Autism, Susceptibility To, 9

Description

Autism, the prototypic pervasive developmental disorder (PDD), is usually apparent by 3 years of age. It is characterized by a triad of limited or absent verbal communication, a lack of reciprocal social interaction or responsiveness, and restricted, stereotypic, and ritualized patterns of interests and behavior (Bailey et al., 1996; Risch et al., 1999). 'Autism spectrum disorder,' sometimes referred to as ASD, is a broader phenotype encompassing the less severe disorders Asperger syndrome (see ASPG1; 608638) and pervasive developmental disorder, not otherwise specified (PDD-NOS). 'Broad autism phenotype' includes individuals with some symptoms of autism, but who do not meet the full criteria for autism or other disorders. Mental retardation coexists in approximately two-thirds of individuals with ASD, except for Asperger syndrome, in which mental retardation is conspicuously absent (Jones et al., 2008). Genetic studies in autism often include family members with these less stringent diagnoses (Schellenberg et al., 2006).

For a discussion of genetic heterogeneity of autism, see 209850.

Mapping

The International Molecular Genetic Study of Autism Consortium (1998) conducted a 2-stage genome search for susceptibility loci for autism, using 87 affected sib pairs and 12 non-sib affected relative pairs from a total of 99 families. Regions on 6 chromosomes were identified that generated a multipoint maximum lod score of greater than 1. A region on 7q31-q34 was the most significant, with a maximum lod score of 3.55 near markers D7S530 and D7S684 in the subset of 56 U.K. affected sib-pair families, and a maximum lod score of 2.53 in all 87 affected sib-pair families. An area on 16p near the telomere was the next most significant, with a maximum lod score of 1.97 in the U.K. families and 1.51 in all families.

Vincent et al. (2000) identified an autistic individual carrying a translocation, t(7;13)(q31.3;q21), with the chromosome 7 breakpoint located in the region of 7q in which a susceptibility locus for autism had been postulated. They found that a novel gene, called RAY1 (ST7; 600833), on 7q31 was interrupted by the translocation breakpoint. Mutation screening of the entire coding region in a set of 27 unrelated autistic individuals failed to identify phenotype-specific variants, suggesting that coding mutations in the RAY1 gene are unlikely to be involved in the etiology of autism.

Lamb et al. (2005) analyzed 219 affected sib pairs with autism and found evidence for 2 susceptibility loci on chromosome 7q, at D7S477 and the interval D7S530 to D7S640. Multipoint linkage analysis yielded a maximum lod score of 2.31 near D7S530. The lod score increased to 2.55 between D7S480 and D7S530 when 145 male sibs were considered, suggesting that genomic imprinting may play a role.

Gutknecht (2001) reviewed published full-genome scans and found that a region of approximately 50 cM on 7q appeared to play a role in the etiology of autistic disorder. She noted, however, that the finding must be considered with caution because lod score values did not reach the threshold for significant linkage.

Folstein and Mankoski (2000) suggested a relationship between autism and specific language impairment (SLI; see 602081) because genetic studies in each disorder point to a locus on 7q31.

In a metaanalysis of 9 published genome scans on autism or autism spectrum disorders, Trikalinos et al. (2006) found evidence for significant linkage to 7q22-q32, confirming the findings of previous studies. The flanking region 7q32-qter reached a less stringent threshold for significance.

Molecular Genetics

Associations Pending Confirmation

In 204 families with autism, Campbell et al. (2006) found a significant association between autism and a G-C transversion in the promoter of the MET gene (rs1858830; 164860.0011). The association was confirmed in a replication study of 539 additional autistic families and in the combined sample. Multiplex families, in which more than 1 child has autism, exhibited the strongest allelic association (p = 0.000007). In case-control analysis, the relative risk for autism was 2.27 for the CC genotype and 1.67 for the GC genotype compared to the GG genotype.

Wassink et al. (2001) examined WNT2 (147870) as a candidate gene for autism for several reasons: the WNT family of genes influences the development of numerous organs and systems, including the central nervous system; WNT2 is located in the 7q31-q33 region linked to autism and is adjacent to a chromosomal breakpoint in an individual with autism; and a mouse knockout of the dishevelled-1 (DVL1; 601365) gene, a member of a gene family essential for the function of the WNT pathway, exhibits a behavioral phenotype characterized primarily by diminished social interaction (Lijam et al., 1997). Wassink et al. (2001) found 2 families containing nonconservative coding sequence variants that segregated with autism. They also identified linkage disequilibrium between a WNT2 3-prime untranslated region SNP and their sample of autism-affected sib-pair families and trios (2 parents and 1 affected child). Linkage disequilibrium occurred almost exclusively in a subgroup of affected sib-pair families defined by the presence of severe language abnormalities and was also found to be associated with evidence for linkage to 7q.

However, in a later study, McCoy et al. (2002) found no significant association between autistic disorder and WNT2 genotypes in either an overall dataset or a language-impaired subset of families. No activating mutation in the coding region of WNT2 was found.

Exclusion of the FOXP2 Gene

Mutation in the FOXP2 gene (605317) on chromosome 7q31 is responsible for a severe monogenic form of speech and language impairment known as developmental verbal dyspraxia (SPCH1; 602081). Since AUTS9 maps to a similar region, it has been proposed that a single genetic factor on chromosome 7q31 contributes to both autism and language disorders. However, Newbury et al. (2002) used association and mutation screening analyses to conclude that the coding region variants in FOXP2 do not underlie the AUTS9 linkage, and that the FOXP2 gene is unlikely to play a role in autism or more common forms of language impairment.