Congenital secretory chloride diarrhea 1

Summary

Congenital secretory chloride diarrhea 1 (MONDO:0008964) is a disease caused by SLC26A3 (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Causal gene: SLC26A3 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 157
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital secretory chloride diarrhea 1
Mondo ID	MONDO:0008964
MeSH	C536210
OMIM	214700
Orphanet	53689
DOID	DOID:0060296
SNOMED CT	24412005
UMLS	C0267662
MedGen	78631
GARD	0010001
Is cancer (heuristic)	no

Also known as: CLD · congenital chloride diarrhoea · congenital chloridorrhea · congenital secretory chloride diarrhea type 1 · congenital secretory chloride diarrhoea type 1 · Darrow-gamble disease · DIAR1 · diarrhea 1, secretory chloride, congenital · diarrhoea 1, secretory chloride, congenital · familial chloride diarrhea · familial chloride diarrhoea · secretory diarrhea caused by mutation in SLC26A3 · secretory diarrhoea caused by mutation in SLC26A3 · SLC26A3 secretory diarrhea · SLC26A3 secretory diarrhoea

Data availability: 157 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 › secretory diarrhea › congenital secretory diarrhea › congenital secretory chloride diarrhea 1

Related subtypes (4): microvillus inclusion disease, congenital secretory sodium diarrhea 3, congenital diarrhea 5 with tufting enteropathy, 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

157 retrieved; paginated sample, class counts are floors:

46 likely pathogenic, 41 uncertain significance, 22 pathogenic, 16 conflicting classifications of pathogenicity, 13 benign/likely benign, 10 pathogenic/likely pathogenic, 6 benign, 3 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1071195	NM_000111.3(SLC26A3):c.614del (p.Leu205fs)	SLC26A3	Pathogenic	criteria provided, multiple submitters, no conflicts
1275759	NM_000111.3(SLC26A3):c.1312-1G>T	SLC26A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16754	NM_000111.3(SLC26A3):c.951_953del (p.Val318del)	SLC26A3	Pathogenic	criteria provided, multiple submitters, no conflicts
16755	NM_000111.3(SLC26A3):c.371A>T (p.His124Leu)	SLC26A3	Pathogenic	no assertion criteria provided
16757	NM_000111.3(SLC26A3):c.735+708_971+1514del	SLC26A3	Pathogenic	no assertion criteria provided
16759	NM_000111.3(SLC26A3):c.559G>T (p.Gly187Ter)	SLC26A3	Pathogenic	criteria provided, multiple submitters, no conflicts
16761	NM_000111.3(SLC26A3):c.1386G>A (p.Trp462Ter)	SLC26A3	Pathogenic	no assertion criteria provided
1803226	NM_000111.3(SLC26A3):c.1514+1G>A	SLC26A3	Pathogenic	criteria provided, multiple submitters, no conflicts
2506951	NM_000111.3(SLC26A3):c.1679T>A (p.Val560Asp)	SLC26A3	Pathogenic	no assertion criteria provided
2713332	NM_000111.3(SLC26A3):c.1735C>T (p.Arg579Ter)	SLC26A3	Pathogenic	criteria provided, multiple submitters, no conflicts
2735075	NM_000111.3(SLC26A3):c.735+4_735+7del	SLC26A3	Pathogenic	criteria provided, multiple submitters, no conflicts
2835412	NM_000111.3(SLC26A3):c.1674del (p.Asp558fs)	SLC26A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2884959	NM_000111.3(SLC26A3):c.926_927del (p.Asp308_Phe309insTer)	SLC26A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2995866	NM_000111.3(SLC26A3):c.-3_13del (p.Met1fs)	SLC26A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
55965	NM_000111.3(SLC26A3):c.1148_1149del (p.Ile383fs)	SLC26A3	Pathogenic	criteria provided, single submitter
55966	NM_000111.3(SLC26A3):c.1306C>T (p.Gln436Ter)	SLC26A3	Pathogenic	criteria provided, single submitter
55971	NM_000111.3(SLC26A3):c.1387C>T (p.Arg463Ter)	SLC26A3	Pathogenic	criteria provided, single submitter
55974	NM_000111.3(SLC26A3):c.145_157del (p.Lys49fs)	SLC26A3	Pathogenic/Likely pathogenic	no assertion criteria provided
55983	NM_000111.3(SLC26A3):c.1609del (p.Ile537fs)	SLC26A3	Pathogenic	criteria provided, single submitter
55985	NM_000111.3(SLC26A3):c.1631T>A (p.Ile544Asn)	SLC26A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
55986	NM_000111.3(SLC26A3):c.177dup (p.Ile60fs)	SLC26A3	Pathogenic	criteria provided, multiple submitters, no conflicts
55988	NM_000111.3(SLC26A3):c.2024_2026dup (p.Ile675dup)	SLC26A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
55989	NM_000111.3(SLC26A3):c.2063-1G>T	SLC26A3	Pathogenic	criteria provided, multiple submitters, no conflicts
55994	NM_000111.3(SLC26A3):c.269_270dup (p.Gly91fs)	SLC26A3	Pathogenic	criteria provided, multiple submitters, no conflicts
55996	NM_000111.3(SLC26A3):c.344del (p.Ile115fs)	SLC26A3	Pathogenic	criteria provided, single submitter
55997	NM_000111.3(SLC26A3):c.358G>A (p.Gly120Ser)	SLC26A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
55999	NM_000111.3(SLC26A3):c.392C>G (p.Pro131Arg)	SLC26A3	Pathogenic	criteria provided, single submitter
56000	NM_000111.3(SLC26A3):c.392C>T (p.Pro131Leu)	SLC26A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56004	NM_000111.3(SLC26A3):c.571-1G>T	SLC26A3	Pathogenic	criteria provided, multiple submitters, no conflicts
56005	NM_000111.3(SLC26A3):c.571-2A>G	SLC26A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 4 · 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
SLC26A3	Definitive	Autosomal recessive	congenital secretory chloride diarrhea 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC26A3	Orphanet:53689	Congenital chloride diarrhea
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

