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Pathogenicity and selective constraint on variation near splice sites

Pathogenicity and selective constraint on variation near splice sites
Pathogenicity and selective constraint on variation near splice sites
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.
1088-9051
159-170
Lord, Jenny
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Gallone, Giuseppe
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Short, Patrick J
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Mcrae, Jeremy F
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Ironfield, Holly
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Wynn, Elizabeth H
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Gerety, Sebastian S
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He, Liu
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Kerr, Bronwyn
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Johnson, Diana S
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Mccann, Emma
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Kinning, Esther
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Flinter, Frances
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Temple, I. Karen
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Clayton-smith, Jill
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Mcentagart, Meriel
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Lynch, Sally Ann
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Joss, Shelagh
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Douzgou, Sofia
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Dabir, Tabib
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Clowes, Virginia
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Mcconnell, Vivienne P.m
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Lam, Wayne
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Fitzpatrick, David R
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Wright, Caroline F
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Firth, Helen V
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Barrett, Jeffrey C
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Hurles, Matthew E
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Lord, Jenny
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Gallone, Giuseppe
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Short, Patrick J
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Mcrae, Jeremy F
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Ironfield, Holly
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Wynn, Elizabeth H
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Gerety, Sebastian S
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He, Liu
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Kerr, Bronwyn
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Johnson, Diana S
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Mccann, Emma
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Kinning, Esther
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Flinter, Frances
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Temple, I. Karen
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Clayton-smith, Jill
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Mcentagart, Meriel
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Lynch, Sally Ann
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Joss, Shelagh
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Douzgou, Sofia
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Dabir, Tabib
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Clowes, Virginia
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Mcconnell, Vivienne P.m
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Lam, Wayne
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Fitzpatrick, David R
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Wright, Caroline F
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Firth, Helen V
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Barrett, Jeffrey C
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Hurles, Matthew E
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Lord, Jenny, Gallone, Giuseppe, Short, Patrick J, Mcrae, Jeremy F, Ironfield, Holly, Wynn, Elizabeth H, Gerety, Sebastian S, He, Liu, Kerr, Bronwyn, Johnson, Diana S, Mccann, Emma, Kinning, Esther, Flinter, Frances, Temple, I. Karen, Clayton-smith, Jill, Mcentagart, Meriel, Lynch, Sally Ann, Joss, Shelagh, Douzgou, Sofia, Dabir, Tabib, Clowes, Virginia, Mcconnell, Vivienne P.m, Lam, Wayne, Fitzpatrick, David R, Wright, Caroline F, Firth, Helen V, Barrett, Jeffrey C and Hurles, Matthew E (2019) Pathogenicity and selective constraint on variation near splice sites. Genome Research, 29 (2), 159-170. (doi:10.1101/gr.238444.118).

Record type: Article

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.

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More information

Accepted/In Press date: 21 December 2018
e-pub ahead of print date: 26 December 2018
Published date: 1 February 2019

Identifiers

Local EPrints ID: 427211
URI: http://eprints.soton.ac.uk/id/eprint/427211
ISSN: 1088-9051
PURE UUID: 8ecd25ff-606f-4114-87ca-951fcb9ef15b
ORCID for I. Karen Temple: ORCID iD orcid.org/0000-0002-6045-1781

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Date deposited: 08 Jan 2019 17:30
Last modified: 26 Nov 2021 02:41

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Contributors

Author: Jenny Lord
Author: Giuseppe Gallone
Author: Patrick J Short
Author: Jeremy F Mcrae
Author: Holly Ironfield
Author: Elizabeth H Wynn
Author: Sebastian S Gerety
Author: Liu He
Author: Bronwyn Kerr
Author: Diana S Johnson
Author: Emma Mccann
Author: Esther Kinning
Author: Frances Flinter
Author: I. Karen Temple ORCID iD
Author: Jill Clayton-smith
Author: Meriel Mcentagart
Author: Sally Ann Lynch
Author: Shelagh Joss
Author: Sofia Douzgou
Author: Tabib Dabir
Author: Virginia Clowes
Author: Vivienne P.m Mcconnell
Author: Wayne Lam
Author: David R Fitzpatrick
Author: Caroline F Wright
Author: Helen V Firth
Author: Jeffrey C Barrett
Author: Matthew E Hurles

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