Hereditary cancer genes are highly susceptible to splicing mutations.

Substitutions that disrupt pre-mRNA splicing are a common cause of genetic disease. On average, 13.4% of all hereditary disease alleles are classified as splicing mutations mapping to the canonical 5' and 3' splice sites. However, splicing mutations present in exons and deeper intronic pos...

Full description

Bibliographic Details
Main Authors: Christy L Rhine, Kamil J Cygan, Rachel Soemedi, Samantha Maguire, Michael F Murray, Sean F Monaghan, William G Fairbrother
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2018-03-01
Series:PLoS Genetics
Online Access:http://europepmc.org/articles/PMC5854443?pdf=render
id doaj-9045e7911a7344f29ae0d2cd685a1647
record_format Article
spelling doaj-9045e7911a7344f29ae0d2cd685a16472020-11-24T21:41:58ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042018-03-01143e100723110.1371/journal.pgen.1007231Hereditary cancer genes are highly susceptible to splicing mutations.Christy L RhineKamil J CyganRachel SoemediSamantha MaguireMichael F MurraySean F MonaghanWilliam G FairbrotherSubstitutions that disrupt pre-mRNA splicing are a common cause of genetic disease. On average, 13.4% of all hereditary disease alleles are classified as splicing mutations mapping to the canonical 5' and 3' splice sites. However, splicing mutations present in exons and deeper intronic positions are vastly underreported. A recent re-analysis of coding mutations in exon 10 of the Lynch Syndrome gene, MLH1, revealed an extremely high rate (77%) of mutations that lead to defective splicing. This finding is confirmed by extending the sampling to five other exons in the MLH1 gene. Further analysis suggests a more general phenomenon of defective splicing driving Lynch Syndrome. Of the 36 mutations tested, 11 disrupted splicing. Furthermore, analyzing past reports suggest that MLH1 mutations in canonical splice sites also occupy a much higher fraction (36%) of total mutations than expected. When performing a comprehensive analysis of splicing mutations in human disease genes, we found that three main causal genes of Lynch Syndrome, MLH1, MSH2, and PMS2, belonged to a class of 86 disease genes which are enriched for splicing mutations. Other cancer genes were also enriched in the 86 susceptible genes. The enrichment of splicing mutations in hereditary cancers strongly argues for additional priority in interpreting clinical sequencing data in relation to cancer and splicing.http://europepmc.org/articles/PMC5854443?pdf=render
collection DOAJ
language English
format Article
sources DOAJ
author Christy L Rhine
Kamil J Cygan
Rachel Soemedi
Samantha Maguire
Michael F Murray
Sean F Monaghan
William G Fairbrother
spellingShingle Christy L Rhine
Kamil J Cygan
Rachel Soemedi
Samantha Maguire
Michael F Murray
Sean F Monaghan
William G Fairbrother
Hereditary cancer genes are highly susceptible to splicing mutations.
PLoS Genetics
author_facet Christy L Rhine
Kamil J Cygan
Rachel Soemedi
Samantha Maguire
Michael F Murray
Sean F Monaghan
William G Fairbrother
author_sort Christy L Rhine
title Hereditary cancer genes are highly susceptible to splicing mutations.
title_short Hereditary cancer genes are highly susceptible to splicing mutations.
title_full Hereditary cancer genes are highly susceptible to splicing mutations.
title_fullStr Hereditary cancer genes are highly susceptible to splicing mutations.
title_full_unstemmed Hereditary cancer genes are highly susceptible to splicing mutations.
title_sort hereditary cancer genes are highly susceptible to splicing mutations.
publisher Public Library of Science (PLoS)
series PLoS Genetics
issn 1553-7390
1553-7404
publishDate 2018-03-01
description Substitutions that disrupt pre-mRNA splicing are a common cause of genetic disease. On average, 13.4% of all hereditary disease alleles are classified as splicing mutations mapping to the canonical 5' and 3' splice sites. However, splicing mutations present in exons and deeper intronic positions are vastly underreported. A recent re-analysis of coding mutations in exon 10 of the Lynch Syndrome gene, MLH1, revealed an extremely high rate (77%) of mutations that lead to defective splicing. This finding is confirmed by extending the sampling to five other exons in the MLH1 gene. Further analysis suggests a more general phenomenon of defective splicing driving Lynch Syndrome. Of the 36 mutations tested, 11 disrupted splicing. Furthermore, analyzing past reports suggest that MLH1 mutations in canonical splice sites also occupy a much higher fraction (36%) of total mutations than expected. When performing a comprehensive analysis of splicing mutations in human disease genes, we found that three main causal genes of Lynch Syndrome, MLH1, MSH2, and PMS2, belonged to a class of 86 disease genes which are enriched for splicing mutations. Other cancer genes were also enriched in the 86 susceptible genes. The enrichment of splicing mutations in hereditary cancers strongly argues for additional priority in interpreting clinical sequencing data in relation to cancer and splicing.
url http://europepmc.org/articles/PMC5854443?pdf=render
work_keys_str_mv AT christylrhine hereditarycancergenesarehighlysusceptibletosplicingmutations
AT kamiljcygan hereditarycancergenesarehighlysusceptibletosplicingmutations
AT rachelsoemedi hereditarycancergenesarehighlysusceptibletosplicingmutations
AT samanthamaguire hereditarycancergenesarehighlysusceptibletosplicingmutations
AT michaelfmurray hereditarycancergenesarehighlysusceptibletosplicingmutations
AT seanfmonaghan hereditarycancergenesarehighlysusceptibletosplicingmutations
AT williamgfairbrother hereditarycancergenesarehighlysusceptibletosplicingmutations
_version_ 1725919631606022144