De Novo Variants Predominate in Autism Spectrum Disorder.

Scientists studied the DNA of 100 autistic people and their parents to look for new genetic changes that weren't passed down from parents. They found these 'new mutations' in nearly half (47%) of the autistic individuals. Surprisingly, they also found that some genetic changes that don't affect proteins were still linked to autism. This research suggests autism might involve both inherited genes and new mutations that could be influenced by environmental factors.

This genetic study used whole-genome sequencing to examine de novo variants (new mutations not inherited from parents) in 100 autistic individuals and their parents. The researchers found that 47% of participants had de novo variants likely associated with autism, particularly in genes previously linked to the condition. Unexpectedly, they also found that 'silent' genetic variants (which don't change proteins) were statistically associated with autism, both inherited and de novo types. The authors propose that de novo variants may help explain autism's high genetic component while accounting for its increasing prevalence, potentially linking environmental factors to new genetic mutations.

Findings suggest genetic testing may identify autism-associated variants in approximately half of cases. The discovery of silent variant associations may expand understanding of autism's genetic architecture, though clinical applications remain unclear without functional validation.

Study included predominantly severely affected individuals, lacked an unaffected control group, and did not provide functional validation of variant pathogenicity. Sample was limited to 100 participants from a single research team.

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. The current study was designed to support this observation with trio-WGS in 100 additional unrelated ASD patients. 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 (< 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 (< 0.0001). Highly unexpectedly, silent variants, both inherited (< 0.0001) and de novo (< 0.007), were also statistically associated with ASD, and, among inherited variants, silent variants were more associated with ASD than were missense variants (< 0.0001). Adding silent DNVs as PDVs increases the proportion of our subjects with at least one DNV-PDV to 55% of the subjects. 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.