Congenital malabsorptive diarrhea 4

Summary

Congenital malabsorptive diarrhea 4 (MONDO:0012479) is a disease caused by NEUROG3 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NEUROG3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 25
• Phenotypes (HPO): 9

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (Orphanet curated; top 9 by frequency):

HPO ID	Term	Frequency
HP:0001944	Dehydration	Very frequent (80-99%)
HP:0002013	Vomiting	Very frequent (80-99%)
HP:0002014	Diarrhea	Very frequent (80-99%)
HP:0002024	Malabsorption	Very frequent (80-99%)
HP:0004918	Hyperchloremic metabolic acidosis	Very frequent (80-99%)
HP:0001409	Portal hypertension	Frequent (30-79%)
HP:0002611	Cholestatic liver disease	Frequent (30-79%)
HP:0025354	Abnormal cellular phenotype	Frequent (30-79%)
HP:0100651	Type I diabetes mellitus	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital malabsorptive diarrhea 4
Mondo ID	MONDO:0012479
MeSH	C563673
OMIM	610370
Orphanet	83620
DOID	DOID:0060779
ICD-11	302560695
SNOMED CT	722392003
UMLS	C1835888
MedGen	372151
GARD	0016729
Is cancer (heuristic)	no

Also known as: congenital diarrhea caused by mutation in NEUROG3 · congenital diarrhoea caused by mutation in NEUROG3 · congenital malabsorptive diarrhea due to paucity of enteroendocrine cells · congenital malabsorptive diarrhea type 4 · congenital malabsorptive diarrhoea due to paucity of enteroendocrine cells · congenital malabsorptive diarrhoea type 4 · DIAR4 · diarrhea 4, malabsorptive, congenital · diarrhoea 4, malabsorptive, congenital · enteric anendocrinosis · NEUROG3 congenital diarrhea · NEUROG3 congenital diarrhoea

Data availability: 25 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › diarrheal disease › congenital diarrhea › congenital malabsorptive diarrhea 4

Related subtypes (11): congenital diarrhea 6, congenital diarrhea 7 with exudative enteropathy, congenital sodium diarrhea, diarrhea 12, with microvillus atrophy, diarrhea 9, diarrhea 10, protein-losing enteropathy type, diarrhea 11, malabsorptive, congenital, congenital secretory diarrhea, diarrhea 13, diarrhea 14, congenital, diarrhea 15, congenital

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

25 retrieved; paginated sample, class counts are floors:

