familial hyperaldosteronism type II

Summary

familial hyperaldosteronism type II (MONDO:0011576) is a disease with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 176
• Phenotypes (HPO): 14

Clinical features

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0000822	Hypertension	Obligate (100%)
HP:0011740	Glucocortocoid-insensitive primary hyperaldosteronism	Very frequent (80-99%)
HP:0040084	Abnormal circulating renin	Very frequent (80-99%)
HP:0011746	Secretory adrenocortical adenoma	Frequent (30-79%)
HP:0000360	Tinnitus	Occasional (5-29%)
HP:0000421	Epistaxis	Occasional (5-29%)
HP:0001324	Muscle weakness	Occasional (5-29%)
HP:0002018	Nausea	Occasional (5-29%)
HP:0002170	Intracranial hemorrhage	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0002900	Hypokalemia	Occasional (5-29%)
HP:0008221	Adrenal hyperplasia	Occasional (5-29%)
HP:0200114	Metabolic alkalosis	Occasional (5-29%)
HP:0011739	Dexamethasone-suppresible primary hyperaldosteronism	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial hyperaldosteronism type II
Mondo ID	MONDO:0011576
MeSH	C565312
OMIM	605635
Orphanet	404
DOID	DOID:0061249
NCIT	C127162
SNOMED CT	703233008
UMLS	C1854107
MedGen	340137
GARD	0002789
Is cancer (heuristic)	no

Also known as: familial adrenal adenoma · familial hyperaldosteronism type 2 · FH-II · FH2 · FHII · HALD2

Data availability: 176 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › adrenal gland disorder › adrenal cortex disorder › adrenal gland hyperfunction › hyperaldosteronism › primary aldosteronism › familial hyperaldosteronism › familial hyperaldosteronism type II

Related subtypes (4): glucocorticoid-remediable aldosteronism, familial hyperaldosteronism type III, aldosterone-producing adenoma with seizures and neurological abnormalities, hyperaldosteronism, familial, type IV

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

176 retrieved; paginated sample, class counts are floors:

119 uncertain significance, 17 conflicting classifications of pathogenicity, 13 likely benign, 8 benign/likely benign, 7 likely pathogenic, 7 pathogenic, 4 pathogenic/likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
100629	NM_004366.6(CLCN2):c.1709G>A (p.Trp570Ter)	CLCN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1279936	NM_004366.6(CLCN2):c.668_672del (p.Leu223fs)	CLCN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217788	NM_004366.6(CLCN2):c.1143del (p.Gly382fs)	CLCN2	Pathogenic	criteria provided, multiple submitters, no conflicts
2724374	NM_004366.6(CLCN2):c.1828C>T (p.Arg610Ter)	CLCN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
427066	NM_004366.6(CLCN2):c.71G>A (p.Gly24Asp)	CLCN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
441164	NM_004366.6(CLCN2):c.515G>A (p.Arg172Gln)	CLCN2	Pathogenic	criteria provided, multiple submitters, no conflicts
441165	NM_004366.6(CLCN2):c.65T>A (p.Met22Lys)	CLCN2	Pathogenic	no assertion criteria provided
441166	NM_004366.6(CLCN2):c.76T>A (p.Tyr26Asn)	CLCN2	Pathogenic	no assertion criteria provided
441167	NM_004366.6(CLCN2):c.1084A>T (p.Lys362Ter)	CLCN2	Pathogenic	no assertion criteria provided
441168	NM_004366.6(CLCN2):c.2593A>C (p.Ser865Arg)	CLCN2	Pathogenic	no assertion criteria provided
559516	CLCN2, LYS362DEL	SATB1	Pathogenic	no assertion criteria provided
1194517	NM_004366.6(CLCN2):c.898+1G>A	CLCN2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
217785	NM_004366.6(CLCN2):c.925C>T (p.Arg309Ter)	CLCN2	Likely pathogenic	criteria provided, single submitter
217791	NM_004366.6(CLCN2):c.1412G>A (p.Arg471His)	CLCN2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3589028	NM_004366.6(CLCN2):c.1069del (p.Arg357fs)	CLCN2	Likely pathogenic	criteria provided, single submitter
3589053	NM_004366.6(CLCN2):c.221-2A>G	CLCN2	Likely pathogenic	criteria provided, single submitter
3589056	NM_004366.6(CLCN2):c.194del (p.Gly65fs)	CLCN2	Likely pathogenic	criteria provided, single submitter
3589059	NM_004366.6(CLCN2):c.64-1G>A	CLCN2	Likely pathogenic	criteria provided, single submitter
1106292	NM_004366.6(CLCN2):c.1067A>G (p.Asn356Ser)	CLCN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1315588	NM_004366.6(CLCN2):c.1969A>C (p.Thr657Pro)	CLCN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1394236	NM_004366.6(CLCN2):c.2174G>A (p.Arg725Gln)	CLCN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1621558	NM_004366.6(CLCN2):c.2657G>A (p.Arg886Gln)	CLCN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1958391	NM_004366.6(CLCN2):c.63+4A>G	CLCN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1959620	NM_004366.6(CLCN2):c.220+15G>A	CLCN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2040196	NM_004366.6(CLCN2):c.773-9C>G	CLCN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2040248	NM_004366.6(CLCN2):c.2425A>G (p.Ile809Val)	CLCN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2082041	NM_004366.6(CLCN2):c.2197C>T (p.Pro733Ser)	CLCN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2174239	NM_004366.6(CLCN2):c.2399G>A (p.Arg800Gln)	CLCN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
217771	NM_004366.6(CLCN2):c.246C>G (p.Phe82Leu)	CLCN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
217773	NM_004366.6(CLCN2):c.1856-3C>T	CLCN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
CLCN2	Moderate	Autosomal dominant	familial hyperaldosteronism type II	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CLCN2	Orphanet:307	Juvenile myoclonic epilepsy
CLCN2	Orphanet:363540	Leukoencephalopathy with mild cerebellar ataxia and white matter edema
CLCN2	Orphanet:404	Familial hyperaldosteronism type II
SATB1	Orphanet:684232	Intellectual disability-epilepsy-dental anomalies-facial dysmorphism syndrome

