Polyhydramnios

Summary

Polyhydramnios (MONDO:0004585) is a disease with 9 cohort genes and 6 clinical trials.

At a glance

• Cohort genes: 9
• ClinVar variants: 17
• Clinical trials: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	polyhydramnios
Mondo ID	MONDO:0004585
MeSH	D006831
DOID	DOID:8488
ICD-10-CM	O40
SNOMED CT	86203003
UMLS	C0020224
MedGen	6936
Anatomy (UBERON)	UBERON:0000301
Is cancer (heuristic)	no

Also known as: polyhydramnios · polyhydramnios (disease)

Data availability: 17 ClinVar variants · 1 HPO phenotype.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › obstetric disorder › pregnancy disorder › polyhydramnios

Related subtypes (28): funisitis, chorea gravidarum, luteoma of pregnancy, impetigo herpetiformis, gestational diabetes, placenta disorder, pemphigoid gestationis, dystocia, hyperemesis gravidarum, pruritic urticarial papules and plaques of pregnancy, familial gestational hyperthyroidism, pseudohyperaldosteronism type 2, aromatase deficiency, acute fatty liver of pregnancy, malignancy diagnosed during pregnancy, postpartum psychosis, peripartum cardiomyopathy, gestational trophoblastic neoplasm, hypertension, pregnancy-induced, chronic intervillositis of unknown etiology, pregnancy disorder with abortive outcome, postpartum amenorrhea-galactorrhea syndrome, pregnancy associated osteoporosis, twin anemia-polycythemia sequence, twin-reversed arterial perfusion sequence, selective intrauterine growth restriction, amniotic fluid embolism, vasa previa

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

17 retrieved; paginated sample, class counts are floors:

7 pathogenic, 4 uncertain significance, 2 pathogenic/likely pathogenic, 2 conflicting classifications of pathogenicity, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
267923	46;XX;t(10;15)(q25.2;q11.2)		Pathogenic	criteria provided, single submitter
997073	GRCh37/hg19 17q12(chr17:34437475-36243028)	DHRS11	Pathogenic	criteria provided, single submitter
4073652	NM_004463.3(FGD1):c.1531del (p.His511fs)	FGD1	Pathogenic	criteria provided, single submitter
268107	NM_181789.4(GLDN):c.1240C>T (p.Arg414Ter)	GLDN	Pathogenic	criteria provided, single submitter
488521	NM_181789.4(GLDN):c.1305G>A (p.Trp435Ter)	GLDN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
978657	NM_031307.4(PUS3):c.838C>T (p.Arg280Ter)	HYLS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
55994	NM_000111.3(SLC26A3):c.269_270dup (p.Gly91fs)	SLC26A3	Pathogenic	criteria provided, multiple submitters, no conflicts
978616	NM_000111.3(SLC26A3):c.2006C>A (p.Ser669Ter)	SLC26A3	Pathogenic	criteria provided, single submitter
978618	NM_000111.3(SLC26A3):c.1000G>T (p.Glu334Ter)	SLC26A3	Pathogenic	criteria provided, single submitter
978637	NM_181789.4(GLDN):c.1027G>A (p.Gly343Ser)	GLDN	Likely pathogenic	criteria provided, single submitter
978659	NM_031307.4(PUS3):c.340T>C (p.Cys114Arg)	HYLS1	Likely pathogenic	criteria provided, single submitter
523360	NM_000352.6(ABCC8):c.1024G>T (p.Gly342Trp)	ABCC8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
978654	NM_001142864.4(PIEZO1):c.4885G>A (p.Gly1629Arg)	PIEZO1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2692226	NM_001142864.4(PIEZO1):c.6392T>C (p.Leu2131Pro)	PIEZO1	Uncertain significance	no assertion criteria provided
978653	NM_001142864.4(PIEZO1):c.4519G>C (p.Val1507Leu)	PIEZO1	Uncertain significance	criteria provided, single submitter
374250	NM_001003787.4(STRADA):c.792T>A (p.Ser264Arg)	STRADA	Uncertain significance	criteria provided, single submitter
2572007	NM_015045.5(WAPL):c.2020C>T (p.Arg674Cys)	WAPL	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 15 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HYLS1	Orphanet:2189	Hydrolethalus
HYLS1	Orphanet:475	Isolated Joubert syndrome
PIEZO1	Orphanet:3202	Dehydrated hereditary stomatocytosis
PIEZO1	Orphanet:568062	PIEZO1-related generalized lymphatic dysplasia with non-immune hydrops fetalis
GLDN	Orphanet:994	Fetal akinesia deformation sequence
STRADA	Orphanet:500533	Polyhydramnios-megalencephaly-symptomatic epilepsy syndrome
SLC26A3	Orphanet:53689	Congenital chloride diarrhea
FGD1	Orphanet:915	Aarskog-Scott syndrome
ABCC8	Orphanet:276575	Autosomal dominant hyperinsulinism due to SUR1 deficiency
ABCC8	Orphanet:276598	Diazoxide-resistant focal hyperinsulinism due to SUR1 deficiency
ABCC8	Orphanet:552	MODY
ABCC8	Orphanet:79134	DEND syndrome
ABCC8	Orphanet:79643	Autosomal recessive hyperinsulinism due to SUR1 deficiency
ABCC8	Orphanet:99885	Isolated permanent neonatal diabetes mellitus
ABCC8	Orphanet:99886	Transient neonatal diabetes mellitus

