Genome sequencing identifies complex structural MLH1 variant in unsolved Lynch syndrome.

Area of Science:

• Genetics
• Oncology
• Genomic Medicine

Background:

• Lynch syndrome is a common hereditary cancer predisposition.
• Caused by inherited mismatch repair pathway defects.
• Current diagnostics identify causative variants in <50% of Lynch syndrome cases.

Purpose of the Study:

• To investigate the utility of clinical genome sequencing in Lynch syndrome diagnosis.
• To identify genetic variants missed by standard diagnostic methods.
• To demonstrate the advantages of comprehensive genomic analysis.

Main Methods:

• Clinical genome sequencing and transcriptome sequencing were employed.
• Data analysis utilized the megSAP pipeline.
• Segregation analyses were performed using breakpoint PCR.

Main Results:

• A complex structural variant involving MLH1 and LRRFIP2 was identified in a Lynch syndrome family.
• This variant was missed by standard panel or exome sequencing.
• Segregation analysis identified additional at-risk family members.

Conclusions:

• Clinical genome sequencing is advantageous for detecting structural variants in Lynch syndrome.
• Structural variants may be underreported due to technical challenges.
• Comprehensive genetic characterization is crucial for accurate Lynch syndrome diagnosis and management.