Congenital diarrhea 5 with tufting enteropathy

Summary

Congenital diarrhea 5 with tufting enteropathy (MONDO:0013184) is a disease caused by EPCAM (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: EPCAM (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 51
• Phenotypes (HPO): 26
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.5	Europe	Validated

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0002024	Malabsorption	Very frequent (80-99%)
HP:0002028	Chronic diarrhea	Very frequent (80-99%)
HP:0011473	Villous atrophy	Very frequent (80-99%)
HP:0000737	Irritability	Frequent (30-79%)
HP:0001824	Weight loss	Frequent (30-79%)
HP:0001944	Dehydration	Frequent (30-79%)
HP:0002570	Steatorrhea	Frequent (30-79%)
HP:0003270	Abdominal distention	Frequent (30-79%)
HP:0005208	Secretory diarrhea	Frequent (30-79%)
HP:0025129	Abnormal small intestinal mucosa morphology	Frequent (30-79%)
HP:0032486	Elevated fecal osmolality	Frequent (30-79%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0000613	Photophobia	Occasional (5-29%)
HP:0000951	Abnormality of the skin	Occasional (5-29%)
HP:0001369	Arthritis	Occasional (5-29%)
HP:0025090	Abnormal large intestinal mucosa morphology	Occasional (5-29%)
HP:0200020	Corneal erosion	Occasional (5-29%)
HP:0000202	Orofacial cleft	Very rare (<1-4%)
HP:0000453	Choanal atresia	Very rare (<1-4%)
HP:0000588	Optic disc coloboma	Very rare (<1-4%)
HP:0002013	Vomiting	Very rare (<1-4%)
HP:0002023	Anal atresia	Very rare (<1-4%)
HP:0002611	Cholestatic liver disease	Very rare (<1-4%)
HP:0002652	Skeletal dysplasia	Very rare (<1-4%)
HP:0011859	Punctate keratitis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital diarrhea 5 with tufting enteropathy
Mondo ID	MONDO:0013184
MeSH	C567703
OMIM	613217
Orphanet	92050
DOID	DOID:0060776
ICD-11	1536004957
SNOMED CT	715669000
UMLS	C2750737
MedGen	413031
GARD	0010630
Is cancer (heuristic)	no

Also known as: congenital diarrhea 5 with tufting enteropathy · congenital enteropathy · congenital familial intractable diarrhea with enterocytes assembly abnormalities · congenital familial intractable diarrhoea with enterocytes assembly abnormalities · congenital tufting enteropathy · DIAR5 · diarrhea 5, with tufting enteropathy, congenital · diarrhoea 5, with tufting enteropathy, congenital · EPCAM secretory diarrhea · EPCAM secretory diarrhoea · IED · intestinal epithelial dysplasia · secretory diarrhea caused by mutation in EPCAM · secretory diarrhoea caused by mutation in EPCAM · tufting enteropathy

Data availability: 51 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › diarrheal disease › secretory diarrhea › congenital secretory diarrhea › congenital diarrhea 5 with tufting enteropathy

Related subtypes (4): congenital secretory chloride diarrhea 1, microvillus inclusion disease, congenital secretory sodium diarrhea 3, congenital secretory sodium diarrhea 8

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

51 retrieved; paginated sample, class counts are floors:

