Detection of a 39 kb structural variant causing Lynch syndrome using optical genome mapping and nanopore sequencing

Research Background

Lynch syndrome (LS) is a hereditary cancer syndrome primarily caused by pathogenic germline variants in four genes of the MMR (mismatch repair) gene family: MLH1, MSH2, MSH6, and PMS2. This syndrome is characterized by a significantly increased risk of multiple cancer types, especially colorectal and endometrial cancers, and displays autosomal dominant inheritance. Early detection and cancer prevention become possible when the variant is known, making accurate and sensitive genetic testing methods crucial. This study aims to discover potential pathogenic variants of LS that standard genetic testing failed to confirm.

Article Source

This article was written by Pål Marius Bjørnstad, Ragnhild Aaløkken, and others from research institutions such as Oslo University Hospital, Norwegian University of Science and Technology, and St. Olavs Hospital. The article was published in the “European Journal of Human Genetics” in 2023.

Research Details

Research Process

After conventional immunohistochemistry and microsatellite instability analysis, two Norwegian families showed pathogenic variants in the MSH2 gene. Standard exon sequencing and multiplex ligation-dependent probe amplification (MLPA) failed to detect the variant. Subsequently, Bionano optical genome mapping technology detected a 39 kb insertion in the MSH2 gene. Oxford Nanopore MinION was used for whole genome sequencing to precisely locate the insertion breakpoints and sequence. This variant was present in both families and was also found in other families in the same region of Norway, suggesting it might be a founder event. To the researchers’ knowledge, this is the first time these technologies have been used to diagnose structural variants causing LS.

Main Results

The study found that both families carried the same insertion variant. Subsequent sequencing revealed that the inserted sequence was a duplication from the nearby MSH6 gene, and Oxford Nanopore sequencing determined the precise insertion point.

Conclusions and Significance

By combining optical genome mapping and nanopore sequencing, the study successfully detected a new structural variant in the MMR gene that was not found in traditional genetic testing. The research emphasizes the importance of structural variant detection when standard genetic testing fails to confirm LS.

Research Highlights

For the first time, optical genome mapping and nanopore sequencing technologies were successfully used to detect and diagnose structural variants causing Lynch syndrome. Additionally, this study revealed the relationship between two families with a common ancestor, a finding that helps increase our understanding of genetic pathology and structural variations in the human genome.

Additional Content

The research team believes that this achievement reveals potential shortcomings in genetic testing and demonstrates the importance of new technologies such as optical genome mapping and nanopore sequencing in detecting structural variants. These technologies have significant application prospects in clinical diagnosis, providing new genetic diagnostic methods for patients suspected of LS but not yet confirmed through routine genetic testing.