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Hereditary cancer genes are highly susceptible to splicing mutations

Christy L Rhine1, Kamil J Cygan1,2, Rachel Soemedi1,2

  • 1Molecular and Cellular Biology and Biochemistry, Brown University, Providence, Rhode Island, United States of America.

Plos Genetics
|March 6, 2018
PubMed

Insights

Splicing mutations are a major cause of genetic diseases, particularly Lynch Syndrome. Our study reveals these mutations are more common than previously thought, especially in cancer genes, highlighting their importance in genetic diagnostics.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cancer Research

Background:

  • Splicing mutations are a significant cause of genetic disorders, with canonical splice sites accounting for 13.4% of hereditary disease alleles.
  • Mutations in exons and introns are often underreported, yet can lead to defective pre-mRNA splicing.
  • A re-analysis of MLH1 mutations revealed a high rate (77%) of splicing defects, suggesting a broader role in Lynch Syndrome.

Purpose of the Study:

  • To investigate the prevalence and impact of splicing mutations in genetic diseases, with a focus on Lynch Syndrome.
  • To determine if splicing mutations are enriched in specific disease-associated genes, including those related to hereditary cancers.
  • To emphasize the need for prioritizing splicing mutation analysis in clinical sequencing data.

Main Methods:

  • Re-analysis of coding mutations in MLH1 gene exons.
  • Testing of 36 MLH1 mutations for splicing disruption.
  • Comprehensive analysis of splicing mutations across 86 human disease genes.

Main Results:

  • 77% of tested MLH1 exon 10 mutations caused defective splicing, a rate confirmed in other MLH1 exons.
  • 11 out of 36 tested mutations disrupted splicing.
  • MLH1, MSH2, and PMS2, key Lynch Syndrome genes, are part of a group of 86 genes significantly enriched for splicing mutations.
  • Other cancer-associated genes also showed enrichment for splicing mutations.

Conclusions:

  • Defective splicing is a more prevalent driver of Lynch Syndrome than previously recognized.
  • A significant number of disease genes, particularly those linked to hereditary cancers, are enriched for splicing mutations.
  • Clinical sequencing data interpretation should prioritize the analysis of splicing mutations in hereditary cancer contexts.

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