Dehydrated hereditary stomatocytosis 2

Summary

Dehydrated hereditary stomatocytosis 2 (MONDO:0014737) is a disease caused by KCNN4 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: KCNN4 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 49

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	dehydrated hereditary stomatocytosis 2
Mondo ID	MONDO:0014737
OMIM	616689
DOID	DOID:0111577
UMLS	C4225242
MedGen	908701
GARD	0016152
Is cancer (heuristic)	no

Also known as: Dehydrated hereditary stomatocytosis 2 · dehydrated hereditary stomatocytosis 2; DHS2 · dehydrated hereditary stomatocytosis caused by mutation in KCNN4 · Dehydrated hereditary stomatocytosis type 2 · DHS2 · KCNN4 dehydrated hereditary stomatocytosis

Data availability: 49 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › normocytic anemia › hemolytic anemia › familial hemolytic anemia › dehydrated hereditary stomatocytosis 2

Related subtypes (22): congenital nonspherocytic hemolytic anemia, elliptocytosis 2, southeast Asian ovalocytosis, overhydrated hereditary stomatocytosis, cryohydrocytosis, dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema, abetalipoproteinemia, hemolytic anemia due to diphosphoglycerate mutase deficiency, glycogen storage disease VII, cutaneous porphyria, hereditary cryohydrocytosis with reduced stomatin, familial pseudohyperkalemia, renal tubular acidosis, distal, 4, with hemolytic anemia, elliptocytosis 1, glycogen storage disease due to aldolase A deficiency, primary CD59 deficiency, triosephosphate isomerase deficiency, Rh deficiency syndrome, hereditary spherocytosis, congenital dyserythropoietic anemia, X-linked congenital hemolytic anemia, hemolytic disease of fetus and newborn, RH-induced

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

49 retrieved; paginated sample, class counts are floors:

