Genotype-phenotype correlations in EPCAM-associated congenital tufting enteropathy: a case report and systematic review

Background Congenital tufting enteropathy (CTE) is a rare autosomal-recessive enteropathy caused by EPCAM variants. While the clinical spectrum ranges from intractable diarrhea to manageable outcomes, the genotype-phenotype correlation remains undefined. Methods We report a case of an infant diagnosed with CTE carrying a novel frameshift variant (c.315delT), and present a systematic review of previously published molecularly confirmed cases. Genotypes were stratified into truncating (nonsense, frameshift, large deletions) and non-truncating (missense, splicing, in-frame indel) groups to assess their impact on intestinal failure severity. Results The index patient, carrying a homozygous truncating variant, presented with severe malnutrition and intestinal failure. In the pooled cohort ( n = 150), truncating variants were significantly associated with dependency on total parenteral nutrition (TPN) compared to non-truncating variants (OR 2.37, 95% CI 1.15–4.90, p = 0.020). Sensitivity analysis supported this association (OR 2.42, 95% CI 1.07–5.47, p = 0.045). Geographically, truncating variants were enriched in the Eastern Mediterranean Region (OR 9.32, p < 0.001). Conclusions Truncating EPCAM variants showed a preliminary but significant clinical association with severe intestinal failure requiring TPN. These findings support early risk stratification for aggressive nutritional management but warrant further validation in prospective cohorts.