Pathogenicity and selective constraint on variation near splice sites
- Jenny Lord1,
- Giuseppe Gallone1,
- Patrick J Short1,
- Jeremy F McRae1,
- Holly Ironfield1,
- Elizabeth H Wynn1,
- Sebastian S Gerety1,
- Liu He1,
- Bronwyn Kerr2,
- Diana S Johnson3,
- Emma McCann4,
- Esther Kinning5,
- Frances Flinter6,
- I. Karen Temple7,
- Jill Clayton-Smith2,
- Meriel McEntagart8,
- Sally Ann Lynch9,
- Shelagh Joss5,
- Sofia Douzgou2,
- Tabib Dabir10,
- Virginia Clowes11,
- Vivienne P.M McConnell12,
- Wayne Lam13,
- Caroline F Wright14,
- David R FitzPatrick13,
- Helen V Firth15,
- Jeffrey C Barrett1,
- Matthew E Hurles1,17,
- The Deciphering Developmental Disorders Study16
- 1 Wellcome Sanger Institute;
- 2 Manchester Centre for Genomic Medicine;
- 3 Sheffield Clinical Genetics Service;
- 4 Liverpool Women's Hospital Foundation Trust;
- 5 West of Scotland Regional Genetics Service;
- 6 South East Thames Regional Genetics Centre;
- 7 Wessex Clinical Genetics Service;
- 8 South West Thames Regional Genetics Centre;
- 9 Temple Street Children's Hospital;
- 10 Northern Ireland Regional Genetics Centre;
- 11 North West Thames Regional Genetics Service;
- 12 Northern Ireland Regional Genetics Service;
- 13 University of Edinburgh;
- 14 University of Exeter;
- 15 East Anglian Medical Genetics Service;
- 16 -
Abstract
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.
- Received April 13, 2018.
- Accepted December 20, 2018.
- Published by Cold Spring Harbor Laboratory Press
This manuscript is Open Access.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International license), as described at http://creativecommons.org/licenses/by/4.0/.
