Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema

Summary

Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema (MONDO:0008689) is a disease caused by PIEZO1 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: PIEZO1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 132

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema
Mondo ID	MONDO:0008689
OMIM	194380
DOID	DOID:0111576
UMLS	C4551512
MedGen	1638271
GARD	0015126
Is cancer (heuristic)	no

Also known as: DEHYDRATED hereditary stomatocytosis 1 with or without pseudohyperkalemia and/OR perinatal oedema · Dehydrated hereditary stomatocytosis 1 with or without pseudohyperkalemia and/Or perinatal oedema · Dehydrated hereditary stomatocytosis pseudohyperkalemia and perinatal edema · Dehydrated hereditary stomatocytosis pseudohyperkalemia and perinatal oedema · dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema · DEHYDRATED hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal oedema · DHS · DHS1

Data availability: 132 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 with or without pseudohyperkalemia and/or perinatal edema

Related subtypes (22): congenital nonspherocytic hemolytic anemia, elliptocytosis 2, southeast Asian ovalocytosis, overhydrated hereditary stomatocytosis, cryohydrocytosis, 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, dehydrated hereditary stomatocytosis 2, 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

132 retrieved; paginated sample, class counts are floors:

35 uncertain significance, 34 benign, 23 conflicting classifications of pathogenicity, 16 benign/likely benign, 9 likely pathogenic, 8 pathogenic, 5 pathogenic/likely pathogenic, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
55809	NM_001142864.2(PIEZO1):[c.3350C>T;c.6059C>T]		Pathogenic	no assertion criteria provided
55813	NM_001142864.2(PIEZO1):c.[1848+31C>G;2344G>A;2423G>A]		Pathogenic	no assertion criteria provided
1707478	NM_001142864.4(PIEZO1):c.1381C>T (p.Gln461Ter)	HSALR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
829815	NM_001142864.4(PIEZO1):c.2005G>T (p.Asp669Tyr)	HSALR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
978810	NM_002250.3(KCNN4):c.940T>C (p.Ser314Pro)	KCNN4	Pathogenic	criteria provided, single submitter
1163992	NM_001142864.4(PIEZO1):c.5289C>G (p.Tyr1763Ter)	PIEZO1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344888	NM_001142864.4(PIEZO1):c.307C>T (p.Arg103Ter)	PIEZO1	Pathogenic	criteria provided, single submitter
3581334	NM_001142864.4(PIEZO1):c.3367G>T (p.Glu1123Ter)	PIEZO1	Pathogenic	criteria provided, single submitter
418948	NM_001142864.4(PIEZO1):c.7477CTGGAG[3] (p.2493LE[3])	PIEZO1	Pathogenic	criteria provided, multiple submitters, no conflicts
55806	NM_001142864.4(PIEZO1):c.7367G>A (p.Arg2456His)	PIEZO1	Pathogenic	criteria provided, multiple submitters, no conflicts
55807	NM_001142864.4(PIEZO1):c.6058G>A (p.Ala2020Thr)	PIEZO1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
55808	NM_001142864.4(PIEZO1):c.4073G>C (p.Arg1358Pro)	PIEZO1	Pathogenic	no assertion criteria provided
55811	NM_001142864.4(PIEZO1):c.6380C>T (p.Thr2127Met)	PIEZO1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3907701	NM_001142864.4(PIEZO1):c.2281G>T (p.Glu761Ter)	HSALR1	Likely pathogenic	criteria provided, single submitter
978720	NM_001142864.4(PIEZO1):c.3191G>T (p.Cys1064Phe)	HSALR1	Likely pathogenic	no assertion criteria provided
2632265	NM_001142864.4(PIEZO1):c.6008C>A (p.Ala2003Asp)	PIEZO1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3235926	NM_001142864.4(PIEZO1):c.7367G>C (p.Arg2456Pro)	PIEZO1	Likely pathogenic	criteria provided, single submitter
3362637	NM_001142864.4(PIEZO1):c.157del (p.Gln53fs)	PIEZO1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3891953	NM_001142864.4(PIEZO1):c.7493_7496dup (p.Tyr2500fs)	PIEZO1	Likely pathogenic	criteria provided, single submitter
4278383	NM_001142864.4(PIEZO1):c.7170dup (p.Arg2391fs)	PIEZO1	Likely pathogenic	criteria provided, single submitter
55805	NM_001142864.4(PIEZO1):c.6674T>G (p.Met2225Arg)	PIEZO1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
978719	NM_001142864.4(PIEZO1):c.3197A>G (p.Asp1066Gly)	PIEZO1	Likely pathogenic	no assertion criteria provided
1206134	NM_001142864.4(PIEZO1):c.2247GGA[9] (p.Glu756dup)	HSALR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1693683	NM_001142864.4(PIEZO1):c.1333G>A (p.Val445Ile)	HSALR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2218477	NM_001142864.4(PIEZO1):c.2440G>A (p.Val814Ile)	HSALR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2445985	NM_001142864.4(PIEZO1):c.2165C>T (p.Pro722Leu)	HSALR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3581335	NM_001142864.4(PIEZO1):c.1813A>G (p.Met605Val)	HSALR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
427211	NM_001142864.4(PIEZO1):c.3181C>G (p.Pro1061Ala)	HSALR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
440061	NM_001142864.4(PIEZO1):c.2247GGA[7] (p.Glu756del)	HSALR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
982873	NM_001142864.4(PIEZO1):c.2860C>T (p.Arg954Trp)	HSALR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
PIEZO1	Strong	Autosomal dominant	dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PIEZO1	HGNC:28993	ENSG00000103335	Q92508	Piezo-type mechanosensitive ion channel component 1	gencc,clinvar
HSALR1	HGNC:56095	ENSG00000224888		HSP90AB1 associated lncRNA 1	clinvar
KCNN4	HGNC:6293	ENSG00000104783	O15554	Intermediate conductance calcium-activated potassium channel protein 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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)
PIEZO1	Other/Unknown	no		Piezo, Piezo_cap_dom, Piezo_TM25-28
HSALR1	Other/Unknown	no
KCNN4	Ion channel	yes		CaM-bd_dom, K_chnl_dom, K_chnl_Ca-activ_SK

