The state of research on the genetics of autism spectrum disorder: methodological, clinical and conceptual progress

Abstract

Autism spectrum disorder (ASD) is a behaviorally heterogeneous disorder with a strong genetic component, as evidenced by decades of twin and family studies. In recent years, enhanced methods of genomic sequencing have revealed that structural variation and mutations to both coding and non-coding regions of single, candidate genes may account for more than 30% of ASD cases. The current review highlights a genotype-first approach that builds upon these molecular findings to parse the heterogeneity of ASD. Advantages of this approach include strong potential for precision medicine diagnosis and treatment, as well as opportunity to advance basic science research on neurodevelopmental disorders. Psychosocial benefits of identifying genetic subtypes of ASD have already been realized through social networking, comprehensive clinical phenotyping, and increased awareness among providers of rare genetic mutations.

Figure 1.

A genotype-first approach to parsing phenotypic heterogeneity in ASD entails subgrouping individuals that share recurrent rare disruptive mutations in the same gene or genomic region. This approach has identified several neurogenetic subtypes yielding insight into neurological mechanisms and potential novel treatment targets for ASD, including CHD8, 16p11.2 CNV, and SCN2A. CHD8 has emerged as an ASD-specific subtype; 16p11.2 CNV demonstrates the potential for variant-specific expression; SCN2A presents targets for pharmacological intervention.