Structural Variants Are a Major Component of the Missing Heritability of Autism Spectrum Disorder

The heritability of autism spectrum disorder (ASD), based on 680,000 families and five countries, is estimated to be nearly 80%, yet we lack genetic markers that adequately explain it. It is increasingly clear that genomic structural variants (SVs) are a major component of the "missing heritability" for many complex phenotypes. Here we use a novel method to identify SVs based on non-Mendelian inheritance patterns in pedigrees using parent-child genotypes from ASD families and demonstrate that the genes that the ASD-specific SVs overlap recapitulate the known molecular biology of ASD including dendritic spinogenesis, axon guidance, and chromatin modification. We further define fine-grained biological pathways that strongly implicate aberrant early development of the cerebellum. Importantly, using these previously excluded variants, we identify the ACMSD gene in the kynurenine pathway as significantly associated with non-verbal cases of ASD and we then use an explainable artificial intelligence approach to define subgroups for future diagnosis and deployment of personalized medicine.