@article {Brandler102327, author = {William M Brandler and Danny Antaki and Madhusudan Gujral and Morgan L Kleiber and Michelle S Maile and Oanh Hong and Timothy R Chapman and Shirley Tan and Prateek Tandon and Timothy Pang and Shih C Tang and Keith K Vaux and Yan Yang and Eoghan Harrington and Sissel Juul and Daniel J Turner and Stephen F Kingsmore and Joseph G Gleeson and Boyko Kakaradov and Amalio Telenti and J Craig Venter and Roser Corominas and Bru Cormand and Isabel Rueda and Karen S Messer and Caroline M Nievergelt and Maria J Arranz and Eric Courchesne and Karen Pierce and Alysson R Muotri and Lilia M Iakoucheva and Amaia Hervas and Christina Corsello and Jonathan Sebat}, title = {Paternally inherited noncoding structural variants contribute to autism}, elocation-id = {102327}, year = {2017}, doi = {10.1101/102327}, publisher = {Cold Spring Harbor Laboratory}, abstract = {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.}, URL = {https://www.biorxiv.org/content/early/2017/04/03/102327}, eprint = {https://www.biorxiv.org/content/early/2017/04/03/102327.full.pdf}, journal = {bioRxiv} }