Genetics of Autism Spectrum Disorders: The Opportunity and Challenge in the Genetics Clinic

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The involvement of genetic etiology in autism spectrum disorders (ASDs) was first suggested from a twin study reported in 1970s. This initial observation has then been validated in many subsequent studies. The identification of single genes in syndromic ASDs in 1990s provided the evidence to support a genetic cause of ASDs. Since 2005, genome-wide copy number variant and sequence analyses have uncovered a list of rare and highly penetrant copy number variants (CNVs) or single nucleotide variants (SNVs) associated with ASDs which strengthen the claim of a genetic etiology for ASDs. However, the cause in majority of ASDs (> 75 %) remains elusive. The increasing prevalence of ASD also has intensified a debate about the role of non-genetic factors, such as epigenetics, environment, and gene and environment interaction, in the ASD etiology. Although it remains a significant challenge to determine the cause in majority cases of ASDs, the findings from ASD genetics studies now support an important application for molecular diagnostics in the clinical genetics evaluation of ASDs. Various molecular diagnostic assays including single gene tests, targeted multiple gene panels and copy number analysis are all appropriate to be considered in the clinical genetics evaluation of ASDs in clinics. Whole exome sequencing could also be considered in selective clinical cases. However, the challenge remains to determine the causal role of the various types of genetic variants identified through molecular testing. The variable expressivity, pleiotropic effect and incomplete penetrance associated with CNVs and SNVs also present a significant challenge for genetic counseling and prenatal diagnosis.