Long-Read Genome Sequencing Improves Detection and Functional Interpretation of Structural and Repeat Variants in Autism

Long–read whole genome sequencing (LR–WGS) technologies enhance the discovery of structural variants (SVs) and tandem repeats (TRs). We performed LR–WGS on 267 individuals from 63 ASD families and generated an integrated call set combining long– and short–read data. LR–WGS increased detection of gene–disrupting SVs and TRs by 33% and 38%, respectively, and enabled identification of novel exonic de novo germline and somatic SVs. We observed complex SV patterns, including a class of nested duplication–deletion events. By joint analysis of phased genetic variation and DNA methylation, we identified deletions of imprinted genes, and demonstrated the effect of intermediate TR expansions (35–54 CGG) on the methylation of FMR1 promoter. Rare SVs, TRs, and damaging SNVs together accounted for 7.4% (95% CI: 2.7–17%) of the heritability of ASD. These findings demonstrate how LR–WGS can resolve complex genetic variation and its functional consequences and regulatory effects in a single assay.