A 39 kb structural variant causing Lynch Syndrome detected by optical genome mapping and nanopore sequencing

Area of Science:

• Genomics
• Cancer Genetics
• Molecular Diagnostics

Background:

• Lynch Syndrome (LS) is an inherited disorder increasing cancer risk, particularly colorectal and endometrial cancers.
• Genetic testing for LS relies on identifying pathogenic germline variants in mismatch repair (MMR) genes.
• Standard genetic tests can miss certain complex variants, complicating LS diagnosis.

Purpose of the Study:

• To investigate the cause of LS in families with suspected MSH2 variants where standard genetic testing was negative.
• To identify novel genetic mechanisms underlying Lynch Syndrome.
• To evaluate advanced genomic technologies for diagnosing LS.

Main Methods:

• Immunohistochemistry (IHC) and microsatellite instability (MSI) analysis.
• Targeted exon sequencing and multiplex ligation-dependent probe amplification (MLPA).
• Bionano optical genome mapping and Oxford Nanopore MinION whole-genome sequencing.

Main Results:

• IHC and MSI suggested a pathogenic MSH2 variant, but sequencing and MLPA were negative.
• Bionano optical genome mapping identified a 39kb insertion in the MSH2 gene.
• This insertion was confirmed in multiple families, suggesting a founder effect in Norway.

Conclusions:

• Structural variants, such as insertions, can cause Lynch Syndrome and may be missed by standard genetic testing.
• Advanced genomic techniques like optical genome mapping are crucial for diagnosing LS when conventional methods fail.
• Implementing structural variant detection can improve diagnostic yield for hereditary cancer syndromes.