Dehydrated hereditary stomatocytosis

Summary

Dehydrated hereditary stomatocytosis (MONDO:0017910) is a disease with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• Phenotypes (HPO): 27
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated
Point prevalence	1-5 / 10 000	0.7	Denmark	Validated
Point prevalence	1-9 / 100 000	0.1	North America	Validated

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0001878	Hemolytic anemia	Very frequent (80-99%)
HP:0001930	Nonspherocytic hemolytic anemia	Very frequent (80-99%)
HP:0005502	Increased red cell osmotic fragility	Very frequent (80-99%)
HP:0001081	Cholelithiasis	Frequent (30-79%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0001923	Reticulocytosis	Frequent (30-79%)
HP:0001972	Macrocytic anemia	Frequent (30-79%)
HP:0001981	Schistocytosis	Frequent (30-79%)
HP:0003281	Increased circulating ferritin concentration	Frequent (30-79%)
HP:0003573	Increased total bilirubin	Frequent (30-79%)
HP:0011042	Abnormality of potassium homeostasis	Frequent (30-79%)
HP:0025435	Increased circulating lactate dehydrogenase concentration	Frequent (30-79%)
HP:0032231	Hypochromia	Frequent (30-79%)
HP:0000969	Edema	Occasional (5-29%)
HP:0001046	Intermittent jaundice	Occasional (5-29%)
HP:0001907	Thromboembolism	Occasional (5-29%)
HP:0002027	Abdominal pain	Occasional (5-29%)
HP:0003265	Neonatal hyperbilirubinemia	Occasional (5-29%)
HP:0004804	Congenital hemolytic anemia	Occasional (5-29%)
HP:0005518	Increased mean corpuscular volume	Occasional (5-29%)
HP:0010972	Anemia of inadequate production	Occasional (5-29%)
HP:0012431	Episodic fatigue	Occasional (5-29%)
HP:0025548	Increased mean corpuscular hemoglobin concentration	Occasional (5-29%)
HP:0001900	Increased circulating hemoglobin concentration	Occasional (5-29%)
HP:0001901	Polycythemia	Very rare (<1-4%)
HP:0030242	Portal vein thrombosis	Very rare (<1-4%)
HP:0030950	Pulmonary venous hypertension	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	dehydrated hereditary stomatocytosis
Mondo ID	MONDO:0017910
Orphanet	3202
DOID	DOID:0111575
ICD-11	799088159
SNOMED CT	715526002
UMLS	C0272051
MedGen	124415
GARD	0005623
Is cancer (heuristic)	no

Also known as: Desiccytosis hereditary · hereditary xerocytosis · xerocytosis hereditary

Data availability: 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 › hematologic disorder › anemia › normocytic anemia › hemolytic anemia › hereditary stomatocytosis › dehydrated hereditary stomatocytosis

Related subtypes (6): southeast Asian ovalocytosis, overhydrated hereditary stomatocytosis, cryohydrocytosis, hereditary cryohydrocytosis with reduced stomatin, familial pseudohyperkalemia, Rh deficiency syndrome

Subtypes (2): dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema, dehydrated hereditary stomatocytosis 2

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 27 · Orphanet: 10 · 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
PIEZO1	Strong	Autosomal dominant	dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema	7
SLC4A1	Supportive	Autosomal dominant	dehydrated hereditary stomatocytosis	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC4A1	Orphanet:3202	Dehydrated hereditary stomatocytosis
SLC4A1	Orphanet:398088	Hereditary cryohydrocytosis with normal stomatin
SLC4A1	Orphanet:822	Hereditary spherocytosis
SLC4A1	Orphanet:93608	Autosomal dominant distal renal tubular acidosis
SLC4A1	Orphanet:93610	Distal renal tubular acidosis with anemia
SLC4A1	Orphanet:98868	Southeast Asian ovalocytosis
PIEZO1	Orphanet:3202	Dehydrated hereditary stomatocytosis
PIEZO1	Orphanet:568062	PIEZO1-related generalized lymphatic dysplasia with non-immune hydrops fetalis
KCNN4	Orphanet:3202	Dehydrated hereditary stomatocytosis
KCNN4	Orphanet:586	Cystic fibrosis

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
SLC4A1	HGNC:11027	ENSG00000004939	P02730	Band 3 anion transport protein	gencc
PIEZO1	HGNC:28993	ENSG00000103335	Q92508	Piezo-type mechanosensitive ion channel component 1	gencc
KCNN4	HGNC:6293	ENSG00000104783	O15554	Intermediate conductance calcium-activated potassium channel protein 4	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC4A1	Band 3 anion transport protein	Functions both as a transporter that mediates electroneutral anion exchange across the cell membrane and as a structural protein.
PIEZO1	Piezo-type mechanosensitive ion channel component 1	Pore-forming subunit of the mechanosensitive non-specific cation Piezo channel required for rapidly adapting mechanically activated (MA) currents and has a key role in sensing touch and tactile pain.
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…

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
Ion channel	1	37.2×	0.053
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC4A1	Other/Unknown	no		Anion_exchange, Anion_exchange_1, HCO3_transpt_euk
PIEZO1	Other/Unknown	no		Piezo, Piezo_cap_dom, Piezo_TM25-28
KCNN4	Ion channel	yes		CaM-bd_dom, K_chnl_dom, K_chnl_Ca-activ_SK