39 uncertain significance, 6 conflicting classifications of pathogenicity, 2 likely pathogenic, 1 pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
252601	NM_002250.3(KCNN4):c.1055G>A (p.Arg352His)	KCNN4	Pathogenic	criteria provided, multiple submitters, no conflicts
372185	NM_002250.3(KCNN4):c.844G>A (p.Val282Met)	KCNN4	Likely pathogenic	criteria provided, single submitter
372186	NM_002250.3(KCNN4):c.845T>A (p.Val282Glu)	KCNN4	Likely pathogenic	criteria provided, single submitter
2007816	NM_002250.3(KCNN4):c.1018C>A (p.His340Asn)	KCNN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2209966	NM_002250.3(KCNN4):c.1169G>A (p.Arg390Gln)	KCNN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2433015	NM_002250.3(KCNN4):c.263T>G (p.Met88Arg)	KCNN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2689292	NM_002250.3(KCNN4):c.20T>C (p.Leu7Pro)	KCNN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2689296	NM_002250.3(KCNN4):c.40C>T (p.Arg14Cys)	KCNN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246074	NM_170707.4(LMNA):c.1004G>A (p.Arg335Gln)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1333884	NM_002250.3(KCNN4):c.1007C>T (p.Ala336Val)	KCNN4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2239456	NM_002250.3(KCNN4):c.850G>A (p.Val284Met)	KCNN4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2282735	NM_002250.3(KCNN4):c.36G>C (p.Leu12Phe)	KCNN4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2349305	NM_002250.3(KCNN4):c.970A>G (p.Met324Val)	KCNN4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2433012	NM_002250.3(KCNN4):c.289C>A (p.Arg97Ser)	KCNN4	Uncertain significance	criteria provided, single submitter
2433013	NM_002250.3(KCNN4):c.1272G>T (p.Gln424His)	KCNN4	Uncertain significance	criteria provided, single submitter
2433014	NM_002250.3(KCNN4):c.1193C>T (p.Thr398Met)	KCNN4	Uncertain significance	criteria provided, single submitter
2433016	NM_002250.3(KCNN4):c.391T>A (p.Leu131Ile)	KCNN4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2433017	NM_002250.3(KCNN4):c.787G>A (p.Gly263Ser)	KCNN4	Uncertain significance	criteria provided, single submitter
2433018	NM_002250.3(KCNN4):c.340G>T (p.Val114Leu)	KCNN4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2433020	NM_002250.3(KCNN4):c.839T>A (p.Leu280Gln)	KCNN4	Uncertain significance	criteria provided, single submitter
2433021	NM_002250.3(KCNN4):c.8G>A (p.Gly3Glu)	KCNN4	Uncertain significance	criteria provided, single submitter
2433022	NM_002250.3(KCNN4):c.766G>A (p.Val256Met)	KCNN4	Uncertain significance	criteria provided, single submitter
2578032	NM_002250.3(KCNN4):c.43C>G (p.Arg15Gly)	KCNN4	Uncertain significance	criteria provided, single submitter
2628991	NM_002250.3(KCNN4):c.228C>G (p.Ile76Met)	KCNN4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2689293	NM_002250.3(KCNN4):c.726_729del (p.Leu241_Trp242insTer)	KCNN4	Uncertain significance	criteria provided, single submitter
2689294	NM_002250.3(KCNN4):c.611C>G (p.Pro204Arg)	KCNN4	Uncertain significance	criteria provided, single submitter
2689295	NM_002250.3(KCNN4):c.904A>T (p.Met302Leu)	KCNN4	Uncertain significance	criteria provided, multiple submitters, no conflicts
3113458	NM_002250.3(KCNN4):c.4G>A (p.Gly2Ser)	KCNN4	Uncertain significance	criteria provided, multiple submitters, no conflicts
3287722	NM_002250.3(KCNN4):c.1001C>T (p.Ser334Phe)	KCNN4	Uncertain significance	criteria provided, multiple submitters, no conflicts
3891454	NM_002250.3(KCNN4):c.22_23insCAAG (p.Gly8fs)	KCNN4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 23 · 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
KCNN4	Strong	Autosomal dominant	dehydrated hereditary stomatocytosis 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCNN4	Orphanet:3202	Dehydrated hereditary stomatocytosis
KCNN4	Orphanet:586	Cystic fibrosis
LMNA	Orphanet:154	Familial isolated dilated cardiomyopathy
LMNA	Orphanet:157973	Congenital muscular dystrophy due to LMNA mutation
LMNA	Orphanet:1662	Restrictive dermopathy
LMNA	Orphanet:168796	Heart-hand syndrome, Slovenian type
LMNA	Orphanet:2229	Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome
LMNA	Orphanet:2348	Familial partial lipodystrophy, Dunnigan type
LMNA	Orphanet:280365	Autosomal semi-dominant severe lipodystrophic laminopathy
LMNA	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
LMNA	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
LMNA	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
LMNA	Orphanet:300751	Familial dilated cardiomyopathy with conduction defect due to LMNA mutation
LMNA	Orphanet:363618	LMNA-related cardiocutaneous progeria syndrome
LMNA	Orphanet:54260	Left ventricular noncompaction
LMNA	Orphanet:675396	Epithelioid hemangioma
LMNA	Orphanet:740	Hutchinson-Gilford progeria syndrome
LMNA	Orphanet:79084	Familial partial lipodystrophy, Köbberling type
LMNA	Orphanet:79474	Atypical Werner syndrome
LMNA	Orphanet:90153	Mandibuloacral dysplasia with type A lipodystrophy
LMNA	Orphanet:98853	Autosomal dominant Emery-Dreifuss muscular dystrophy
LMNA	Orphanet:98855	Autosomal recessive Emery-Dreifuss muscular dystrophy
LMNA	Orphanet:98856	Charcot-Marie-Tooth disease type 2B1