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
SLC26A3	HGNC:3018	ENSG00000091138	P40879	Chloride anion exchanger	gencc,clinvar
GUCY2C	HGNC:4688	ENSG00000070019	P25092	Guanylyl cyclase C	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC26A3	Chloride anion exchanger	Mediates chloride-bicarbonate exchange with a chloride bicarbonate stoichiometry of 2:1 in the intestinal epithelia.
GUCY2C	Guanylyl cyclase C	Guanylyl cyclase that catalyzes synthesis of cyclic GMP (cGMP) from GTP.

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
Transporter	1	38.9×	0.051
Kinase	1	13.9×	0.071

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC26A3	Transporter	yes		SLC26A/SulP_fam, STAS_dom, SLC26A/SulP_dom
GUCY2C	Kinase	yes	4.6.1.2	Prot_kinase_dom, A/G_cyclase, Ser-Thr/Tyr_kinase_cat_dom

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	2
mucosa of sigmoid colon	2
rectum	1
jejunal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC26A3	159	tissue_specific	marker	colonic mucosa, mucosa of sigmoid colon, rectum
GUCY2C	84	tissue_specific	marker	jejunal mucosa, mucosa of sigmoid colon, colonic mucosa

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC26A3	1,831
GUCY2C	986

Intra-cohort edges

A	B	Sources
GUCY2C	SLC26A3	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC26A3	P40879	13
GUCY2C	P25092	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
Defective SLC26A3 causes congenital secretory chloride diarrhea 1 (DIAR1)	1	5710.0×	0.002	SLC26A3
Intestinal infectious diseases	1	1903.3×	0.003	GUCY2C
Inorganic anion exchange by SLC26 transporters	1	634.4×	0.005	SLC26A3
Digestion	1	285.5×	0.009	GUCY2C
SLC transporter disorders	1	102.0×	0.020	SLC26A3
Disorders of transmembrane transporters	1	69.6×	0.022	SLC26A3
R-HSA-425393	1	64.9×	0.022	SLC26A3
SLC-mediated transmembrane transport	1	29.6×	0.042	SLC26A3
Transport of small molecules	1	12.6×	0.087	SLC26A3
Disease	1	6.5×	0.147	SLC26A3

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
intracellular pH elevation	1	2808.7×	0.004	SLC26A3
membrane hyperpolarization	1	936.2×	0.004	SLC26A3
cGMP biosynthetic process	1	702.2×	0.004	GUCY2C
monoatomic anion transport	1	702.2×	0.004	SLC26A3
receptor guanylyl cyclase signaling pathway	1	648.1×	0.004	GUCY2C
sulfate transmembrane transport	1	601.9×	0.004	SLC26A3
sperm capacitation	1	337.0×	0.006	SLC26A3
cellular response to cAMP	1	145.3×	0.011	SLC26A3
chloride transmembrane transport	1	118.7×	0.012	SLC26A3
response to toxic substance	1	105.3×	0.012	GUCY2C
monoatomic ion transport	1	78.0×	0.015	SLC26A3
regulation of cell population proliferation	1	57.7×	0.019	GUCY2C
intracellular signal transduction	1	19.1×	0.052	GUCY2C

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

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
SLC26A3	0	0
GUCY2C	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SLC26A3	6	Binding:6
GUCY2C	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: 2; 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	2	SLC26A3, GUCY2C
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
SLC26A3	6	—
GUCY2C	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
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns