test if two new variants of possible functional significance
in the DDC gene increase the susceptibility to autism. A total of 90 parent-offspring
trios recruited in Denmark and France were investigated using the transmission
disequilibrium test (TDT). We found no evidence of linkage disequilibrium between
autism and either of the two polymorphisms. Nor did we find linkage disequilibrium
between autism and haplotypes of the two variants using a multiallelic TDT. These
findings suggest that the DDC gene is unlikely to play a major role in the development
of autism in our data set. [Abstract]
J, Sobell JL, Heston LL, Cook EH, Goldman D, Sommer SS
of the dopamine D1 and D5 receptor genes by REF in neuropsychiatric patients reveals
a novel missense change at a highly conserved amino acid.
J Med Genet. 1998 Mar 28;81(2):172-8.
In previous analyses of schizophrenic
patients, multiple missense changes and one nonsense change were identified in
the D5 dopamine receptor (DRD5) gene, but no sequence changes of likely functional
significance were identified in the D1 dopamine receptor (DRD1) gene. In the present
study, we examined these genes in patients with certain other neuropsychiatric
disorders that may be related to dopaminergic dysregulation. The coding regions
of the DRD1 and DRD5 genes were examined in 25 and 25 autistic patients, 25 and
28 attention deficit hyperactivity disorder patients, and 51 and 43 alcoholic
patients, respectively. In addition, the DRD5 gene was examined in 75 schizophrenic
patients to search for additional variants affecting protein structure or expression
(VAPSEs). These patients were analyzed with REF (restriction endonuclease fingerprinting),
a hybrid between SSCP and restriction endonuclease digestion, which allows the
entire coding sequence to be screened in one lane of a gel. Approximately 800
kb of genomic sequence were examined. No sequence changes were identified in the
DRD1 gene among the 101 patient samples analyzed. Two sequence changes were identified
in the DRD5 gene among the 171 patient samples. These included one previously
identified silent polymorphism at base pair 978 (P326P). The change was identified
in patients from all disease categories and from different ethnic backgrounds.
One novel missense change, L88F, occurred in transmembrane domain II at a highly
conserved amino acid in all dopamine receptors as well as in alpha1- and beta-adrenergic
receptors. The mutation was identified in a Caucasian male patient with autism.
Further analysis is necessary to determine if this missense change is associated
with a particular neuropsychiatric phenotype. [Abstract]
J, Petek E, Nakabayashi K, Tsui LC, Vincent JB, Scherer SW
of the human cortactin-binding protein-2 gene from the autism candidate region
Genomics. 2001 Nov;78(1-2):7-11.
chromosome 7q31 contains putative susceptibility loci for autism (AUTS1) and speech
and language disorder (SPCH1). We report here the identification and characterization
of a novel gene encoding cortactin-binding protein-2 (CORTBP2), which is located
45 kb telomeric to the cystic fibrosis transmembrane conductance regulator gene
(CFTR) at 7q31.3. The full-length (5975-bp) gene was isolated and found to be
composed of 23 exons encompassing 170 kb of DNA. In addition to being a positional
candidate for AUTS1, CORTBP2 was expressed at highest levels in the brain, as
shown by northern blot analysis. Subsequent mutation analysis of CORTBP2 in 90
autistic patients identified two polymorphisms, including a leucine to valine
change caused by a T to G substitution in exon 15. However, comparison of allele
frequencies between autistic and control populations (n=96) showed no significant
difference, suggesting that this variant is not a susceptibility factor for autism.
AM, Militerni R, Bravaccio C, Schneider C, Melmed R, Trillo S, Montecchi F, Palermo
M, Pascucci T, Puglisi-Allegra S, Reichelt KL, Conciatori M, Keller F
association between the 4g/5G polymorphism of the plasminogen activator inhibitor-1
gene promoter and autistic disorder.
Plasmin, a serine protease, is involved in many physiologically
relevant processes, including haemostasis, cellular recruitment during immune
response, tumour growth, and also neuronal migration and synaptic remodelling.
