Autism, Susceptibility To, 10

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.

Gutknecht (2001) reviewed the 4 first full-genome scans published to that date with the conclusion that, although findings must be considered with caution because lod score values did not reach the threshold for significant linkage, a region of approximately 50 cM on the long arm of chromosome 7 to which the EN2 gene (131310) maps appeared to play a role in the etiology of autistic disorder.

Molloy et al. (2005) reported 34 families in which 1 individual had autism, a relative had either autism or autism spectrum disorder, and both had a definite history of developmental regression. Developmental regression was defined as loss of language skills and/or loss of other socially communicative skills, such as eye contact or gestures, between the ages of 18 and 24 months. However, the authors noted that most children who experience regression do not have completely normal development prior to the regressive episode. Genomewide analysis found significant linkage to 7q35-q36 (nonparametric lod score of 3.7 near marker D7S483; maximum multipoint lod score of 2.0 under dominant inheritance). Significant linkage for this phenotypic subgroup was also identified on chromosome 21p13-q11 (AUTS12; 610838).

For another form of susceptibility to autism in the chromosome 7q35-q36 region, see AUTS15 (612100).

Molecular Genetics

Associations Pending Confirmation

Petit et al. (1995) tested 2 markers of the homeogene engrailed-2 (EN2; 131310) on chromosome 7q36 in separate populations of 100 autistic and 100 control children. The gene is involved in cerebellar development. With a probe showing a PvuII polymorphism, the investigators found significant differences in the allele frequencies between the 2 populations. With a second probe showing an SstI polymorphism, no difference was apparent.

Benayed et al. (2005) examined EN2 as a candidate gene for autism spectrum disorder because En2 mouse mutants display anatomic phenotypes in the cerebellum that are similar to those reported for individuals with autism, and because EN2 maps to a region of 7q36 that had provided suggestive evidence for linkage to autism spectrum disorder. Benayed et al. (2005) replicated the finding of Gharani et al. (2004) of association between autism spectrum disorder and 2 intronic SNPs of the EN2 gene, rs1861972 (131310.0001) and rs1861973 (131310.0002). Population-attributable risk calculations for the associated haplotype performed using their entire sample of 518 families determined that the risk allele contributes to as many as 40% of autism spectrum disorder cases. These data and the results of functional studies in which misexpression of mouse En2 in primary cortical cultures elicited a reduction in neuronal differentiation provided additional genetic evidence that EN2 may act as an autism spectrum disorder susceptibility locus, and suggested that a risk allele that perturbs the spatial/temporal expression of EN2 could significantly alter normal brain development.