Lynch syndrome caused by a pathogenic SINE-VNTR-Alu (SVA) insertion in MSH2 gene identified by long-read DNA sequencing.

~3.2-kb SINE-VNTR-Alu (SVA) retrotransposon insertion in exon 12 of MSH2

Lynch syndrome is caused by germline variants in DNA mismatch repair (MMR) genes, some complex structural variants of which escape short-read sequencing. The authors report a family with MSH2-deficient tumours in whom short-read multigene panel testing found no variant. Oxford Nanopore adaptive sampling long-read sequencing, targeting 104 hereditary cancer genes, identified a ~3.2-kb SVA insertion in exon 12 of MSH2 in the proband and her father. Targeted PCR segregation confirmed three additional carriers; three of five heterozygous carriers were affected with at least one MSH2-deficient tumour each. The study supports incorporating long-read sequencing into diagnostic workflows after a negative germline test.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This case concretely demonstrates the diagnostic value of long-read sequencing for detecting pathogenic mobile-element insertions invisible to short-read, a recognised gap in current Lynch syndrome diagnostics. In a patient with an MMR-deficient tumour and no identified germline variant, escalating to long-read becomes a rational option. The result directly impacts colorectal surveillance and family cascade testing.

Analysis by Dr Thibaut Benquey