Both tissue-type and urokinase-type plasminogen activators can be efficiently
inhibited by plasminogen activator inhibitor-1 (PAI-1), a protease inhibitor of
the serpin family. The human PAI-1 gene is located on chromosome 7q, within or
close to a region that has been linked to autism in several linkage studies. Autism
seems to be characterized by altered neuronal cytoarchitecture, synaptogenesis
and possibly also cellular immune responses. We began addressing the potential
involvement of the PAI-1 gene in autistic disorder with this linkage/association
study, assessing transmission patterns of the 4G/5G polymorphism in the PAI-1
gene promoter that was previously shown to significantly affect PAI-1 plasma levels.
No linkage/association was found in 167 trios with autistic probands, recruited
in Italy and in the USA. We thus found no evidence that this polymorphism, or
putative functionally relevant gene variants in linkage disequilibrium with it,
confer vulnerability to autistic disorder. [Abstract]
P, Bacchelli E, Blasi F, Lipp HP, Toniolo D, Maestrini E
variants in the human RAB3A gene are not associated with autism.
Brain Behav. 2004 Apr;3(2):123-4.
Mutation screening of the RAB3A gene in 47
individuals with autism provided no evidence that DNA variants in this gene are
associated with autism. Since Rab3a constitutive knockout mice react to novel
stimuli with hyperactivity, a further search for association of RAB3A DNA variants
with other neurobehavioral disorders such as attention deficit/hyperactivity disorder
appears justified. [Abstract]
K, Murch A, Petterson B, Hill W, Nikolova-Hill A, Bradley L, Jackson S, Hallmayer
An investigation into sub-telomeric deletions of
chromosome 22 and pervasive developmental disorders.
J Med Genet. 2004 Feb 15;125B(1):99-104.
Deletions of the sub-telomeric region
of chromosome 22 have been associated with mental retardation, developmental delay,
and autistic behaviors. This study investigated sub-telomeric anomalies of chromosome
22 using fluorescent in situ hybridization (FISH) probes in 82 subjects diagnosed
with autism and atypical autism. No microdeletions were detected in this group.
Similar FISH analyses were undertaken on two children with developmental delay,
who were ascertained to be ring 22 during routine cytogenetic investigations.
One subject was shown to have a microdeletion in the sub-telomeric region tested.
Both children met the social and communication cut off for autism on the ADI and
but did not meet the cut off for restrictive and repetitive behaviors. Only one
of the two children met the criteria for PDD on the ADOS. [Abstract]
S, Yamazaki K, Yamamoto K, Koishi S, Enseki Y, Nakamura Y, Oya A, Yasueda M, Asakura
A, Aoki Y, Atsumi M, Inomata J, Inoko H, Matsumoto H
gene polymorphisms are not associated with autism in Japanese population.
J Med Genet. 2004 Feb 15;125B(1):61-2. [Abstract]
MB, Nyegaard M, Betancur C, Colineaux C, Josiassen TL, Kruse TA, Leboyer M, Ewald
Analysis of transmission of novel polymorphisms
in the somatostatin receptor 5 (SSTR5) gene in patients with autism.
J Med Genet. 2003 Aug 15;121B(1):100-4.
Infantile autism is a pervasive developmental
disorder with a strong genetic component. The mode of inheritance appears to be
complex and no specific susceptibility genes have yet been identified. Chromosome
16p13.3 may contain a susceptibility gene based on findings from genome scans
and reports of chromosome abnormalities in individuals with autism. The somatostatin
receptor 5 (SSTR5) gene is located on chromosome 16p13.3 and is thus a positional
candidate gene for autism. SSTR5 may also be a functional candidate gene for autism
because somatostatin inhibits growth hormone secretion, and increased growth hormone
response has been reported in some individuals with autism. Moreover, the somatostatinergic
system interacts with the dopaminergic system, which has been hypothesized to
be involved in the etiology of autism; in particular, somatostatin secretion is
regulated by dopamine, and the dopamine D2 receptor and the SSTR5 receptor interact
to form a receptor complex with enhanced functional activity. In the present study,
we tested whether the alleles of twelve new single nucleotide polymorphisms (SNPs)
in the SSTR5 gene were preferentially transmitted, using the transmission disequilibrium
test (TDT) in a sample of 79 trios with autism (18 from Denmark and 61 from France).