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
bone marrow	1
bone marrow cell	1
trabecular bone tissue	1
lower esophagus mucosa	1
muscle layer of sigmoid colon	1
upper lobe of left lung	1
olfactory segment of nasal mucosa	1
parotid gland	1
saliva-secreting gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC4A1	161	tissue_specific	marker	trabecular bone tissue, bone marrow, bone marrow cell
PIEZO1	142	ubiquitous	marker	muscle layer of sigmoid colon, lower esophagus mucosa, upper lobe of left lung
KCNN4	200	ubiquitous	marker	olfactory segment of nasal mucosa, parotid gland, saliva-secreting gland

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PIEZO1	2,266
KCNN4	1,698
SLC4A1	1,598

Intra-cohort edges

A	B	Sources
KCNN4	PIEZO1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC4A1	P02730	54
KCNN4	O15554	17
PIEZO1	Q92508	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. 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
Defective SLC4A1 causes hereditary spherocytosis type 4 (HSP4), distal renal tubular acidosis (dRTA) and dRTA with hemolytic anemia (dRTA-HA)	1	3806.7×	0.004	SLC4A1
Erythrocytes take up oxygen and release carbon dioxide	1	423.0×	0.009	SLC4A1
O2/CO2 exchange in erythrocytes	1	423.0×	0.009	SLC4A1
Ca2+ activated K+ channels	1	380.7×	0.009	KCNN4
Bicarbonate transporters	1	380.7×	0.009	SLC4A1
Erythrocytes take up carbon dioxide and release oxygen	1	292.8×	0.010	SLC4A1
Mechanical load activates signaling by PIEZO1 and integrins in osteocytes	1	223.9×	0.011	PIEZO1
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	119.0×	0.018	PIEZO1
SLC transporter disorders	1	68.0×	0.028	SLC4A1
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	53.6×	0.030	PIEZO1
Disorders of transmembrane transporters	1	46.4×	0.030	SLC4A1
Potassium Channels	1	44.8×	0.030	KCNN4
R-HSA-425393	1	43.3×	0.030	SLC4A1
SLC-mediated transmembrane transport	1	19.7×	0.061	SLC4A1
Neuronal System	1	14.8×	0.075	KCNN4
Transport of small molecules	1	8.4×	0.122	SLC4A1
Disease	1	4.4×	0.212	SLC4A1

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
response to increased oxygen levels	1	5617.3×	0.003	SLC4A1
pH elevation	1	5617.3×	0.003	SLC4A1
stabilization of membrane potential	1	1872.4×	0.005	KCNN4
intracellular monoatomic ion homeostasis	1	1404.3×	0.005	SLC4A1
negative regulation of urine volume	1	1404.3×	0.005	SLC4A1
negative regulation of glycolytic process through fructose-6-phosphate	1	936.2×	0.006	SLC4A1
regulation of calcium ion import across plasma membrane	1	936.2×	0.006	KCNN4
positive regulation of cell-cell adhesion mediated by integrin	1	702.2×	0.006	PIEZO1
saliva secretion	1	702.2×	0.006	KCNN4
positive regulation of integrin activation	1	624.1×	0.006	PIEZO1
macropinocytosis	1	624.1×	0.006	KCNN4
positive regulation of myotube differentiation	1	510.7×	0.006	PIEZO1
plasma membrane phospholipid scrambling	1	510.7×	0.006	SLC4A1
monoatomic anion transport	1	468.1×	0.006	SLC4A1
detection of mechanical stimulus	1	401.2×	0.006	PIEZO1
positive regulation of potassium ion transmembrane transport	1	330.4×	0.007	KCNN4
bicarbonate transport	1	267.5×	0.008	SLC4A1
monoatomic cation transport	1	255.3×	0.008	PIEZO1
positive regulation of T cell receptor signaling pathway	1	255.3×	0.008	KCNN4
phospholipid translocation	1	208.1×	0.009	KCNN4
cell volume homeostasis	1	200.6×	0.009	KCNN4
regulation of intracellular pH	1	200.6×	0.009	SLC4A1
erythrocyte development	1	175.5×	0.009	SLC4A1
chloride transport	1	151.8×	0.010	SLC4A1
immune system process	1	130.6×	0.012	KCNN4
positive regulation of protein secretion	1	114.6×	0.013	KCNN4
protein homotetramerization	1	79.1×	0.017	KCNN4
chloride transmembrane transport	1	79.1×	0.017	SLC4A1
regulation of membrane potential	1	77.0×	0.017	PIEZO1
defense response	1	72.0×	0.017	KCNN4

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNN4	2	4
SLC4A1	0	0
PIEZO1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CLOTRIMAZOLE	4	KCNN4
SENICAPOC	3	KCNN4

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
PIEZO1	17	Binding:17

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

2 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
SENICAPOC	3	KCNN4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KCNN4
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	SLC4A1, PIEZO1

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)
SLC4A1	0	—
PIEZO1	17	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04372498	PHASE1/PHASE2	COMPLETED	Senicapoc and Dehydrated Stomatocytosis