Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

Abstract

Autism spectrum disorder (ASD) is a group of highly genetic neurodevelopmental disorders characterized by language, social, cognitive, and behavioral abnormalities. ASD is a complex disorder with a heterogeneous etiology. The genetic architecture of autism is such that a variety of different rare mutations have been discovered, including rare monogenic conditions that involve autistic symptoms. Also, de novo copy number variants and single nucleotide variants contribute to disease susceptibility. Finally, autosomal recessive loci are contributing to our understanding of inherited factors. We will review the progress that the field has made in the discovery of these rare genetic variants in autism. We argue that mutation discovery of this sort offers an important opportunity to identify neurodevelopmental mechanisms in disease. The hope is that these mechanisms will show some degree of convergence that may be amenable to treatment intervention.

Fig. 1

Model on genetic architecture of autism spectrum disorder (ASD; adapted from Morrow et al. [11]). The heterogeneity in autism may be dissected into 2 groups, approximately lower-functioning and higher-functioning groupings. One hypothesis with some support is that the genetic architecture of lower-functioning autism may involve a relatively smaller number per patient of rare and highly penetrant mutations. By contrast, the genetic architecture of higher-functioning autism may involve a large number of common variants with minor effect. The pie chart indicates the multitude of individually rare, highly penetrant genetic causes that may be identified in lower-functioning ASD. Of the cases of autism, at least 70 % have no known genetic mechanisms [16]. The data in the pie chart are hypothetical to reflect a large number of individually rare loci identified in cases; the largest piece of the pie represents a majority of cases in whom a genetic mutation is still not identified