ASDs are highly heritable,1 and genomic studies have revealed that a substantial proportion of ASD risk resides in high-impact rare variation, ranging from chromosome abnormalities and copy-number variation (CNV)2–6 to single-nucleotide variation (SNV).7–11 These studies have highlighted a striking degree of genetic heterogeneity, implicating both de novo germline mutation and rare inherited ASD variation distributed across numerous genes. De novo CNVs are observed in 5%–10% of screened ASD-affected individuals, and after further follow-up studies, some of them have proven to alter high-risk genes (e.g., NRXN112 [MIM 600565]). De novo or transmitted CNVs, such as 15q11.2–q13 duplications of the affected region in Prader-Willi syndrome (PWS [MIM 176270]) and Angelman syndrome (AS [MIM 105830]), 16p11.2 deletion (MIM 611913), 16p11.2 duplication (MIM 614671), and X-linked deletions including the PTCHD1-PTCHD1AS locus (MIM 300828), have also been found to contribute to risk.6,13,14 Exome and whole-genome sequencing studies have estimated at least another ∼6% contribution to ASD7–10,15 and an additional 5% conferred by rare inherited recessive or X-linked loss-of-function (LoF) SNVs.11,16 A genetic overlap between ASD and other neuropsychiatric conditions has also been increasingly recognized.