Marden-Walker syndrome

disease

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Also known as connective tissue disorder Marden Walker typeMarden Walker SyndromeMWKS

Summary

Marden-Walker syndrome (MONDO:0009564) is a disease with 1 cohort gene.

At a glance

Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
Cohort genes: 1
ClinVar variants: 63
Phenotypes (HPO): 61

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		50	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated
Prevalence at birth	1-9 / 100 000	2.5	Belgium	Validated

Signs & symptoms

Clinical features (HPO)

61 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000160	Narrow mouth	Very frequent (80-99%)
HP:0000175	Cleft palate	Very frequent (80-99%)
HP:0000176	Submucous cleft hard palate	Very frequent (80-99%)
HP:0000193	Bifid uvula	Very frequent (80-99%)
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0000278	Retrognathia	Very frequent (80-99%)
HP:0000298	Mask-like facies	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0000358	Posteriorly rotated ears	Very frequent (80-99%)
HP:0000369	Low-set ears	Very frequent (80-99%)
HP:0000508	Ptosis	Very frequent (80-99%)
HP:0000581	Blepharophimosis	Very frequent (80-99%)
HP:0001166	Arachnodactyly	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001328	Specific learning disability	Very frequent (80-99%)
HP:0001387	Joint stiffness	Very frequent (80-99%)
HP:0001460	Aplasia/Hypoplasia involving the skeletal musculature	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0002804	Arthrogryposis multiplex congenita	Very frequent (80-99%)
HP:0002974	Radioulnar synostosis	Very frequent (80-99%)
HP:0003202	Skeletal muscle atrophy	Very frequent (80-99%)
HP:0003510	Severe short stature	Very frequent (80-99%)
HP:0003560	Muscular dystrophy	Very frequent (80-99%)
HP:0011968	Feeding difficulties	Very frequent (80-99%)
HP:0012745	Short palpebral fissure	Very frequent (80-99%)
HP:0000767	Pectus excavatum	Frequent (30-79%)
HP:0000768	Pectus carinatum	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002808	Kyphosis	Frequent (30-79%)
HP:0007018	Attention deficit hyperactivity disorder	Frequent (30-79%)
HP:0100490	Camptodactyly of finger	Frequent (30-79%)
HP:0000003	Multicystic kidney dysplasia	Occasional (5-29%)
HP:0000036	Abnormality of the penis	Occasional (5-29%)
HP:0000039	Epispadias	Occasional (5-29%)
HP:0000047	Hypospadias	Occasional (5-29%)
HP:0000072	Hydroureter	Occasional (5-29%)
HP:0000077	Abnormality of the kidney	Occasional (5-29%)
HP:0000079	Abnormality of the urinary system	Occasional (5-29%)
HP:0000104	Renal agenesis	Occasional (5-29%)
HP:0000110	Renal dysplasia	Occasional (5-29%)
HP:0000126	Hydronephrosis	Occasional (5-29%)
HP:0000238	Hydrocephalus	Occasional (5-29%)
HP:0001274	Agenesis of corpus callosum	Occasional (5-29%)
HP:0001321	Cerebellar hypoplasia	Occasional (5-29%)
HP:0001331	Absent septum pellucidum	Occasional (5-29%)
HP:0001629	Ventricular septal defect	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Marden-Walker syndrome
Mondo ID	MONDO:0009564
MeSH	C535910
OMIM	248700
Orphanet	2461
ICD-11	1983460876
SNOMED CT	449824004
UMLS	C0796033
MedGen	163206
GARD	0006973
NORD	1402
Is cancer (heuristic)	no

Also known as: connective tissue disorder Marden Walker type · Marden Walker Syndrome · Marden-Walker syndrome · MWKS

Data availability: 63 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › ciliopathy › Marden-Walker syndrome

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

63 retrieved; paginated sample, class counts are floors:

