4.6 Article

Hereditary cancer genes are highly susceptible to splicing mutations

Journal

PLOS GENETICS
Volume 14, Issue 3, Pages -

Publisher

PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1007231

Keywords

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Funding

  1. Postdoctoral Fellowship from Center for Computational Molecular Biology (CCMB), Brown University
  2. Graduate Research Fellowship from National Science Foundation (NSF)
  3. National Institutes of Health (NIH) [R01GM095612, R01GM105681, R21HG007905]
  4. SFARI [342705]
  5. FAGS, Faculty Research Fellowship for the Study of Trauma and Critical Care from the American College of Surgeons
  6. Deans Emerging Area of New Science (DEANS) Award from Brown University

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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.

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