TY - JOUR T1 - Paternally inherited noncoding structural variants contribute to autism JF - bioRxiv DO - 10.1101/102327 SP - 102327 AU - William M. Brandler AU - Danny Antaki AU - Madhusudan Gujral AU - Morgan L. Kleiber AU - Michelle S. Maile AU - Oanh Hong AU - Timothy R. Chapman AU - Shirley Tan AU - Prateek Tandon AU - Timothy Pang AU - Shih C. Tang AU - Keith K. Vaux AU - Yan Yang AU - Eoghan Harrington AU - Sissel Juul AU - Daniel J. Turner AU - Stephen F. Kingsmore AU - Joseph G. Gleeson AU - Boyko Kakaradov AU - Amalio Telenti AU - J Craig Venter AU - Roser Corominas AU - Bru Cormand AU - Isabel Rueda AU - Karen S. Messer AU - Caroline M. Nievergelt AU - Maria J. Arranz AU - Eric Courchesne AU - Karen Pierce AU - Alysson R. Muotri AU - Lilia M. Iakoucheva AU - Amaia Hervas AU - Christina Corsello AU - Jonathan Sebat Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/04/27/102327.abstract N2 - The genetic architecture of autism spectrum disorder (ASD) is known to consist of contributions from gene-disrupting de novo mutations and common variants of modest effect. We hypothesize that the unexplained heritability of ASD also includes rare inherited variants with intermediate effects. We investigated the genome-wide distribution and functional impact of structural variants (SVs) through whole genome analysis (≥30X coverage) of 3,169 subjects from 829 families affected by ASD. Genes that are intolerant to inactivating variants in the exome aggregation consortium (ExAC) were depleted for SVs in parents, specifically within fetal-brain promoters, UTRs and exons. Rare paternally-inherited SVs that disrupt promoters or UTRs were over-transmitted to probands (P = 0.0013) and not to their typically-developing siblings. Recurrent functional noncoding deletions implicate the gene LEO1 in ASD. Protein-coding SVs were also associated with ASD (P = 0.0025). Our results establish that rare inherited SVs predispose children to ASD, with differing contributions from each parent. ER -