RT Journal
A1 Lord, Jenny
A1 Gallone, Giuseppe
A1 Short, Patrick J.
A1 McRae, Jeremy F.
A1 Ironfield, Holly
A1 Wynn, Elizabeth H.
A1 Gerety, Sebastian S.
A1 He, Liu
A1 Kerr, Bronwyn
A1 Johnson, Diana S.
A1 McCann, Emma
A1 Kinning, Esther
A1 Flinter, Frances
A1 Temple, I. Karen
A1 Clayton-Smith, 
Jill
A1 McEntagart, Meriel
A1 Lynch, Sally Ann
A1 Joss, Shelagh
A1 Douzgou, Sofia
A1 Dabir, Tabib
A1 Clowes, Virginia
A1 McConnell, Vivienne P.M.
A1 Lam, Wayne
A1 Wright, Caroline F.
A1 FitzPatrick, David R.
A1 Firth, Helen V.
A1 Barrett, 
Jeffrey C.
A1 Hurles, Matthew E.
A1 on behalf of the Deciphering Developmental Disorders study
T1 Pathogenicity and selective constraint on variation near splice sites
JF Genome Research 
JO Genome Research 
YR 2019 
FD February 01 
VO 29 
IS 2 
SP 159 
OP 170 
DO 10.1101/gr.238444.118 
UL http://genome.cshlp.org/content/29/2/159.abstract 
AB Mutations that perturb normal pre-mRNA splicing are significant contributors to human disease. We used exome sequencing data from 7833 probands with developmental disorders (DDs) and their unaffected parents, as well as more than 60,000 aggregated exomes from the Exome Aggregation Consortium, to investigate selection around the splice sites 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. By 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 noncanonical positions (27%), and calculate 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 noncanonical positions in splice sites. We estimate 35%–40% of pathogenic variants in noncanonical splice site positions are missing from public databases.