Mutation deep within an intron of MSH2 causes Lynch syndrome

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Lynch syndrome is a hereditary cancer predisposition caused by germline mutations in DNA mismatch repair (MMR) genes.
• Current diagnostic methods focus on detecting MMR gene mutations within exonic and splice site regions.
• A significant number of Lynch syndrome families remain undiagnosed due to the absence of detectable mutations in these conventional regions.

Purpose of the Study:

• To investigate the genetic basis of Lynch syndrome in families where routine mutation screening has failed.
• To identify novel mutation types and mechanisms contributing to Lynch syndrome.
• To improve diagnostic strategies for hereditary cancer syndromes.

Main Methods:

• Haplotype analysis of the affected gene locus to identify segregating haplotypes.
• Investigation of splicing aberrations to detect cryptic splice sites.
• Sequencing of intronic regions outside standard screening areas.

Main Results:

• An intronic mutation, located 478 bp upstream of exon 2 in the MSH2 gene, was identified as causative.
• This mutation created a novel splice donor site, leading to pseudoexon activation.
• The identified mutation explains Lynch syndrome in a family previously lacking a molecular diagnosis.

Conclusions:

• Intronic mutations creating cryptic splice sites are a significant cause of Lynch syndrome.
• Extended sequencing approaches, including intronic regions, are crucial for comprehensive diagnosis.
• This finding expands the spectrum of known Lynch syndrome-causing mutations and improves diagnostic yield.