Congenital sodium diarrhea

Summary

Congenital sodium diarrhea (MONDO:0015170) is a disease with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		50	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital sodium diarrhea
Mondo ID	MONDO:0015170
Orphanet	103908
SNOMED CT	18805001
UMLS	C0267663
MedGen	78632
GARD	0016945
Is cancer (heuristic)	no

Also known as: Na-H exchange deficiency

Data availability: 2 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 3 Mondo subtypes.

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

Related subtypes (11): congenital malabsorptive diarrhea 4, congenital diarrhea 6, congenital diarrhea 7 with exudative enteropathy, 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

Subtypes (3): congenital secretory sodium diarrhea 3, congenital secretory sodium diarrhea 8, syndromic congenital sodium diarrhea

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

2 retrieved; paginated sample, class counts are floors:

2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1028719	NM_021102.4(SPINT2):c.553C>T (p.Arg185Cys)	SPINT2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1355375	NM_021102.4(SPINT2):c.406A>G (p.Asn136Asp)	SPINT2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 6 · 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
GUCY2C	Definitive	Autosomal dominant	congenital diarrhea 6	10
SLC9A3	Strong	Autosomal recessive	congenital secretory sodium diarrhea 8	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC9A3	Orphanet:103908	Congenital sodium diarrhea
SLC9A3	Orphanet:586	Cystic fibrosis
GUCY2C	Orphanet:103908	Congenital sodium diarrhea
GUCY2C	Orphanet:314373	Chronic infantile diarrhea due to guanylate cyclase 2C overactivity
GUCY2C	Orphanet:314376	Intestinal obstruction in the newborn due to guanylate cyclase 2C deficiency
SPINT2	Orphanet:563708	Syndromic congenital sodium diarrhea

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC9A3	HGNC:11073	ENSG00000066230	P48764	Sodium/hydrogen exchanger 3	gencc
GUCY2C	HGNC:4688	ENSG00000070019	P25092	Guanylyl cyclase C	gencc
SPINT2	HGNC:11247	ENSG00000167642	O43291	Kunitz-type protease inhibitor 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC9A3	Sodium/hydrogen exchanger 3	Plasma membrane Na(+)/H(+) antiporter.
GUCY2C	Guanylyl cyclase C	Guanylyl cyclase that catalyzes synthesis of cyclic GMP (cGMP) from GTP.
SPINT2	Kunitz-type protease inhibitor 2	Inhibitor of HGFAC.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Kinase	1	9.2×	0.209
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC9A3	Other/Unknown	no		NaH_exchanger, Cation/H_exchanger_TM, Na/H_exchanger_3/5
GUCY2C	Kinase	yes	4.6.1.2	Prot_kinase_dom, A/G_cyclase, Ser-Thr/Tyr_kinase_cat_dom
SPINT2	Other/Unknown	no		Kunitz_BPTI, Prtase_inh_Kunz-CS, Kunitz_BPTI_sf

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mucosa of transverse colon	2
metanephros cortex	1
sural nerve	1
colonic mucosa	1
jejunal mucosa	1
mucosa of sigmoid colon	1
parotid gland	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC9A3	164	tissue_specific	yes	mucosa of transverse colon, sural nerve, metanephros cortex
GUCY2C	84	tissue_specific	marker	jejunal mucosa, mucosa of sigmoid colon, colonic mucosa
SPINT2	288	ubiquitous	marker	type B pancreatic cell, mucosa of transverse colon, parotid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC9A3	1,800
SPINT2	1,426
GUCY2C	986

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GUCY2C	P25092	3
SLC9A3	P48764	1
SPINT2	O43291	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Intestinal infectious diseases	1	1268.9×	0.006	GUCY2C
Signaling by MST1	1	761.3×	0.006	SPINT2
MET Receptor Activation	1	634.4×	0.006	SPINT2
Sodium/Proton exchangers	1	423.0×	0.006	SLC9A3
Digestion	1	190.3×	0.012	GUCY2C
Signaling by MET	1	105.7×	0.017	SPINT2
R-HSA-425393	1	43.3×	0.036	SLC9A3
SLC-mediated transmembrane transport	1	19.7×	0.069	SLC9A3
Signaling by Receptor Tyrosine Kinases	1	17.2×	0.070	SPINT2
Transport of small molecules	1	8.4×	0.126	SLC9A3
Signal Transduction	1	3.4×	0.267	SPINT2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
epithelial cell morphogenesis involved in placental branching	1	1872.4×	0.008	SPINT2
negative regulation of neural precursor cell proliferation	1	510.7×	0.008	SPINT2
cGMP biosynthetic process	1	468.1×	0.008	GUCY2C
receptor guanylyl cyclase signaling pathway	1	432.1×	0.008	GUCY2C
negative regulation of cell motility	1	432.1×	0.008	SPINT2
negative regulation of cell-cell adhesion	1	330.4×	0.009	SPINT2
sodium ion import across plasma membrane	1	208.1×	0.010	SLC9A3
regulation of intracellular pH	1	200.6×	0.010	SLC9A3
cellular response to BMP stimulus	1	187.2×	0.010	SPINT2
basement membrane organization	1	170.2×	0.010	SPINT2
establishment or maintenance of cell polarity	1	133.8×	0.012	SPINT2
response to toxic substance	1	70.2×	0.020	GUCY2C
neural tube closure	1	62.4×	0.021	SPINT2
monoatomic ion transport	1	52.0×	0.023	SLC9A3
potassium ion transmembrane transport	1	45.3×	0.025	SLC9A3
regulation of cell population proliferation	1	38.5×	0.027	GUCY2C
intracellular signal transduction	1	12.7×	0.077	GUCY2C

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 3 of 3 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SLC9A3	TENAPANOR HYDROCHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC9A3	3	4
GUCY2C	0	0
SPINT2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TENAPANOR HYDROCHLORIDE	4	SLC9A3
TENAPANOR	4	SLC9A3
ENIPORIDE	2	SLC9A3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SLC9A3	20	Binding:18, Functional:2
GUCY2C	1	Binding:1
SPINT2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GUCY2C	4.6.1.2	guanylate cyclase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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)
TENAPANOR HYDROCHLORIDE	4	SLC9A3
TENAPANOR	4	SLC9A3
ENIPORIDE	2	SLC9A3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SLC9A3
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	GUCY2C
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SPINT2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GUCY2C	1	—
SPINT2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.