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lower esophagus mucosa	1
muscle layer of sigmoid colon	1
upper lobe of left lung	1
bone marrow cell	1
colonic epithelium	1
sural nerve	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
PIEZO1	142	ubiquitous	marker	muscle layer of sigmoid colon, lower esophagus mucosa, upper lobe of left lung
HSALR1	126		yes	colonic epithelium, bone marrow cell, sural nerve
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
HSALR1	0

Intra-cohort edges

A	B	Sources
KCNN4	PIEZO1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNN4	O15554	17
PIEZO1	Q92508	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 3 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
Ca2+ activated K+ channels	1	571.0×	0.009	KCNN4
Mechanical load activates signaling by PIEZO1 and integrins in osteocytes	1	335.9×	0.009	PIEZO1
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	178.4×	0.011	PIEZO1
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	80.4×	0.018	PIEZO1
Potassium Channels	1	67.2×	0.018	KCNN4
Neuronal System	1	22.1×	0.045	KCNN4

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
regulation of calcium ion import across plasma membrane	1	1404.3×	0.004	KCNN4
positive regulation of cell-cell adhesion mediated by integrin	1	1053.2×	0.004	PIEZO1
saliva secretion	1	1053.2×	0.004	KCNN4
positive regulation of integrin activation	1	936.2×	0.004	PIEZO1
macropinocytosis	1	936.2×	0.004	KCNN4
positive regulation of myotube differentiation	1	766.0×	0.004	PIEZO1
detection of mechanical stimulus	1	601.9×	0.005	PIEZO1
positive regulation of potassium ion transmembrane transport	1	495.6×	0.005	KCNN4
monoatomic cation transport	1	383.0×	0.005	PIEZO1
positive regulation of T cell receptor signaling pathway	1	383.0×	0.005	KCNN4
phospholipid translocation	1	312.1×	0.006	KCNN4
cell volume homeostasis	1	300.9×	0.006	KCNN4
immune system process	1	195.9×	0.008	KCNN4
positive regulation of protein secretion	1	172.0×	0.009	KCNN4
protein homotetramerization	1	118.7×	0.011	KCNN4
regulation of membrane potential	1	115.4×	0.011	PIEZO1
defense response	1	108.0×	0.011	KCNN4
cellular response to mechanical stimulus	1	108.0×	0.011	PIEZO1
potassium ion transport	1	95.8×	0.012	KCNN4
calcium ion transport	1	90.6×	0.012	KCNN4
establishment of localization in cell	1	80.2×	0.013	KCNN4
potassium ion transmembrane transport	1	68.0×	0.015	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
PIEZO1	0	0
HSALR1	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: 2; 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	PIEZO1, HSALR1

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)
PIEZO1	17	—
HSALR1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.