16 uncertain significance, 11 pathogenic, 7 benign, 6 likely pathogenic, 4 conflicting classifications of pathogenicity, 3 likely benign, 3 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
12771	NM_002354.3(EPCAM):c.491+1G>A	EPCAM	Pathogenic	criteria provided, multiple submitters, no conflicts
12773	NM_002354.3(EPCAM):c.197G>A (p.Cys66Tyr)	EPCAM	Pathogenic	no assertion criteria provided
12774	NM_002354.3(EPCAM):c.499dup (p.Gln167fs)	EPCAM	Pathogenic	criteria provided, multiple submitters, no conflicts
157603	NM_002354.3(EPCAM):c.556-14A>G	EPCAM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
157604	NM_002354.3(EPCAM):c.492-2A>G	EPCAM	Pathogenic	criteria provided, multiple submitters, no conflicts
3255333	NM_002354.3(EPCAM):c.227C>G (p.Ser76Ter)	EPCAM	Pathogenic	criteria provided, multiple submitters, no conflicts
3255334	NM_002354.3(EPCAM):c.540del (p.Phe180fs)	EPCAM	Pathogenic	criteria provided, single submitter
3255335	NM_002354.3(EPCAM):c.579del (p.Ile193fs)	EPCAM	Pathogenic	criteria provided, single submitter
3255336	NM_002354.3(EPCAM):c.589C>T (p.Gln197Ter)	EPCAM	Pathogenic	criteria provided, single submitter
3775404	NM_002354.3(EPCAM):c.607dup (p.Thr203fs)	EPCAM	Pathogenic	criteria provided, single submitter
40256	NM_002354.3(EPCAM):c.412C>T (p.Arg138Ter)	EPCAM	Pathogenic	criteria provided, single submitter
488505	NM_002354.3(EPCAM):c.373_374insC (p.Arg125fs)	EPCAM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
800510	NM_002354.3(EPCAM):c.265C>T (p.Gln89Ter)	EPCAM	Pathogenic	criteria provided, multiple submitters, no conflicts
973534	NM_002354.3(EPCAM):c.13C>T (p.Gln5Ter)	EPCAM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3255332	NM_002354.3(EPCAM):c.83_88del (p.Val28_Cys29del)	EPCAM	Likely pathogenic	criteria provided, single submitter
3377746	NM_002354.3(EPCAM):c.610C>T (p.Gln204Ter)	EPCAM	Likely pathogenic	criteria provided, single submitter
3779619	NM_002354.3(EPCAM):c.567_568insAATA (p.Val190fs)	EPCAM	Likely pathogenic	criteria provided, single submitter
4277342	NM_002354.3(EPCAM):c.1_7del (p.Met1fs)	EPCAM	Likely pathogenic	criteria provided, single submitter
4292053	NM_002354.3(EPCAM):c.225del (p.Ser76fs)	EPCAM	Likely pathogenic	criteria provided, single submitter
973535	NM_002354.3(EPCAM):c.439G>T (p.Glu147Ter)	EPCAM	Likely pathogenic	criteria provided, single submitter
1788402	NM_002354.3(EPCAM):c.224G>A (p.Gly75Asp)	EPCAM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
216559	NM_002354.3(EPCAM):c.518G>A (p.Arg173His)	EPCAM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2562277	NM_002354.3(EPCAM):c.377G>A (p.Arg126Lys)	EPCAM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3361565	NM_002354.3(EPCAM):c.347G>A (p.Cys116Tyr)	EPCAM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4277300	NM_012079.6(DGAT1):c.329+4A>C	DGAT1	Uncertain significance	criteria provided, single submitter
12772	NM_002354.3(EPCAM):c.426-1G>A	EPCAM	Uncertain significance	criteria provided, single submitter
136018	NM_002354.3(EPCAM):c.232C>G (p.Leu78Val)	EPCAM	Uncertain significance	criteria provided, multiple submitters, no conflicts
136022	NM_002354.3(EPCAM):c.466C>T (p.Pro156Ser)	EPCAM	Uncertain significance	criteria provided, multiple submitters, no conflicts
136026	NM_002354.3(EPCAM):c.574A>T (p.Thr192Ser)	EPCAM	Uncertain significance	criteria provided, multiple submitters, no conflicts
136027	NM_002354.3(EPCAM):c.577A>G (p.Ile193Val)	EPCAM	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
EPCAM	Definitive	Autosomal recessive	congenital diarrhea 5 with tufting enteropathy	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EPCAM	Orphanet:144	Lynch syndrome
EPCAM	Orphanet:92050	Congenital tufting enteropathy
DGAT1	Orphanet:329242	Congenital chronic diarrhea with protein-losing enteropathy

