Polyhydramnios, megalencephaly, and symptomatic epilepsy

Summary

Polyhydramnios, megalencephaly, and symptomatic epilepsy (MONDO:0012611) is a disease caused by STRADA (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: STRADA (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 405
• Phenotypes (HPO): 34

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		17	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

34 HPO clinical features (Orphanet curated; top 34 by frequency):

HPO ID	Term	Frequency
HP:0000256	Macrocephaly	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001355	Megalencephaly	Very frequent (80-99%)
HP:0001561	Polyhydramnios	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0012469	Infantile spasms	Very frequent (80-99%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0012430	Cerebral white matter hypoplasia	Frequent (30-79%)
HP:0030891	Periventricular white matter hyperintensities	Frequent (30-79%)
HP:0000121	Nephrocalcinosis	Occasional (5-29%)
HP:0000154	Wide mouth	Occasional (5-29%)
HP:0000194	Open mouth	Occasional (5-29%)
HP:0000275	Narrow face	Occasional (5-29%)
HP:0000297	Facial hypotonia	Occasional (5-29%)
HP:0000348	High forehead	Occasional (5-29%)
HP:0000873	Diabetes insipidus	Occasional (5-29%)
HP:0001344	Absent speech	Occasional (5-29%)
HP:0001382	Joint hypermobility	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001631	Atrial septal defect	Occasional (5-29%)
HP:0001635	Congestive heart failure	Occasional (5-29%)
HP:0002133	Status epilepticus	Occasional (5-29%)
HP:0002307	Drooling	Occasional (5-29%)
HP:0002384	Focal impaired awareness seizure	Occasional (5-29%)
HP:0002553	Highly arched eyebrow	Occasional (5-29%)
HP:0003199	Decreased muscle mass	Occasional (5-29%)
HP:0006829	Severe muscular hypotonia	Occasional (5-29%)
HP:0010804	Tented upper lip vermilion	Occasional (5-29%)
HP:0011182	Interictal epileptiform activity	Occasional (5-29%)
HP:0011344	Severe global developmental delay	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0030680	Abnormal cardiovascular system morphology	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	polyhydramnios, megalencephaly, and symptomatic epilepsy
Mondo ID	MONDO:0012611
MeSH	C567020
OMIM	611087
Orphanet	500533
DOID	DOID:0070511
UMLS	C1970203
MedGen	370203
GARD	0012913
Is cancer (heuristic)	no

Also known as: PMSE · PMSE syndrome · polyhydramnios, megalencephaly, and symptomatic epilepsy · polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome · pretzel syndrome

Data availability: 405 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › epilepsy › monogenic epilepsy › polyhydramnios, megalencephaly, and symptomatic epilepsy

Related subtypes (17): Mowat-Wilson syndrome, developmental and epileptic encephalopathy, 2, severe neonatal-onset encephalopathy with microcephaly, familial infantile myoclonic epilepsy, neuronal ceroid lipofuscinosis 8 northern epilepsy variant, neonatal-onset encephalopathy with rigidity and seizures, developmental and epileptic encephalopathy, 23, spastic paraplegia-severe developmental delay-epilepsy syndrome, X-linked intellectual disability-epilepsy syndrome, focal epilepsy-intellectual disability-cerebro-cerebellar malformation, infantile-onset mesial temporal lobe epilepsy with severe cognitive regression, autosomal recessive cerebellar ataxia - epilepsy - intellectual disability syndrome, developmental and epileptic encephalopathy, 73, neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, epilepsy, X-linked, with or without impaired intellectual development and dysmorphic features, neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism

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

405 retrieved; paginated sample, class counts are floors:

