EPCAM mutation update: Variants associated with congenital tufting enteropathy and Lynch syndrome. Issue 2 (29th November 2018)

• Record Type: Journal Article
• Authors: Pathak, Sagar J.; Mueller, James L.; Okamoto, Kevin; Das, Barun; Hertecant, Jozef; Greenhalgh, Lynn; Cole, Trevor; Pinsk, Vered; Yerushalmi, Baruch; Gurkan, Odul E.; Yourshaw, Michael; Hernandez, Erick; Oesterreicher, Sandy; Naik, Sandhia; Sanderson, Ian R.; Axelsson, Irene; Agardh, Daniel; Boland, C. Richard; Martin, Martin G.; Putnam, Christopher D.; Sivagnanam, Mamata
• Is Part Of: Human mutation. Volume 40:Issue 2(2019)
• Page Start: 142
• Page End: 161
• Publication Date: 2018-11-29
• Subjects: congenital tufting enteropathy -- EPCAM -- genotype‐phenotype correlation -- in silico simulation -- Lynch syndrome -- protein modeling; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23688
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: The epithelial cell adhesion molecule gene ( EPCAM, previously known as TACSTD1 or TROP1 ) encodes a membrane‐bound protein that is localized to the basolateral membrane of epithelial cells and is overexpressed in some tumors. Biallelic mutations in EPCAM cause congenital tufting enteropathy (CTE), which is a rare chronic diarrheal disorder presenting in infancy. Monoallelic deletions of the 3′ end of EPCAM that silence the downstream gene, MSH2, cause a form of Lynch syndrome, which is a cancer predisposition syndrome associated with loss of DNA mismatch repair. Here, we report 13 novel EPCAM mutations from 17 CTE patients from two separate centers, review EPCAM mutations associated with CTE and Lynch syndrome, and structurally model pathogenic missense mutations. Statistical analyses indicate that the c.499dupC (previously reported as c.498insC) frameshift mutation was associated with more severe treatment regimens and greater mortality in CTE, whereas the c.556‐14A>G and c.491+1G>A splice site mutations were not correlated with treatments or outcomes significantly different than random simulation. These findings suggest that genotype–phenotype correlations may be useful in contributing to management decisions of CTE patients. Depending on the type and nature of EPCAM mutation, one of two unrelated diseases may occur, CTE or Lynch syndrome. Abstract : Mutations in the epithelial cell adhesion molecule gene ( EPCAM ) can result in one of two unrelated diseases, congenital tufting enteropathy or Lynch Syndrome depending on the type and nature of the mutation. We report 13 novel EPCAM mutations from 17 CTE patients, review EPCAM mutations associated with CTE and Lynch syndrome, and structurally model pathogenic mutations. Statistical analyses to evaluate genotype‐phenotype correlations indicate that the c.499dupC frameshift mutation is associated with more severe treatment regimens and greater mortality in CTE.