Autism, Susceptibility To, 15

A number sign (#) is used with this entry because of evidence that variation in the CNTNAP2 gene (604569) on chromosome 7q35-q36 influences susceptibility to autism.

For another form of susceptibility to autism in the 7q35-q36 region, see AUTS10 (611016).

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

To study the genetics of autism, Alarcon et al. (2002) divided the syndrome into component autism-related traits (endophenotypes), hypothesizing that quantitative trait loci (QTLs) related to one or more of these traits might underlie putative or significant regions of autism linkage. They performed nonparametric linkage analyses in 152 families segregating autism, focusing on 3 traits derived from the Autism Diagnostic Interview: 'age at first word,' 'age at first phrase,' and a composite measure of 'repetitive and stereotyped behaviors.' Using nonparametric multipoint linkage analysis, they found the strongest QTL evidence for the age at first word on 7q35-q36, and subsequent linkage analyses of additional markers and association analyses of the same region supported the initial result. Moreover, the peak fine-mapping result for repetitive behaviors localized to a region overlapping this language QTL. The authors suggested that a putative autism susceptibility locus on distal chromosome 7q may be the result of separate QTLs for the language and repetitive or stereotyped behavior deficits that are associated with the disorder.

Cytogenetics

Poot et al. (2010) reported a boy with autism, delayed motor development, mild ataxia with poor coordination, hyperactivity, poor speech development, outbursts, and some features of Tourette syndrome (137580). The authors described a highly complex chromosomal rearrangement involving at least 3 breaks in chromosome 1 and 7 breaks in chromosome 7 on the paternally derived chromosome. There was a de novo paracentric inversion inv(7)(q32.1q35) that disrupted the CNTNAP2 gene (604569). Additionally, 2 CNTNAP2 gene segments were inserted into a gene-poor region on the chromosome 1q31.2 region. There was also a de novo deletion encompassing the distal part of intron 1 and exon 2 of CNTNAP2, and a de novo deletion of chromosome 1q41, spanning 15 annotated genes including KCTD3 (613272) and USH2A (608400), which has been reported as an autism susceptibility locus (AUTS11; 610836). Poot et al. (2010) suggested that haploinsufficiency for the CNTNAP2 gene may have caused the Tourette syndrome features, and that the combination of CNTNAP2 disruption and 1q41 deletion may have acted together to result in full-blown autism.

Molecular Genetics

Following up on the work of Alarcon et al. (2002), Alarcon et al. (2008) described results from 2 complementary approaches used to identify risk variants on chromosome 7 that likely contribute to the etiology of autism (209850). A 2-stage association study across a 10-Mb 7q35 language-related autism quantitative trait locus (QTL) in trios demonstrated significant association with CNTNAP2 (rs270102; 604569.0002), a strong a priori candidate. Male-only-containing families were identified as primarily responsible for this association signal, consistent with a strong male affection bias in autism and other language-based disorders. Gene expression analyses in developing human brain further identified CNTNAP2 as enriched in circuits important for language development. Together, these results provided convergent evidence for involvement of CNTNAP2, a neurexin family member, in autism, and demonstrated a connection between genetic risk for autism and specific brain structures.

Arking et al. (2008) performed a 2-stage genetic study in which genomewide linkage and family-based association mapping were followed up by association and replication studies in an independent sample. They identified a common polymorphism in CNTNAP2 (604569.0003) that was significantly associated with autism susceptibility. Importantly, the genetic variant displayed a parent-of-origin and gender effect recapitulating the inheritance of autism.

Bakkaloglu et al. (2008) identified a de novo chromosome 7q inversion disrupting autism susceptibility candidate-2 (AUTS2; 607270) and CNTNAP2 in a child with cognitive and social delay. By in situ and biochemical analyses they confirmed expression of CNTNAP2 in relevant brain regions and demonstrated the presence of CNTNAP2 in the synaptic plasma membrane fraction of rat forebrain lysates. They comprehensively resequenced CNTNAP2 in 635 patients and 942 controls. Among patients, they identified a total of 27 nonsynonymous changes; 13 were rare and unique to patients, and 8 of these were predicted to be deleterious by bioinformatic approaches and/or altered residues conserved across all species tested. One variant at a highly conserved position, I869T (604569.0004), was inherited by 4 affected children in 3 unrelated families, but was not found in 4,010 control chromosomes. Overall, these resequencing data were interpreted as demonstrating a modest nonsignificant increase in the burden of rare variants in cases versus controls. Bakkaloglu et al. (2008) concluded that in light of other studies (Alarcon et al. (2008), Arking et al. (2008)) showing a relationship between autism and common CNTNAP2 alleles, the cytogenetic and mutation screening data suggested that rare variants may also contribute to the pathophysiology of autism spectrum disorder (ASD) but place limits on the magnitude of this contribution.

A genomewide association study by Ma et al. (2009) of 438 Caucasian families with 1,390 individuals with autism and validation in an additional cohort of 2,390 samples from 457 families did not show a significant association between autism and rs270102, which was the tagging SNP in the study of Alarcon et al. (2008). No tested markers linking to the CNTNAP2 gene were significant after correction.