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
KCNN4	HGNC:6293	ENSG00000104783	O15554	Intermediate conductance calcium-activated potassium channel protein 4	gencc,clinvar
LMNA	HGNC:6636	ENSG00000160789	P02545	Prelamin-A/C	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KCNN4	Intermediate conductance calcium-activated potassium channel protein 4	Intermediate conductance calcium-activated potassium channel that mediates the voltage-independent transmembrane transfer of potassium across the cell membrane through a constitutive interaction with calmodulin which binds the intracellula…
LMNA	Prelamin-A/C	Lamins are intermediate filament proteins that assemble into a filamentous meshwork, and which constitute the major components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Ion channel	1	55.8×	0.036
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCNN4	Ion channel	yes		CaM-bd_dom, K_chnl_dom, K_chnl_Ca-activ_SK
LMNA	Other/Unknown	no		Lamin_tail_dom, IF_conserved, Lamin_tail_dom_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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
olfactory segment of nasal mucosa	1
parotid gland	1
saliva-secreting gland	1
mucosa of stomach	1
nipple	1
skin of abdomen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNN4	200	ubiquitous	marker	olfactory segment of nasal mucosa, parotid gland, saliva-secreting gland
LMNA	295	ubiquitous	marker	nipple, mucosa of stomach, skin of abdomen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LMNA	7,173
KCNN4	1,698

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LMNA	P02545	28
KCNN4	O15554	17

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. 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
Breakdown of the nuclear lamina	1	1903.3×	0.009	LMNA
Ca2+ activated K+ channels	1	571.0×	0.011	KCNN4
Depolymerization of the Nuclear Lamina	1	380.7×	0.011	LMNA
Initiation of Nuclear Envelope (NE) Reformation	1	300.5×	0.011	LMNA
IRE1alpha activates chaperones	1	259.6×	0.011	LMNA
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models	1	259.6×	0.011	LMNA
Nuclear Envelope Breakdown	1	228.4×	0.011	LMNA
Unfolded Protein Response (UPR)	1	178.4×	0.013	LMNA
Oncogenic MAPK signaling	1	124.1×	0.016	LMNA
XBP1(S) activates chaperone genes	1	107.7×	0.017	LMNA
Signaling by BRAF and RAF1 fusions	1	85.2×	0.019	LMNA
Meiotic synapsis	1	70.5×	0.021	LMNA
Potassium Channels	1	67.2×	0.021	KCNN4
Diseases of signal transduction by growth factor receptors and second messengers	1	28.4×	0.045	LMNA
Neuronal System	1	22.1×	0.054	KCNN4
Cellular responses to stress	1	18.4×	0.060	LMNA
Cellular responses to stimuli	1	15.7×	0.066	LMNA
Disease	1	6.5×	0.147	LMNA

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
stabilization of membrane potential	1	2808.7×	0.004	KCNN4
DNA double-strand break attachment to nuclear envelope	1	2808.7×	0.004	LMNA
establishment or maintenance of microtubule cytoskeleton polarity	1	2106.5×	0.004	LMNA
nuclear pore localization	1	1685.2×	0.004	LMNA
negative regulation of mesenchymal cell proliferation	1	1404.3×	0.004	LMNA
regulation of calcium ion import across plasma membrane	1	1404.3×	0.004	KCNN4
saliva secretion	1	1053.2×	0.004	KCNN4
protein localization to nuclear envelope	1	1053.2×	0.004	LMNA
regulation of protein localization to nucleus	1	1053.2×	0.004	LMNA
macropinocytosis	1	936.2×	0.004	KCNN4
negative regulation of cardiac muscle hypertrophy in response to stress	1	936.2×	0.004	LMNA
ventricular cardiac muscle cell development	1	766.0×	0.004	LMNA
nuclear envelope organization	1	495.6×	0.006	LMNA
positive regulation of potassium ion transmembrane transport	1	495.6×	0.006	KCNN4
regulation of telomere maintenance	1	421.3×	0.006	LMNA
negative regulation of release of cytochrome c from mitochondria	1	401.2×	0.006	LMNA
positive regulation of T cell receptor signaling pathway	1	383.0×	0.006	KCNN4
nuclear migration	1	366.4×	0.006	LMNA
phospholipid translocation	1	312.1×	0.007	KCNN4
cell volume homeostasis	1	300.9×	0.007	KCNN4
double-strand break repair via nonhomologous end joining	1	210.7×	0.009	LMNA
negative regulation of extrinsic apoptotic signaling pathway	1	210.7×	0.009	LMNA
immune system process	1	195.9×	0.009	KCNN4
protein localization to nucleus	1	175.5×	0.010	LMNA
positive regulation of protein secretion	1	172.0×	0.010	KCNN4
cellular senescence	1	147.8×	0.011	LMNA
heterochromatin formation	1	127.7×	0.012	LMNA
protein homotetramerization	1	118.7×	0.012	KCNN4
defense response	1	108.0×	0.013	KCNN4
potassium ion transport	1	95.8×	0.014	KCNN4

