Shortly after the description of germline deletions of the last exon(s) of the EPCAM gene, leading to epigenetic silencing of the downstream gene MSH2 in epithelial cells [184], it was acknowledged that 3′-end EPCAM deletions can be a frequent cause of unexplained MSH2 deficiency [185,186], and EPCAM deletion detection is now included in the routine genetic diagnosis of LS. This evidence concerns the gene EPCAM and Leigh syndrome.