200 likely benign, 170 uncertain significance, 16 pathogenic, 6 likely pathogenic, 6 conflicting classifications of pathogenicity, 4 benign, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1452310	NM_001003787.4(STRADA):c.491del (p.Met164fs)	LOC125312417	Pathogenic	criteria provided, single submitter
3663344	NM_001003787.4(STRADA):c.526del (p.Leu176fs)	LOC125312417	Pathogenic	criteria provided, single submitter
2186	NC_000017.11:g.63702091_63709394del	LOC130061404	Pathogenic	no assertion criteria provided
2074680	NM_001003787.4(STRADA):c.207C>G (p.Tyr69Ter)	STRADA	Pathogenic	criteria provided, single submitter
254243	NM_001003787.4(STRADA):c.842dup (p.Asp281fs)	STRADA	Pathogenic	no assertion criteria provided
2700850	NM_001003787.4(STRADA):c.101del (p.Pro34fs)	STRADA	Pathogenic	criteria provided, single submitter
2704723	NM_001003787.4(STRADA):c.156del (p.Phe53fs)	STRADA	Pathogenic	criteria provided, single submitter
2749405	NM_001003787.4(STRADA):c.630C>G (p.Tyr210Ter)	STRADA	Pathogenic	criteria provided, single submitter
2790856	NM_001003787.4(STRADA):c.751C>T (p.Gln251Ter)	STRADA	Pathogenic	criteria provided, single submitter
3243064	NC_000017.10:g.(?61805674)(61805729_?)del	STRADA	Pathogenic	criteria provided, single submitter
3644079	NM_001003787.4(STRADA):c.828_853del (p.Val277fs)	STRADA	Pathogenic	criteria provided, single submitter
3649917	NM_001003787.4(STRADA):c.54del (p.Lys18fs)	STRADA	Pathogenic	criteria provided, single submitter
536756	NM_001003787.4(STRADA):c.1036C>T (p.Arg346Ter)	STRADA	Pathogenic	criteria provided, single submitter
842228	NM_001003787.4(STRADA):c.682C>T (p.Arg228Ter)	STRADA	Pathogenic	criteria provided, multiple submitters, no conflicts
856509	NM_001003787.4(STRADA):c.254_255del (p.Val85fs)	STRADA	Pathogenic	criteria provided, single submitter
952543	NM_001003787.4(STRADA):c.28C>T (p.Arg10Ter)	STRADA	Pathogenic	criteria provided, single submitter
2024937	NM_001003787.4(STRADA):c.458-1G>A	LOC125312417	Likely pathogenic	criteria provided, single submitter
1068097	NM_001003787.4(STRADA):c.36+1G>A	STRADA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3689518	NM_001003787.4(STRADA):c.457+1G>T	STRADA	Likely pathogenic	criteria provided, single submitter
4772793	NM_001003787.4(STRADA):c.95-2A>C	STRADA	Likely pathogenic	criteria provided, single submitter
663375	NM_001003787.4(STRADA):c.37-1G>C	STRADA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
800960	NM_001003787.4(STRADA):c.1101-1G>C	STRADA	Likely pathogenic	no assertion criteria provided
212324	NM_001003787.4(STRADA):c.135G>A (p.Ala45=)	STRADA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
468889	NM_001003787.4(STRADA):c.922G>A (p.Glu308Lys)	STRADA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
573381	NM_001003787.4(STRADA):c.992C>A (p.Thr331Asn)	STRADA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
844584	NM_001003787.4(STRADA):c.1101G>A (p.Arg367=)	STRADA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
937062	NM_001003787.4(STRADA):c.1051C>T (p.His351Tyr)	STRADA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
942810	NM_001003787.4(STRADA):c.140C>G (p.Ser47Ter)	STRADA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1005256	NM_001003787.4(STRADA):c.512C>T (p.Ala171Val)	LOC125312417	Uncertain significance	criteria provided, single submitter
1349012	NM_001003787.4(STRADA):c.466A>G (p.Lys156Glu)	LOC125312417	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
STRADA	Definitive	Autosomal recessive	polyhydramnios, megalencephaly, and symptomatic epilepsy	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STRADA	Orphanet:500533	Polyhydramnios-megalencephaly-symptomatic epilepsy syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
STRADA	HGNC:30172	ENSG00000266173	Q7RTN6	STE20-related kinase adapter protein alpha	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
STRADA	Kinase	yes		Prot_kinase_dom, Kinase-like_dom_sf, STRAD_A/B-like

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	1
mucosa of stomach	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
STRADA	162	ubiquitous	marker	right uterine tube, mucosa of stomach, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
STRADA	780

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
STRADA	Q7RTN6	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Energy dependent regulation of mTOR by LKB1-AMPK	1	393.8×	0.006	STRADA
MTOR signalling	1	265.6×	0.006	STRADA
Signal Transduction	1	10.2×	0.098	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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
activation of protein kinase activity	1	1532.0×	0.001	STRADA
G1 to G0 transition	1	1404.3×	0.001	STRADA
protein export from nucleus	1	510.7×	0.002	STRADA

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
STRADA	RUXOLITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
STRADA	5	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
RUXOLITINIB	4	STRADA
BRIVANIB	3	STRADA
PH-797804	2	STRADA
AZD-1480	2	STRADA
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
STRADA	47	Binding:47

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

5 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
BRIVANIB	3	STRADA
PH-797804	2	STRADA
AZD-1480	2	STRADA
BMS-387032	1	STRADA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	STRADA
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.