Autism, Susceptibility To, 17

A number sign (#) is used with this entry because this form of autism, designated AUTS17, is associated with heterozygous mutation in the SHANK2 gene (603290) on chromosome 11q13.

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.

Clinical Features

Autism spectrum disorder (ASD) and mental retardation are 2 clinically distinct neurodevelopmental disorders with a complex genetic etiology. However, both show a high degree of heritability and can occur either as isolated entities or as a combined phenotype. About 40% of individuals with ASD have some form of developmental delay or mental retardation, suggesting a common underlying etiology (summary by Berkel et al., 2010).

Molecular Genetics

By genomewide microarray scan for copy number variants (CNV) in a German cohort of 184 unrelated individuals with mental retardation and a series of 396 Canadian individuals with ASD, Berkel et al. (2010) found 1 patient in each cohort who had a de novo deletion in the SHANK2 gene: a deletion of 120 kb (603290.0001) and 69 kb (603290.0002), respectively. The clinical report indicated that both patients had ASD of comparable severity as well as mild to moderate mental retardation. CNVs in the SHANK2 gene were not observed in 5,023 matched controls. Both deletions disrupt the highly conserved PDZ domain, leading to a frameshift mutation and presumably causing haploinsufficiency. Sequencing of the SHANK2 gene identified another ASD patient with a de novo nonsense mutation (R462X; 603290.0003). In addition, 6 missense mutations and a 6-bp duplication were found in the SHANK2 gene in individuals with either ASD or mental retardation, and not in 659 controls. All of these variants were inherited from an unaffected parent, although 2 transmitting parents had depression and/or anxiety. Berkel et al. (2010) suggested that these inherited rare variants may show incomplete penetrance, but that the significance was uncertain. Overall, the findings indicated that disruption of the SHANK2 gene, which plays a role in postsynaptic scaffolding, may affect synaptic function and predispose to autism or mental retardation.