PT  - JOURNAL ARTICLE
AU  - Lord, Jenny
AU  - Gallone, Giuseppe
AU  - Short, Patrick J.
AU  - McRae, Jeremy F.
AU  - Ironfield, Holly
AU  - Wynn, Elizabeth H.
AU  - Gerety, Sebastian S.
AU  - He, Liu
AU  - Kerr, Bronwyn
AU  - Johnson, Diana S.
AU  - McCann, Emma
AU  - Kinning, Esther
AU  - Flinter, Frances
AU  - Temple, I. Karen
AU  - Clayton-Smith, Jill
AU  - McEntagart, Meriel
AU  - Lynch, Sally Ann
AU  - Joss, Shelagh
AU  - Douzgou, Sofia
AU  - Dabir, Tabib
AU  - Clowes, Virginia
AU  - McConnell, Vivienne P. M.
AU  - Lam, Wayne
AU  - Wright, Caroline F.
AU  - FitzPatrick, David R.
AU  - Firth, Helen V.
AU  - Barrett, Jeffrey C.
AU  - Hurles, Matthew E.
AU  - , 
TI  - Pathogenicity and selective constraint on variation near splice sites
AID  - 10.1101/256636
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 256636
4099  - http://biorxiv.org/content/early/2018/08/30/256636.short
4100  - http://biorxiv.org/content/early/2018/08/30/256636.full
AB  - 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.