Bartter syndrome type 4

Summary

Bartter syndrome type 4 (MONDO:0019524) is a disease with 3 cohort genes. The dominant Reactome pathway is Stimuli-sensing channels (3 cohort genes).

At a glance

• Prevalence: Unknown (Europe) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 4
• Phenotypes (HPO): 36

Clinical features

Signs & symptoms

Clinical features (HPO)

36 HPO clinical features (Orphanet curated; top 36 by frequency):

HPO ID	Term	Frequency
HP:0000127	Renal salt wasting	Very frequent (80-99%)
HP:0000841	Hyperactive renin-angiotensin system	Very frequent (80-99%)
HP:0000848	Increased circulating renin level	Very frequent (80-99%)
HP:0000859	Hyperaldosteronism	Very frequent (80-99%)
HP:0001960	Hypokalemic metabolic alkalosis	Very frequent (80-99%)
HP:0002900	Hypokalemia	Very frequent (80-99%)
HP:0004727	Impaired renal concentrating ability	Very frequent (80-99%)
HP:0008619	Bilateral sensorineural hearing impairment	Very frequent (80-99%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001518	Small for gestational age	Frequent (30-79%)
HP:0001561	Polyhydramnios	Frequent (30-79%)
HP:0001622	Premature birth	Frequent (30-79%)
HP:0002150	Hypercalciuria	Frequent (30-79%)
HP:0002902	Hyponatremia	Frequent (30-79%)
HP:0002917	Hypomagnesemia	Frequent (30-79%)
HP:0003081	Increased urinary potassium	Frequent (30-79%)
HP:0003113	Hypochloremia	Frequent (30-79%)
HP:0003527	Hyperprostaglandinuria	Frequent (30-79%)
HP:0012622	Chronic kidney disease	Frequent (30-79%)
HP:0025335	Delayed ability to stand	Frequent (30-79%)
HP:0031936	Delayed ability to walk	Frequent (30-79%)
HP:0000121	Nephrocalcinosis	Occasional (5-29%)
HP:0000712	Emotional lability	Occasional (5-29%)
HP:0001525	Severe failure to thrive	Occasional (5-29%)
HP:0001919	Acute kidney injury	Occasional (5-29%)
HP:0001944	Dehydration	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002312	Clumsiness	Occasional (5-29%)
HP:0003774	Stage 5 chronic kidney disease	Occasional (5-29%)
HP:0040288	Nasogastric tube feeding	Occasional (5-29%)
HP:0000822	Hypertension	Excluded (0%)
HP:0000325	Triangular face	Very rare (<1-4%)
HP:0000411	Protruding ear	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Bartter syndrome type 4
Mondo ID	MONDO:0019524
Orphanet	89938
ICD-11	959024909
SNOMED CT	700112007
UMLS	C3838860
MedGen	824706
GARD	0010508
Is cancer (heuristic)	no

Also known as: Bartter syndrome type 4 · Bartter syndrome type IV · Bartter syndrome with sensorineural deafness

Data availability: 4 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › syndromic disease › Bartter syndrome › Bartter syndrome type 4

Related subtypes (5): Bartter disease type 2, Bartter disease type 5, Bartter disease type 3, Bartter syndrome with hypocalcemia, Bartter disease type 1

Subtypes (2): Bartter disease type 4B, Bartter disease type 4A

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

4 retrieved; paginated sample, class counts are floors:

2 uncertain significance, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4387	NM_057176.3(BSND):c.139G>A (p.Gly47Arg)	BSND	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2202510	NM_057176.3(BSND):c.23G>A (p.Arg8Gln)	BSND	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3779090	NM_004070.4(CLCNKA):c.1270G>A (p.Gly424Arg)	CLCNKA	Uncertain significance	criteria provided, single submitter
3779091	NM_004070.4(CLCNKA):c.1498C>T (p.Pro500Ser)	LOC106501712	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · 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
BSND	Definitive	Autosomal recessive	Bartter disease type 4A	6
CLCNKB	Strong	Autosomal recessive	Bartter disease type 3	5
CLCNKA	Moderate	Unknown	Bartter disease type 4B	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BSND	Orphanet:89938	Bartter syndrome type 4
BSND	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
CLCNKA	Orphanet:89938	Bartter syndrome type 4
CLCNKB	Orphanet:358	Gitelman syndrome
CLCNKB	Orphanet:89938	Bartter syndrome type 4
CLCNKB	Orphanet:93605	Bartter syndrome type 3

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
BSND	HGNC:16512	ENSG00000162399	Q8WZ55	Barttin	gencc,clinvar
CLCNKA	HGNC:2026	ENSG00000186510	P51800	Chloride channel protein ClC-Ka	gencc,clinvar
CLCNKB	HGNC:2027	ENSG00000184908	P51801	Chloride channel protein ClC-Kb	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BSND	Barttin	Regulatory subunit of anion-selective CLCNKA:BSND and CLCNKB:BSND heteromeric channels involved in basolateral chloride conductance along the nephron to achieve urine concentration and maintain systemic acid-base homeostasis, and in the st…
CLCNKA	Chloride channel protein ClC-Ka	Anion-selective channel permeable to small monovalent anions with ion selectivity for chloride > bromide > nitrate > iodide.
CLCNKB	Chloride channel protein ClC-Kb	Anion-selective channel permeable to small monovalent anions with ion selectivity for chloride > bromide > nitrate > iodide.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BSND	Other/Unknown	no		Barttin
CLCNKA	Other/Unknown	no		CBS_dom, ClC, Cl_channel-K
CLCNKB	Other/Unknown	no		CBS_dom, ClC, Cl_channel-K

Expression context

Cohort genes with no expression data: 0.

3 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
adult mammalian kidney	3
metanephros cortex	3
kidney epithelium	1
left lobe of thyroid gland	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BSND	22	tissue_specific	marker	kidney epithelium, adult mammalian kidney, metanephros cortex
CLCNKA	130	tissue_specific	marker	metanephros cortex, adult mammalian kidney, left lobe of thyroid gland
CLCNKB	165	broad	marker	renal medulla, adult mammalian kidney, metanephros cortex

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BSND	996
CLCNKB	767
CLCNKA	724

Intra-cohort edges

A	B	Sources
BSND	CLCNKA	string_interaction
BSND	CLCNKB	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CLCNKA	P51800	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CLCNKB	P51801	87.16
BSND	Q8WZ55	53.80

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Stimuli-sensing channels	3	135.9×	1e-06	BSND, CLCNKA, CLCNKB
Ion channel transport	1	32.0×	0.046	BSND
Transport of small molecules	1	8.4×	0.115	BSND

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
chloride transport	3	455.5×	5e-08	BSND, CLCNKA, CLCNKB
transepithelial chloride transport	2	1248.3×	2e-06	CLCNKA, CLCNKB
renal absorption	2	1123.5×	2e-06	CLCNKA, CLCNKB
renal sodium ion absorption	1	330.4×	0.004	CLCNKB
sensory perception of sound	1	33.6×	0.029	BSND

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
BSND	0	0
CLCNKA	0	0
CLCNKB	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	3	BSND, CLCNKA, CLCNKB

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BSND	0	—
CLCNKA	0	—
CLCNKB	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.