Furthermore, we combined four missense SNPs into haplotypes and searched for preferential
transmission using the program TRANSMIT. No significant preferential transmission
of the alleles and haplotypes of the twelve SNPs was found. Our results do not
suggest the SSTR5 gene as a susceptibility gene for autism. [Abstract]
R, Zhong H, Serajee FJ, Huq AH
No association between
single nucleotide polymorphisms in DLX6 and Piccolo genes at 7q21-q22 and autism.
J Med Genet. 2003 May 15;119B(1):98-101.
Several independent genome scans have
revealed excess allele sharing in an overlapping 40 cM region of 7q21-34 in autism.
DLX6 and Piccolo (PCLO) at 7q21-q22 are two positional and functional candidate
genes in autism. We have investigated a single nucleotide polymorphism (SNP) in
exon 4 of the PCLO gene and a SNP in intron 1 of the DLX6 gene for linkage and
association in autistic disorder using both qualitative and quantitative analyses.
One hundred ninety-six multiplex autistic disorder families were tested using
transmission disequilibrium and two-point affected sib pair linkage analysis.
We found no evidence of association or linkage with the two intragenic markers.
In addition, there was also no linkage or association between language and stereotypic
behavior quantitative traits in autism and the SNPs. In conclusion, our studies
suggest that these two SNPs in DLX6 and PCLO genes are not in linkage disequilibrium
with autism. [Abstract]
P, Petit E, Müh JP, Andres C, Bienvenu T, Beldjord C, Chelly J, Barthélémy C
of the coding sequence of the doublecortin gene as a susceptibility locus in autistic
Am J Med Genet. 2002 Mar 1;108(2):164-7.
S, Quach H, Quintana-Murci L, Betancur C, Philippe A, Gillberg C, Sponheim E,
Skjeldal OH, Fellous M, Leboyer M, Bourgeron T
haplogroups in autistic subjects.
The male to female ratio in autism is 4:1 in the global autistic
population, but increases to 23:1 in autistic subjects without physical or brain
abnormalities.(1) Despite this well-recognised gender difference, male predisposition
to autistic disorder remains unexplained and the role of sex chromosomes is still
debated. Numerical and structural abnormalities of the sex chromosomes are among
the most frequently reported chromosomal disorders associated with autism. However,
genome scans have failed to detect linkage on the X chromosome(2,3,4) and this
approach cannot study the non-recombining region of the Y chromosome. In this
study, we searched for a specific Y chromosome effect in autistic subjects. Using
informative Y-polymorphic markers, the Y chromosome haplotypes of 111 autistic
subjects from France, Sweden and Norway were defined and compared with relevant
control populations. No significant difference in Y-haplotype distribution between
the affected and control groups was observed. Although this study cannot exclude
the presence of a Y susceptibility gene, our results are not suggestive of a Y
chromosome effect in autism. [Abstract]
TK, Bischof JM, Wevrick R
A necdin/MAGE-like gene
in the chromosome 15 autism susceptibility region: expression, imprinting, and
mapping of the human and mouse orthologues.
BACKGROUND: Proximal chromosome 15q is implicated in neurodevelopmental
disorders including Prader-Willi and Angelman syndromes, autistic disorder and
developmental abnormalities resulting from chromosomal deletions or duplications.
A subset of genes in this region are subject to genomic imprinting, the expression
of the gene from only one parental allele. RESULTS: We have now identified the
NDNL2 (also known as MAGE-G) gene within the 15q autistic disorder susceptibility
region and have mapped its murine homolog to the region of conserved synteny near
necdin (Ndn) on mouse Chr 7. NDNL2/MAGE-G is a member of a large gene family that
includes the X-linked MAGE cluster, MAGED1 (NRAGE), MAGEL2 and NDN, where the
latter two genes are implicated in Prader-Willi syndrome. We have now determined
that NDNL2/Ndnl2 is widely expressed in mouse and human fetal and adult tissues,
and that it is apparently not subject to genomic imprinting by the PWS/AS Imprinting
Center. CONCLUSION: Although NDNL2/MAGE-G in the broadly defined chromosome 15
autistic disorder susceptibility region, it is not likely to be pathogenic based
on its wide expression pattern and lack of imprinted expression. [Abstract]
J, Craddock N, Jones IR, Cook EH, Goldman D, Heston LL, Peltonen L, DeLisi LE,
Systematic screening for mutations in the
glycine receptor alpha2 subunit gene (GLRA2) in patients with schizophrenia and
other psychiatric diseases.
Psychiatr Genet. 2001
The glycine receptor, which is a member of the ligand-gated
ion channel superfamily, mediates synaptic inhibition in the spinal cord and other
brain regions. This superfamily has been implicated in the pathogenesis of schizophrenia
and other psychiatric diseases. The complete coding sequence and splice junctions
of the GLRA2 gene were scanned by DOVAM-S, a form of SSCP analysis with sufficient
redundancy to detect virtually all mutations. Those analyses were performed in
113 patients with schizophrenia, and in pilot studies of patients with bipolar
illness, alcoholism, puerperal psychosis, autism, and attention-deficit hyperactivity
disorder (533 kb total scanned sequences). We detected three sequence changes
in the coding region, all resulting in silent mutations: C894T in exon 5, C1134T
in exon 7, and C1476T in exon 9. These do not alter the structure or the expression
of the protein. It is unlikely that mutations in the coding region and splice
junction of GLRA2 gene are associated with schizophrenia and other psychiatric
SJ, Gonen D, Hanna GL, Leventhal BL, Cook EH
polymorphism in the coding region of the human NESP55 alternative transcript of
Mol Cell Probes. 2000 Jun;14(3):191-4.
a novel member of the chromogranins, was originally implicated as a precursor
of a peptide LSAL with 5-HT1B receptor antagonist activity. In humans, NESP55
(MIM 139320) is encoded by an alternative transcript of GNAS1, the gene encoding
the guanine nucleotide-binding alpha subunit of G(S). As a result of the potential
relevance of NESP55 to serotoninergic neurotransmission, we screened its sequence
using genomic DNA pools from autistic disorder, obsessive-compulsive disorder
(OCD) probands and control subjects. Six single nucleotide polymorphisms (SNPs)
were identified and the allele frequencies of those SNPs were determined. In addition,
a 24-bp in-frame deletion in the coding region was found in one of the OCD probands.
To further investigate its pattern of inheritance and the relevance to studied
phenotypes, we genotyped 123 total subjects from autism, OCD and attention deficit
hyperactivity disorder (ADHD) families. The deletion was detected only in one
OCD family and followed Mendelian inheritance. All subjects with the deletion
were heterozygous. However, there are no specific behavioural or physical alterations
in the subjects with this deletion variant. The physiological role of NESP55 in
serotoninergic neurotransmission as well as the effect of the deletion on its
function should be evaluated in future studies. [Abstract]
P, Zhong N, Dobkin C, Brown WT
Polymorphism of FXR1
showing lack of association with autism.
Am J Med
Genet. 1997 Jul 25;74(4):453-4. [Abstract]
E, Kuivaniemi H, Huq AH, Tromp G, Behen M, Rothermel R, Herron J, Chugani DC
study of novel polymorphisms in the upstream region of vasoactive intestinal peptide
receptor type 2 gene in autism.
J Child Neurol. 2001
We investigated the vasoactive intestinal peptide receptor
type 2 (VIPR2) gene as a candidate gene for autism. We searched for mutations
in the VIPR2 gene in autistic individuals, and 10 novel polymorphisms were identified.
Three polymorphisms in the upstream region were studied in detail, and there was
no significant difference in the frequencies between the autistic group (n = 14)
and unrelated controls (n = 52). The distribution of the genotypes in two of the
three polymorphisms differed somewhat between autistic subjects with gastrointestinal
problems and those without. Moreover, there was a trend showing a correlation
between the genotypes for the third polymorphism and the severity of stereotypical
behavior as ranked by the Gilliam Autism Rating Scale. These preliminary results
suggest that VIPR2 may have a role in gastrointestinal symptoms and stereotypical
behaviors in autism, although a larger collection of samples suitable for transmission
disequilibrium tests is necessary to validate the results. [Abstract]