Somatic Mosaicism and Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) is a genetically heterogenous neurodevelopmental disorder. In the early years of next-generation sequencing, de novo germline variants were shown to contribute to ASD risk. These germline mutations are present in all of the cells of an affected individual and can be detected in any tissue, including clinically accessible DNA sources such as blood or saliva. In recent years, studies have also implicated de novo somatic variants in ASD risk. These somatic mutations arise postzygotically and are present in only a subset of the cells of an affected individual. Depending on the developmental time and progenitor cell in which a somatic mutation occurs, it may be detectable in some tissues and not in others. Somatic mutations detectable at relatively low sequencing coverage in clinically accessible tissues are suggested to contribute to 3-5% of simplex ASD diagnoses, and "brain limited" somatic mutations have been identified in postmortem ASD brain tissue. Somatic mutations likely represent the genetic diagnosis in a proportion of otherwise unexplained individuals with ASD, and brain limited somatic mutations can be used as markers to discover risk genes, cell types, brain regions, and cellular pathways important for ASD pathogenesis and to potentially target for therapeutics.

Keywords: autism spectrum disorder; genetic diagnosis; mosaic variant; next-generation sequencing; postzygotic mutation; somatic mosaicism.

Figure 1

Detection of germline and somatic mosaic mutations by Sanger sequencing (top row) and next-generation sequencing (bottom row) approaches in DNA extracted from clinically accessible tissues such as blood. In this figure the example of an A (depicted in red) to G (depicted in yellow) mutation is used. A germline inherited mutation, in this example a heterozygous mutation inherited from the mother, is detectable as a heterozygous mutation in Sanger sequencing of both the proband and the mother and detectable in 50% of the NGS reads of the proband. A germline de novo mutation or a parental gonadal mosaic mutation is detectable as a heterozygous mutation in Sanger sequencing of the proband, not detectable in Sanger sequencing of the parents, and detectable in 50% of the NGS reads in the proband. A somatic mutation is sometimes detectable in Sanger sequencing of the proband (in this example, as the small yellow peak) and is detectable in <50% of the NGS reads (in this example, 20% of the NGS reads) in the proband.