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...
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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 |
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