De Novo Variants Predominate in Autism Spectrum Disorder

Background: Autism spectrum disorder (ASD) is a common condition with substantial personal and financial burdens of lifelong implication. Multiple twin studies have confirmed a genetic or inherited component at ~80%, higher than any other common condition. However, ASD’s rapidly accelerating prevalence, now at 1 in 31 in the USA, appears to defy a predominantly genetic basis and implicate our rapidly changing environment. A potential explanation for this paradox is a recent increase in de novo variants (DNVs), which are “new” mutations present in the patient yet absent in both parents. The present authors recently reported using trio whole-genome sequencing (trio-WGS) that DNVs highly likely to be highly disease-associated (“Principal Diagnostic Variants”, PDVs), mostly missense variants, were present in (25/50) 50% of the ASD patients clinically evaluated by our team. Methods: The current study was designed to support this observation with trio-WGS in 100 additional unrelated ASD patients. Results: De novo PDVs were identified in 47/100 (47%) of cases, in close approximation to our previous work. Using non-transcribed (up and downstream) variants for all genes as a control group, these DNV-PDVs were far more likely (p < 0.0001, OR 5.8, 95% C.I. 2.9–11) to be in SFARI-listed genes associated with ASD. Consistent with the emerging polygenic model, using the same analyses, inherited missense variants were also associated with ASD (p < 0.0001). Highly unexpectedly, silent variants, both inherited (p < 0.0001) and de novo (p < 0.007), were also statistically associated with ASD, and, among inherited variants, silent variants were more associated with ASD than were missense variants (p < 0.0001). Adding silent DNVs as PDVs increases the proportion of our subjects with at least one DNV-PDV to 55% of the subjects. Conclusions: Our proposed model for ASD, with prominent DNVs in most that are genetic yet not inherited, predicts the known predominant genetic pathogenesis and the accelerating prevalence of ASD, possibly from environmental factors, including insufficient nutrients and toxicant exposures, and/or the disrupted folate metabolism known to be associated with ASD. Limitations to this study include predominant inclusion of severely affected individuals and the lack of an unaffected control group and functional validation of variant pathogenicity.