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Congenital tufting enteropathy (CTE), also known as congenital diarrhea 5 with tufting enteropathy, is a rare autosomal recessive disorder characterized by early-onset intractable diarrhea, failure to thrive, and villous atrophy with focal epithelial tufts. The epithelial cell adhesion molecule gene (EPCAM) has been firmly established as the causal gene for CTE, with biallelic loss-of-function variants leading to complete absence of cell-surface EpCAM in enterocytes. CTE results from absence of EpCAM-mediated adhesion and barrier integrity in the intestinal epithelium, necessitating lifelong parenteral nutrition and often intestinal transplantation.
Genetic linkage in a consanguineous family with two affected siblings and subsequent sequencing in unrelated patients identified a homozygous splice-site variant, c.426-1G>A, and additional loss-of-function alleles in EPCAM (PMID:18572020). Compound heterozygous mutations, including canonical splice-site and nonsense changes (e.g., c.491+1G>A (p.Thr164Ter)), have been reported in multiple cohorts, confirming autosomal recessive inheritance and a consistent genotype-phenotype correlation (PMID:20981223).
Segregation analysis across families demonstrates full cosegregation of biallelic EPCAM variants with disease phenotype, including first-cousin and second-degree consanguineous pedigrees, accounting for at least 2 additional affected relatives beyond the index sib pair (PMID:26684320). Founder effects (e.g., c.499dupC) have been described in Arabic Gulf populations, supporting recurrent alleles in specific ethnic groups and facilitating carrier screening strategies (PMID:21315192).
The EPCAM mutational spectrum in CTE includes >60 unique pathogenic variants, predominantly frameshift, nonsense, and essential splice-site lesions. Recurrent variants include c.491+1G>A and c.556-14A>G, while deep-intronic and missense alleles (e.g., p.Cys118Tyr) expand the allelic series. No hypomorphic or structural variants have been reported to cause incomplete penetrance; genotype-phenotype correlations are emerging, with truncating alleles associated with more severe parenteral nutrition dependence (PMID:30461124).
Functional studies demonstrate that all CTE-causing EPCAM mutations abolish cell-surface EpCAM expression through mis-splicing, protein misfolding, retention in the endoplasmic reticulum, or premature truncation. Mutant EpCAM fails to traffic to the basolateral membrane and is either degraded or secreted, leading to disrupted epithelial adhesion (PMID:23462293). A murine CTE model harboring EpCAM mutations activates the unfolded protein response via PERK, IRE1, and ATF6 pathways, recapitulating enterocyte stress and tufting pathology (PMID:32290509).
Taken together, the evidence for EPCAM in CTE meets ClinGen criteria for a definitive gene-disease association, supported by robust genetic and experimental data. EPCAM sequencing should be integrated into diagnostic workflows for congenital diarrheal disorders, enabling early genetic counseling, mutation-specific management, and consideration of future gene-targeted therapies. Key take-home: EPCAM loss-of-function mutations are the well-validated cause of congenital tufting enteropathy, justifying routine genetic testing in neonatal-onset enteropathies.
Gene–Disease AssociationDefinitiveBiallelic EPCAM mutations in >60 unrelated patients with multi-family segregation and concordant functional data Genetic EvidenceStrongOver 60 individuals with biallelic loss-of-function variants (splice, nonsense, frameshift) in EPCAM across multiple studies; reached genetic evidence cap Functional EvidenceModerateMultiple assays demonstrate loss of cell-surface EpCAM, aberrant trafficking, and UPR activation; murine model recapitulates pathology |