TY - JOUR T1 - Pathogenicity and selective constraint on variation near splice sites JF - bioRxiv DO - 10.1101/256636 SP - 256636 AU - Jenny Lord AU - Giuseppe Gallone AU - Patrick J. Short AU - Jeremy F. McRae AU - Holly Ironfield AU - Elizabeth H. Wynn AU - Sebastian S. Gerety AU - Liu He AU - Bronwyn Kerr AU - Diana S. Johnson AU - Emma McCann AU - Esther Kinning AU - Frances Flinter AU - I. Karen Temple AU - Jill Clayton-Smith AU - Meriel McEntagart AU - Sally Ann Lynch AU - Shelagh Joss AU - Sofia Douzgou AU - Tabib Dabir AU - Virginia Clowes AU - Vivienne P. M. McConnell AU - Wayne Lam AU - Caroline F. Wright AU - David R. FitzPatrick AU - Helen V. Firth AU - Jeffrey C. Barrett AU - Matthew E. Hurles AU - on behalf of the Deciphering Developmental Disorders study Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/08/30/256636.abstract N2 - Mutations which perturb normal pre-mRNA splicing are significant contributors to human disease. We used exome sequencing data from 7,833 probands with developmental disorders (DD) and their unaffected parents, as well as >60,000 aggregated exomes from the Exome Aggregation Consortium, to investigate selection around the splice site, and quantify the contribution of splicing mutations to DDs. Patterns of purifying selection, a deficit of variants in highly constrained genes in healthy subjects and excess de novo mutations in patients highlighted particular positions within and around the consensus splice site of greater functional relevance. Using mutational burden analyses in this large cohort of proband-parent trios, we could estimate in an unbiased manner the relative contributions of mutations at canonical dinucleotides (73%) and flanking non-canonical positions (27%), and calculated the positive predictive value of pathogenicity for different classes of mutations. We identified 18 patients with likely diagnostic de novo mutations in dominant DD-associated genes at non-canonical positions in splice sites. We estimate 35-40% of pathogenic variants in non-canonical splice site positions are missing from public databases. ER -