Cohort genes → proteins

9 cohort genes, 9 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	9

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
WAPL	HGNC:23293	ENSG00000062650	Q7Z5K2	Wings apart-like protein homolog	clinvar
HYLS1	HGNC:26558	ENSG00000198331	Q96M11	Centriolar and ciliogenesis-associated protein HYLS1	clinvar
DHRS11	HGNC:28639	ENSG00000278535	Q6UWP2	Dehydrogenase/reductase SDR family member 11	clinvar
PIEZO1	HGNC:28993	ENSG00000103335	Q92508	Piezo-type mechanosensitive ion channel component 1	clinvar
GLDN	HGNC:29514	ENSG00000186417	Q6ZMI3	Gliomedin	clinvar
STRADA	HGNC:30172	ENSG00000266173	Q7RTN6	STE20-related kinase adapter protein alpha	clinvar
SLC26A3	HGNC:3018	ENSG00000091138	P40879	Chloride anion exchanger	clinvar
FGD1	HGNC:3663	ENSG00000102302	P98174	FYVE, RhoGEF and PH domain-containing protein 1	clinvar
ABCC8	HGNC:59	ENSG00000006071	Q09428	ATP-binding cassette sub-family C member 8	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WAPL	Wings apart-like protein homolog	Regulator of sister chromatid cohesion in mitosis which negatively regulates cohesin association with chromatin.
HYLS1	Centriolar and ciliogenesis-associated protein HYLS1	Plays a role in ciliogenesis.
DHRS11	Dehydrogenase/reductase SDR family member 11	Catalyzes the conversion of the 17-keto group of estrone, 4- and 5-androstenes and 5-alpha-androstanes into their 17-beta-hydroxyl metabolites and the conversion of the 3-keto group of 3-, 3,17- and 3,20- diketosteroids into their 3beta-hy…
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.
GLDN	Gliomedin	Ligand for NRCAM and NFASC/neurofascin that plays a role in the formation and maintenance of the nodes of Ranvier on myelinated axons.
STRADA	STE20-related kinase adapter protein alpha	Pseudokinase which, in complex with CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta), binds to and activates STK11/LKB1.
SLC26A3	Chloride anion exchanger	Mediates chloride-bicarbonate exchange with a chloride bicarbonate stoichiometry of 2:1 in the intestinal epithelia.
FGD1	FYVE, RhoGEF and PH domain-containing protein 1	Activates CDC42, a member of the Ras-like family of Rho- and Rac proteins, by exchanging bound GDP for free GTP.
ABCC8	ATP-binding cassette sub-family C member 8	Regulator subunit of pancreatic ATP-sensitive potassium channel (KATP), playing a major role in the regulation of insulin release.

Protein-family classification

Druggable: 3 · Difficult: 1 · Unknown: 5 · 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
Transporter	2	17.3×	0.022
Kinase	1	3.1×	0.563
Other/Unknown	5	1.0×	0.687
Transcription factor	1	0.9×	0.687

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
WAPL	Other/Unknown	no		ARM-like, WAPL_dom, ARM-type_fold
HYLS1	Other/Unknown	no		HYLS1, HYLS1_C_dom, Centriolar_ciliogenesis_assoc
DHRS11	Other/Unknown	no		SDR_fam, Sc_DH/Rdtase_CS, NAD(P)-bd_dom_sf
PIEZO1	Other/Unknown	no		Piezo, Piezo_cap_dom, Piezo_TM25-28
GLDN	Other/Unknown	no		Olfac-like_dom, Collagen, Olfactomedin-like_domain
STRADA	Kinase	yes		Prot_kinase_dom, Kinase-like_dom_sf, STRAD_A/B-like
SLC26A3	Transporter	yes		SLC26A/SulP_fam, STAS_dom, SLC26A/SulP_dom
FGD1	Transcription factor	no		DH_dom, Znf_FYVE, PH_domain
ABCC8	Transporter	yes		ABCC8/9, ABCC8, ABC_transporter-like_ATP-bd

Expression context

Cohort genes with no expression data: 0.

