Identification of a novel intergenic EPCAM-MSH2 deletion causing EPCAM-associated Lynch syndrome

Novel EPCAM-MSH2 intergenic deletion disrupting EPCAM transcriptional termination, generating read-through transcripts and epigenetic MSH2 silencing

A novel intergenic deletion between EPCAM and MSH2 is identified in a Lynch syndrome family. This deletion, located at the 3' end of EPCAM, disrupts EPCAM transcriptional termination, generating read-through transcripts that cause epigenetic silencing of MSH2 in EPCAM-expressing tissues. This mechanism is characteristic of EPCAM-associated Lynch syndrome, but the deletion described here is distinct from previously reported deletions and refines the critical boundaries of the EPCAM-MSH2 region for this mechanism.

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

EPCAM-MSH2 deletions causing Lynch via epigenetic mechanism are often missed by conventional NGS analyses targeting coding variants. This new type of intergenic deletion illustrates the importance of large deletion analyses (MLPA, CMA) and long-read sequencing in Lynch workup for patients without MSH2 coding variants.

Clinical impact: 2/3 · Evidence strength: 2/3 · Novelty: 2/2 · Sample size: 0/1 · Publication status: 1/1 → Total: 7/10