Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder

Abstract

Genetic risk factors for autism spectrum disorder (ASD) have yet to be fully elucidated. Postzygotic mosaic mutations (PMMs) have been implicated in several neurodevelopmental disorders and overgrowth syndromes. By leveraging whole-exome sequencing data on a large family-based ASD cohort, the Simons Simplex Collection, we systematically evaluated the potential role of PMMs in autism risk. Initial re-evaluation of published single-nucleotide variant (SNV) de novo mutations showed evidence consistent with putative PMMs for 11% of mutations. We developed a robust and sensitive SNV PMM calling approach integrating complementary callers, logistic regression modeling, and additional heuristics. In our high-confidence call set, we identified 470 PMMs in children, increasing the proportion of mosaic SNVs to 22%. Probands have a significant burden of synonymous PMMs and these mutations are enriched for computationally predicted impacts on splicing. Evidence of increased missense PMM burden was not seen in the full cohort. However, missense burden signal increased in subcohorts of families where probands lacked nonsynonymous germline mutations, especially in genes intolerant to mutations. Parental mosaic mutations that were transmitted account for 6.8% of the presumed de novo mutations in the children. PMMs were identified in previously implicated high-confidence neurodevelopmental disorder risk genes, such as CHD2, CTNNB1, SCN2A, and SYNGAP1, as well as candidate risk genes with predicted functions in chromatin remodeling or neurodevelopment, including ACTL6B, BAZ2B, COL5A3, SSRP1, and UNC79. We estimate that PMMs potentially contribute risk to 3%-4% of simplex ASD case subjects and future studies of PMMs in ASD and related disorders are warranted.

VariCarta: A Comprehensive Database of Harmonized Genomic Variants Found in Autism Spectrum Disorder Sequencing Studies

“…Both representations describe the same resulting genotype. The other three papers report just one of the contiguous SNVs each [Krupp et al, 2017]: C-> A; [Ji et al, 2016]; and [Satterstrom et al, 2019]: C->G). This complex variant can also be viewed directly in VariCarta at varicarta.msl.ubc.ca/variant?chr=5&start=134059281&stop=134059281. central SFARI Human Gene module contains information about human genes that have been associated with ASD, supporting information from scientific literature, and different kinds of genetic data sets that provide evidence for linking the genes to ASD and help categorize and score genes based on the strength of that evidence.…”

Exome sequencing of 457 autism families recruited online provides evidence for novel ASD genes

“…These results indicate that ~10% (65/652) of the total de novo SNVs in the SPARK pilot are of postzygotic origin. Comparing these data to a similar mosaic set from the SSC 22 , we found similar mosaic mutation characteristics, despite the fact that different DNA sources, capture reagents, and sequencing instruments were used (Supplementary Figure 7). Due to the limited number of mosaic calls, we did not attempt to evaluate mosaic mutation burden.…”

“…Assuming that sequencing errors are independent and that errors occur with probability 0.005, with the probability of an allelespecific error being 0.005/3=0.00167, and given the total number of reads (N) supporting a variant site, we iterated over a range of possible Nalt values between 1 and 0.5*N and estimated the expected number of false positives due to sequencing error, exome-wide [(1-Poisson(Nalt, λ=N*(0.00167))* 3x10 7 ]. Assuming one coding de novo SNV per individual 58 and that roughly 10% of de novo SNVs arise post-zygotically [20][21][22] , we estimate there to be 0.1 mosaic mutations per exome. Under this assumption, to constrain theoretical FDR (in terms of distinguishing low allele fraction sites from technical artifacts) to 10%, we allowed a maximum of 0.01 false positives per exome.…”

“…The dashed vertical line denotes 5% VAF, below which estimated detection power is extremely limited and likely to artificially inflate adjusted counts. c) Percentile ranked distribution of Krupp et al 22 logistic mosaic score, 0.518 was the applied threshold for OHSU pipeline. Scores are overall well distributed between overlapping and group specific calls.…”

“…Given their emerging role in genetic risk for ASD and other NDDs, we also assessed postzygotic mosaic mutations [20][21] in the SPARK cohort. In parallel, we utilized a previously established method 22 and a novel approach to identify likely mosaic SNVs (Methods, Supplementary Figures 3-8). We identified 65 likely mosaic mutations (0.142/offspring) (Supplementary Table 6).…”