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
CLCN2	HGNC:2020	ENSG00000114859	P51788	Chloride channel protein 2	gencc,clinvar
SATB1	HGNC:10541	ENSG00000182568	Q01826	DNA-binding protein SATB1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CLCN2	Chloride channel protein 2	Voltage-gated and osmosensitive chloride channel.
SATB1	DNA-binding protein SATB1	Crucial silencing factor contributing to the initiation of X inactivation mediated by Xist RNA that occurs during embryogenesis and in lymphoma.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · 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	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CLCN2	Other/Unknown	no		ClC, Cl-channel-2, Cl-channel_core
SATB1	Transcription factor	no		HD, CUT_dom, Homeodomain-like_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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
mucosa of transverse colon	1
sural nerve	1
tibial nerve	1
frontal pole	1
orbitofrontal cortex	1
thymus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CLCN2	181	broad	yes	mucosa of transverse colon, tibial nerve, sural nerve
SATB1	294	ubiquitous	marker	orbitofrontal cortex, frontal pole, thymus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SATB1	1,890
CLCN2	1,250

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CLCN2	P51788	8
SATB1	Q01826	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Apoptotic cleavage of cellular proteins	1	237.9×	0.018	SATB1
Apoptotic execution phase	1	237.9×	0.018	SATB1
SUMO E3 ligases SUMOylate target proteins	1	89.2×	0.018	SATB1
Apoptosis	1	84.0×	0.018	SATB1
SUMOylation	1	81.6×	0.018	SATB1
SUMOylation of chromatin organization proteins	1	79.3×	0.018	SATB1
Programmed Cell Death	1	73.2×	0.018	SATB1
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	1	73.2×	0.018	SATB1
Stimuli-sensing channels	1	68.0×	0.018	CLCN2
Post-translational protein modification	1	9.6×	0.112	SATB1
Metabolism of proteins	1	6.2×	0.155	SATB1

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
regulation of aldosterone biosynthetic process	1	8426.0×	0.001	CLCN2
cell differentiation involved in salivary gland development	1	4213.0×	0.001	CLCN2
regulation of membrane depolarization during action potential	1	4213.0×	0.001	CLCN2
stabilization of membrane potential	1	2808.7×	0.001	CLCN2
acinar cell differentiation	1	1685.2×	0.002	CLCN2
cellular hypotonic response	1	702.2×	0.004	CLCN2
regulation of resting membrane potential	1	648.1×	0.004	CLCN2
phagocytosis, engulfment	1	337.0×	0.005	CLCN2
positive regulation of oligodendrocyte differentiation	1	337.0×	0.005	CLCN2
chloride transport	1	227.7×	0.007	CLCN2
retina development in camera-type eye	1	127.7×	0.011	CLCN2
lung development	1	99.1×	0.013	CLCN2
chromatin organization	1	49.6×	0.025	SATB1
chromatin remodeling	1	36.5×	0.031	SATB1
negative regulation of transcription by RNA polymerase II	1	8.9×	0.117	SATB1
regulation of transcription by RNA polymerase II	1	5.8×	0.164	SATB1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CLCN2	0	0
SATB1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CLCN2	1	Binding:1

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	CLCN2, SATB1

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)
CLCN2	1	—
SATB1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.