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
KCNN4	CLOTRIMAZOLE
LMNA	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LMNA	823	4
KCNN4	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CLOTRIMAZOLE	4	KCNN4, LMNA
BEPRIDIL	4	LMNA
PHENYLBUTAZONE	4	LMNA
CEFOTAXIME SODIUM	4	LMNA
DIENESTROL	4	LMNA
IFOSFAMIDE	4	LMNA
PROGESTERONE	4	LMNA
DAPSONE	4	LMNA
AMINOCAPROIC ACID	4	LMNA
FLUCONAZOLE	4	LMNA
COLCHICINE	4	LMNA
NABUMETONE	4	LMNA
OXAPROZIN	4	LMNA
BUMETANIDE	4	LMNA
GLIPIZIDE	4	LMNA
BROMFENAC	4	LMNA
ROPIVACAINE	4	LMNA
TIZANIDINE	4	LMNA
METAXALONE	4	LMNA
CARBAMAZEPINE	4	LMNA
SALMETEROL XINAFOATE	4	LMNA
AMIODARONE HYDROCHLORIDE	4	LMNA
METHYL SALICYLATE	4	LMNA
DIBUCAINE	4	LMNA
PHENELZINE	4	LMNA
HYDROCORTISONE ACETATE	4	LMNA
BRETYLIUM TOSYLATE	4	LMNA
IMIPRAMINE	4	LMNA
FURAZOLIDONE	4	LMNA
DROPERIDOL	4	LMNA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KCNN4	27	Binding:27
LMNA	12	Binding:9, Functional:3

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

30 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)
CLOTRIMAZOLE	4	KCNN4, LMNA
BEPRIDIL	4	LMNA
PHENYLBUTAZONE	4	LMNA
CEFOTAXIME SODIUM	4	LMNA
DIENESTROL	4	LMNA
IFOSFAMIDE	4	LMNA
PROGESTERONE	4	LMNA
DAPSONE	4	LMNA
AMINOCAPROIC ACID	4	LMNA
FLUCONAZOLE	4	LMNA
COLCHICINE	4	LMNA
NABUMETONE	4	LMNA
OXAPROZIN	4	LMNA
BUMETANIDE	4	LMNA
GLIPIZIDE	4	LMNA
BROMFENAC	4	LMNA
ROPIVACAINE	4	LMNA
TIZANIDINE	4	LMNA
METAXALONE	4	LMNA
CARBAMAZEPINE	4	LMNA
SALMETEROL XINAFOATE	4	LMNA
AMIODARONE HYDROCHLORIDE	4	LMNA
METHYL SALICYLATE	4	LMNA
DIBUCAINE	4	LMNA
PHENELZINE	4	LMNA
HYDROCORTISONE ACETATE	4	LMNA
BRETYLIUM TOSYLATE	4	LMNA
IMIPRAMINE	4	LMNA
FURAZOLIDONE	4	LMNA
DROPERIDOL	4	LMNA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	KCNN4, LMNA
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.