7 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)	9
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	2
secondary oocyte	2
sperm	2
rectum	2
duodenum	1
mucosa of transverse colon	1
lower esophagus mucosa	1
muscle layer of sigmoid colon	1
upper lobe of left lung	1
inferior vagus X ganglion	1
pons	1
trigeminal ganglion	1
left testis	1
mucosa of stomach	1
right uterine tube	1
colonic mucosa	1
mucosa of sigmoid colon	1
cortical plate	1
ganglionic eminence	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WAPL	298	ubiquitous	marker	secondary oocyte, oocyte, sperm
HYLS1	205	ubiquitous	yes	oocyte, secondary oocyte, sperm
DHRS11	134	ubiquitous	marker	duodenum, mucosa of transverse colon, rectum
PIEZO1	142	ubiquitous	marker	muscle layer of sigmoid colon, lower esophagus mucosa, upper lobe of left lung
GLDN	226	broad	marker	inferior vagus X ganglion, trigeminal ganglion, pons
STRADA	162	ubiquitous	marker	right uterine tube, mucosa of stomach, left testis
SLC26A3	159	tissue_specific	marker	colonic mucosa, mucosa of sigmoid colon, rectum
FGD1	179	ubiquitous	yes	cortical plate, stromal cell of endometrium, ganglionic eminence
ABCC8	185	broad	marker	islet of Langerhans, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DHRS11	3,492
ABCC8	2,826
PIEZO1	2,266
WAPL	2,111
SLC26A3	1,831
FGD1	932
GLDN	866
STRADA	780
HYLS1	453

Structural data

PDB: 7 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC26A3	P40879	13
ABCC8	Q09428	8
PIEZO1	Q92508	6
STRADA	Q7RTN6	4
WAPL	Q7Z5K2	3
DHRS11	Q6UWP2	1
GLDN	Q6ZMI3	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FGD1	P98174	66.18
HYLS1	Q96M11	66.11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 30. Enrichment computed across 9 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC26A3 causes congenital secretory chloride diarrhea 1 (DIAR1)	1	1903.3×	0.011	SLC26A3
Defective ABCC8 can cause hypo- and hyper-glycemias	1	951.7×	0.011	ABCC8
Disorders of transmembrane transporters	2	46.4×	0.011	SLC26A3, ABCC8
ATP sensitive Potassium channels	1	475.8×	0.016	ABCC8
Inorganic anion exchange by SLC26 transporters	1	211.5×	0.025	SLC26A3
Cohesin Loading onto Chromatin	1	190.3×	0.025	WAPL
Establishment of Sister Chromatid Cohesion	1	173.0×	0.025	WAPL
Inwardly rectifying K+ channels	1	119.0×	0.030	ABCC8
Mechanical load activates signaling by PIEZO1 and integrins in osteocytes	1	112.0×	0.030	PIEZO1
ABC transporter disorders	1	73.2×	0.041	ABCC8
Energy dependent regulation of mTOR by LKB1-AMPK	1	65.6×	0.041	STRADA
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	59.5×	0.042	PIEZO1
MTOR signalling	1	44.3×	0.052	STRADA
Regulation of insulin secretion	1	36.6×	0.058	ABCC8
SLC transporter disorders	1	34.0×	0.058	SLC26A3
NRAGE signals death through JNK	1	30.7×	0.059	FGD1
Integration of energy metabolism	1	29.3×	0.059	ABCC8
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	26.8×	0.061	PIEZO1
G alpha (12/13) signalling events	1	22.9×	0.065	FGD1
Potassium Channels	1	22.4×	0.065	ABCC8
R-HSA-425393	1	21.6×	0.065	SLC26A3
Resolution of Sister Chromatid Cohesion	1	14.4×	0.092	WAPL
Disease	2	4.4×	0.093	SLC26A3, ABCC8
CDC42 GTPase cycle	1	12.1×	0.100	FGD1
Separation of Sister Chromatids	1	10.1×	0.112	WAPL
SLC-mediated transmembrane transport	1	9.9×	0.112	SLC26A3
Neuronal System	1	7.4×	0.142	ABCC8
Transport of small molecules	1	4.2×	0.232	SLC26A3
Metabolism	1	1.9×	0.432	ABCC8
Signal Transduction	1	1.7×	0.463	STRADA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of neuroblast migration	1	1872.4×	0.013	ABCC8
positive regulation of uterine smooth muscle relaxation	1	1872.4×	0.013	ABCC8
microvillus organization	1	936.2×	0.013	GLDN
negative regulation of chromatin binding	1	936.2×	0.013	WAPL
negative regulation of sister chromatid cohesion	1	936.2×	0.013	WAPL
intracellular pH elevation	1	624.1×	0.013	SLC26A3
glutamate secretion, neurotransmission	1	624.1×	0.013	ABCC8
negative regulation of blood-brain barrier permeability	1	624.1×	0.013	ABCC8
positive regulation of tight junction disassembly	1	374.5×	0.019	ABCC8
response to pH	1	312.1×	0.019	ABCC8
clustering of voltage-gated sodium channels	1	267.5×	0.019	GLDN
positive regulation of cell-cell adhesion mediated by integrin	1	234.1×	0.019	PIEZO1
positive regulation of potassium ion transport	1	234.1×	0.019	ABCC8
positive regulation of integrin activation	1	208.1×	0.019	PIEZO1
membrane hyperpolarization	1	208.1×	0.019	SLC26A3
negative regulation of glial cell proliferation	1	187.2×	0.019	ABCC8
estrogen biosynthetic process	1	170.2×	0.019	DHRS11
positive regulation of myotube differentiation	1	170.2×	0.019	PIEZO1
negative regulation of low-density lipoprotein particle clearance	1	170.2×	0.019	ABCC8
activation of protein kinase activity	1	170.2×	0.019	STRADA
monoatomic anion transport	1	156.0×	0.019	SLC26A3
G1 to G0 transition	1	156.0×	0.019	STRADA
detection of mechanical stimulus	1	133.8×	0.021	PIEZO1
sulfate transmembrane transport	1	133.8×	0.021	SLC26A3
obsolete inorganic cation transmembrane transport	1	104.0×	0.026	ABCC8
negative regulation of DNA replication	1	98.5×	0.026	WAPL
monoatomic cation transport	1	85.1×	0.029	PIEZO1
sperm capacitation	1	74.9×	0.031	SLC26A3
filopodium assembly	1	72.0×	0.031	FGD1
response to zinc ion	1	69.3×	0.031	ABCC8

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 3 · Undrugged: 6

Druggability breadth: 6 of 9 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
STRADA	RUXOLITINIB
ABCC8	REPAGLINIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ABCC8	6	4
STRADA	5	4
WAPL	1	2
HYLS1	0	0
DHRS11	0	0
PIEZO1	0	0
GLDN	0	0
SLC26A3	0	0
FGD1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
RUXOLITINIB	4	STRADA
REPAGLINIDE	4	ABCC8
DIAZOXIDE	4	ABCC8
GLYBURIDE	4	ABCC8
BRIVANIB	3	STRADA
MOLIBRESIB	2	WAPL
PH-797804	2	STRADA
AZD-1480	2	STRADA
CROMAKALIM	2	ABCC8
CLAMIKALANT	2	ABCC8
TIFENAZOXIDE	2	ABCC8
BMS-387032	1	STRADA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ABCC8	84	Functional:52, Binding:32
STRADA	47	Binding:47
PIEZO1	17	Binding:17
WAPL	6	Binding:6
SLC26A3	6	Binding:6
FGD1	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 9; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

12 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)
RUXOLITINIB	4	STRADA
REPAGLINIDE	4	ABCC8
DIAZOXIDE	4	ABCC8
GLYBURIDE	4	ABCC8
BRIVANIB	3	STRADA
MOLIBRESIB	2	WAPL
PH-797804	2	STRADA
AZD-1480	2	STRADA
CROMAKALIM	2	ABCC8
CLAMIKALANT	2	ABCC8
TIFENAZOXIDE	2	ABCC8
BMS-387032	1	STRADA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	STRADA, ABCC8
B	Phased (≥1) drug, not yet approved	1	WAPL
C	Druggable family + PDB, no drug	1	SLC26A3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	HYLS1, DHRS11, PIEZO1, GLDN, FGD1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HYLS1	0	—
DHRS11	0	—
PIEZO1	17	—
GLDN	0	—
SLC26A3	6	—
FGD1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	6

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05043753	Not specified	RECRUITING	Fetal gRowth AbnorMality dEtection Trial
NCT07067593	Not specified	NOT_YET_RECRUITING	Amnioreduction in Polyhydramnios
NCT00236340	Not specified	COMPLETED	Syringe or Continuous Amnioreduction for Symptomatic Polyhydramnios. A Prospective Randomized Study.
NCT03277417	Not specified	UNKNOWN	Does Amniotic Fluid Index Affect the Fetal Cardiac Performance?
NCT04497532	Not specified	UNKNOWN	Influence of Diet on Pregnancy With Polyhydramnios
NCT05059093	Not specified	COMPLETED	Developing and Testing AI Models for Fetal Biometry and Amniotic Volume Assessment in Fetal Ultrasound Scans.