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EPCAM	HGNC:11529	ENSG00000119888	P16422	Epithelial cell adhesion molecule	gencc,clinvar
DGAT1	HGNC:2843	ENSG00000185000	O75907	Diacylglycerol O-acyltransferase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EPCAM	Epithelial cell adhesion molecule	May act as a physical homophilic interaction molecule between intestinal epithelial cells (IECs) and intraepithelial lymphocytes (IELs) at the mucosal epithelium for providing immunological barrier as a first line of defense against mucosa…
DGAT1	Diacylglycerol O-acyltransferase 1	Catalyzes the terminal and only committed step in triacylglycerol synthesis by using diacylglycerol and fatty acyl CoA as substrates.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	2	12.0×	0.007

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EPCAM	Enzyme (other)	yes	2.4.1.37	Thyroglobulin_1, Thyroglobulin_1_sf, EpCAM_N
DGAT1	Enzyme (other)	yes	2.3.1.20	MBOAT_fam, Oat_ACAT_DAG_ARE, Diacylglycerol_acylTrfase1

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
colonic mucosa	1
jejunal mucosa	1
mucosa of sigmoid colon	1
duodenum	1
mucosa of transverse colon	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EPCAM	253	broad	marker	jejunal mucosa, colonic mucosa, mucosa of sigmoid colon
DGAT1	134	ubiquitous	marker	duodenum, mucosa of transverse colon, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EPCAM	3,359
DGAT1	2,407

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DGAT1	O75907	5
EPCAM	P16422	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Acyl chain remodeling of DAG and TAG	1	815.7×	0.006	DGAT1
Developmental Lineage of Mammary Stem Cells	1	380.7×	0.006	EPCAM
Triglyceride biosynthesis	1	335.9×	0.006	DGAT1
Developmental Lineage of Mammary Gland Alveolar Cells	1	317.2×	0.006	EPCAM
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	271.9×	0.006	EPCAM
Attachment of bacteria to epithelial cells	1	248.3×	0.006	EPCAM
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	228.4×	0.006	EPCAM
Cell surface interactions at the vascular wall	1	47.6×	0.024	EPCAM
Neutrophil degranulation	1	11.5×	0.085	DGAT1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
long-chain fatty-acyl-CoA metabolic process	1	1203.7×	0.005	DGAT1
monoacylglycerol biosynthetic process	1	766.0×	0.005	DGAT1
negative regulation of cell-cell adhesion mediated by cadherin	1	766.0×	0.005	EPCAM
very-low-density lipoprotein particle assembly	1	601.9×	0.005	DGAT1
diacylglycerol metabolic process	1	601.9×	0.005	DGAT1
fatty acid homeostasis	1	468.1×	0.005	DGAT1
triglyceride biosynthetic process	1	366.4×	0.005	DGAT1
signal transduction involved in regulation of gene expression	1	351.1×	0.005	EPCAM
lipid storage	1	271.8×	0.006	DGAT1
positive regulation of stem cell proliferation	1	263.3×	0.006	EPCAM
ureteric bud development	1	227.7×	0.006	EPCAM
triglyceride metabolic process	1	221.7×	0.006	DGAT1
stem cell differentiation	1	150.5×	0.008	EPCAM
positive regulation of cell population proliferation	1	16.8×	0.063	EPCAM
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	EPCAM

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DGAT1	3	3
EPCAM	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PRADIGASTAT	3	DGAT1
PF-04620110	1	DGAT1
AZD-7687	1	DGAT1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
DGAT1	130	Binding:130
EPCAM	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
EPCAM	2.4.1.37, 2.4.1.40	fucosylgalactoside 3-alpha-galactosyltransferase, glycoprotein-fucosylgalactoside alpha-N-acetylgalactosaminyltransferase
DGAT1	2.3.1.20	diacylglycerol O-acyltransferase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
DGAT1	130

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

3 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
PRADIGASTAT	3	DGAT1
PF-04620110	1	DGAT1
AZD-7687	1	DGAT1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	DGAT1
C	Druggable family + PDB, no drug	1	EPCAM
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
EPCAM	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01114035	Not specified	COMPLETED	Characterization Phenotypic and Genetic Study of the Intestinal Epithelial Dysplasia or Tufting Enteropathy (TE)