11 pathogenic, 5 uncertain significance, 3 pathogenic/likely pathogenic, 2 conflicting classifications of pathogenicity, 2 likely pathogenic, 1 benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1327470	NM_020999.4(NEUROG3):c.371C>G (p.Thr124Arg)	NEUROG3	Pathogenic	criteria provided, single submitter
1327471	NM_020999.4(NEUROG3):c.284G>C (p.Arg95Pro)	NEUROG3	Pathogenic	criteria provided, single submitter
1917901	NM_020999.4(NEUROG3):c.117del (p.Thr40fs)	NEUROG3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3767257	NEUROG3, THR138ARG	NEUROG3	Pathogenic	no assertion criteria provided
3767258	E28*	NEUROG3	Pathogenic	no assertion criteria provided
3767259	L135P	NEUROG3	Pathogenic	no assertion criteria provided
3767260	E123*	NEUROG3	Pathogenic	no assertion criteria provided
3767261	NEUROG3, 1-BP DUP, 510G	NEUROG3	Pathogenic	no assertion criteria provided
3767262	I132F	NEUROG3	Pathogenic	no assertion criteria provided
3767263	NEUROG3, THR124ARG (SCV002029230)	NEUROG3	Pathogenic	no assertion criteria provided
3767264	NEUROG3, ARG95PRO (SCV002029231)	NEUROG3	Pathogenic	no assertion criteria provided
435975	NM_020999.4(NEUROG3):c.162C>A (p.Cys54Ter)	NEUROG3	Pathogenic	criteria provided, multiple submitters, no conflicts
5322	NM_020999.4(NEUROG3):c.319C>A (p.Arg107Ser)	NEUROG3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5323	NM_020999.4(NEUROG3):c.278G>T (p.Arg93Leu)	NEUROG3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1162203	NM_020999.4(NEUROG3):c.394A>T (p.Ile132Phe)	NEUROG3	Likely pathogenic	no assertion criteria provided
3255339	NM_020999.4(NEUROG3):c.410A>G (p.Gln137Arg)	NEUROG3	Likely pathogenic	criteria provided, single submitter
1046744	NM_020999.4(NEUROG3):c.46G>C (p.Glu16Gln)	NEUROG3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2049034	NM_020999.4(NEUROG3):c.130G>A (p.Gly44Arg)	NEUROG3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1474835	NM_020999.4(NEUROG3):c.392A>G (p.Tyr131Cys)	NEUROG3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1901433	NM_020999.4(NEUROG3):c.539G>A (p.Gly180Asp)	NEUROG3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2434333	NM_020999.4(NEUROG3):c.221A>G (p.Glu74Gly)	NEUROG3	Uncertain significance	criteria provided, single submitter
2482208	NM_020999.4(NEUROG3):c.389A>G (p.Asn130Ser)	NEUROG3	Uncertain significance	criteria provided, multiple submitters, no conflicts
827677	NM_020999.4(NEUROG3):c.413C>G (p.Thr138Arg)	NEUROG3	Uncertain significance	criteria provided, single submitter
129765	NM_020999.4(NEUROG3):c.596T>C (p.Phe199Ser)	NEUROG3	Benign	criteria provided, multiple submitters, no conflicts
1571931	NM_020999.4(NEUROG3):c.585G>A (p.Leu195=)	NEUROG3	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
NEUROG3	Strong	Autosomal recessive	congenital malabsorptive diarrhea 4	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NEUROG3	Orphanet:83620	Enteric anendocrinosis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NEUROG3	HGNC:13806	ENSG00000122859	Q9Y4Z2	Neurogenin-3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NEUROG3	Neurogenin-3	Is a transcriptional regulator involved in the control of enteroendocrine cell differentiation.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NEUROG3	Transcription factor	no		bHLH_dom, Ngn3_bHLH, HLH_DNA-bd_sf

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
Ammon’s horn	1
duodenum	1
mucosa of transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NEUROG3	46	tissue_specific	yes	mucosa of transverse colon, duodenum, Ammon’s horn

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NEUROG3	1,826

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NEUROG3	Q9Y4Z2	70.55

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of gene expression in endocrine-committed (NEUROG3+) progenitor cells	1	2284.0×	9e-04	NEUROG3
Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells	1	713.8×	0.001	NEUROG3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
enteroendocrine cell differentiation	1	4213.0×	0.004	NEUROG3
transdifferentiation	1	2106.5×	0.004	NEUROG3
hindbrain development	1	1123.5×	0.004	NEUROG3
regulation of dendrite morphogenesis	1	732.7×	0.004	NEUROG3
sensory organ development	1	674.1×	0.004	NEUROG3
peripheral nervous system development	1	581.1×	0.004	NEUROG3
spinal cord development	1	510.7×	0.004	NEUROG3
axon development	1	455.5×	0.004	NEUROG3
forebrain development	1	351.1×	0.005	NEUROG3
positive regulation of neuron differentiation	1	198.3×	0.008	NEUROG3
central nervous system development	1	115.4×	0.012	NEUROG3
nervous system development	1	45.9×	0.027	NEUROG3
positive regulation of DNA-templated transcription	1	27.9×	0.041	NEUROG3
negative regulation of transcription by RNA polymerase II	1	17.7×	0.060	NEUROG3
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	NEUROG3

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NEUROG3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NEUROG3

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)
NEUROG3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.