24 benign, 22 uncertain significance, 6 conflicting classifications of pathogenicity, 4 benign/likely benign, 3 likely pathogenic, 2 pathogenic/likely pathogenic, 1 likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
137630	NM_001378183.1(PIEZO2):c.8395C>T (p.Arg2799Cys)	PIEZO2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
638404	NM_001378183.1(PIEZO2):c.2170-2A>C	PIEZO2	Pathogenic	criteria provided, single submitter
973945	NM_001378183.1(PIEZO2):c.8395C>G (p.Arg2799Gly)	PIEZO2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2431760	NM_001378183.1(PIEZO2):c.7880dup (p.Gln2628fs)	PIEZO2	Likely pathogenic	criteria provided, single submitter
2441988	NM_001378183.1(PIEZO2):c.1379-1G>A	PIEZO2	Likely pathogenic	criteria provided, single submitter
978137	NM_001378183.1(PIEZO2):c.4708+2T>G	PIEZO2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1095976	NM_001378183.1(PIEZO2):c.6623G>A (p.Arg2208Gln)	PIEZO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1465020	NM_001378183.1(PIEZO2):c.6622C>T (p.Arg2208Trp)	PIEZO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2175455	NM_001378183.1(PIEZO2):c.172C>T (p.Arg58Trp)	PIEZO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2355939	NM_001378183.1(PIEZO2):c.3529G>A (p.Ala1177Thr)	PIEZO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3376775	NM_001378183.1(PIEZO2):c.4588C>T (p.Pro1530Ser)	PIEZO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
436313	NM_001378183.1(PIEZO2):c.6475G>C (p.Glu2159Gln)	PIEZO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028748	NM_001378183.1(PIEZO2):c.3193G>C (p.Asp1065His)	PIEZO2	Uncertain significance	criteria provided, single submitter
1310285	NM_001378183.1(PIEZO2):c.86G>T (p.Gly29Val)	PIEZO2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1709333	NM_001378183.1(PIEZO2):c.8173A>G (p.Met2725Val)	PIEZO2	Uncertain significance	criteria provided, single submitter
1803251	NM_001378183.1(PIEZO2):c.3358T>C (p.Phe1120Leu)	PIEZO2	Uncertain significance	criteria provided, multiple submitters, no conflicts
235840	NM_001378183.1(PIEZO2):c.7406C>T (p.Thr2469Met)	PIEZO2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2387383	NM_001378183.1(PIEZO2):c.2449G>C (p.Asp817His)	PIEZO2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2585393	NM_001378183.1(PIEZO2):c.7604T>C (p.Phe2535Ser)	PIEZO2	Uncertain significance	criteria provided, single submitter
3242099	NM_001378183.1(PIEZO2):c.1231C>T (p.Pro411Ser)	PIEZO2	Uncertain significance	criteria provided, single submitter
3714240	NM_001378183.1(PIEZO2):c.1588C>T (p.Leu530Phe)	PIEZO2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3891954	NM_001378183.1(PIEZO2):c.147A>C (p.Lys49Asn)	PIEZO2	Uncertain significance	criteria provided, single submitter
3891955	NM_001378183.1(PIEZO2):c.149C>T (p.Thr50Met)	PIEZO2	Uncertain significance	criteria provided, single submitter
3891956	NM_001378183.1(PIEZO2):c.2021T>A (p.Val674Asp)	PIEZO2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3891957	NM_001378183.1(PIEZO2):c.3568A>G (p.Ile1190Val)	PIEZO2	Uncertain significance	criteria provided, single submitter
3891958	NM_001378183.1(PIEZO2):c.4801A>G (p.Arg1601Gly)	PIEZO2	Uncertain significance	criteria provided, single submitter
3891959	NM_001378183.1(PIEZO2):c.5219G>T (p.Arg1740Ile)	PIEZO2	Uncertain significance	criteria provided, single submitter
3891960	NM_001378183.1(PIEZO2):c.5365T>G (p.Ser1789Ala)	PIEZO2	Uncertain significance	criteria provided, single submitter
3891961	NM_001378183.1(PIEZO2):c.5975C>T (p.Thr1992Met)	PIEZO2	Uncertain significance	criteria provided, single submitter
3891962	NM_001378183.1(PIEZO2):c.6445C>T (p.His2149Tyr)	PIEZO2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · 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
PIEZO2	Moderate	Autosomal dominant	Marden-Walker syndrome	18

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PIEZO2	Orphanet:1154	Arthrogryposis-oculomotor limitation-electroretinal anomalies syndrome
PIEZO2	Orphanet:2461	Marden-Walker syndrome
PIEZO2	Orphanet:376	Gordon syndrome
PIEZO2	Orphanet:707937	Distal arthrogryposis-progressive scoliosis-thumb deformity-impaired proprioception 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
PIEZO2	HGNC:26270	ENSG00000154864	Q9H5I5	Piezo-type mechanosensitive ion channel component 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PIEZO2	Piezo-type mechanosensitive ion channel component 2	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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PIEZO2	Other/Unknown	no		Piezo, Piezo_cap_dom, Piezo_TM25-28

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
corpus callosum	1
dorsal root ganglion	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PIEZO2	237	broad	marker	sural nerve, corpus callosum, dorsal root ganglion

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PIEZO2	1,787

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PIEZO2	Q9H5I5	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
detection of mechanical stimulus involved in sensory perception	1	2808.7×	0.002	PIEZO2
detection of mechanical stimulus	1	1203.7×	0.002	PIEZO2
monoatomic cation transport	1	766.0×	0.003	PIEZO2
response to mechanical stimulus	1	300.9×	0.005	PIEZO2
regulation of membrane potential	1	230.8×	0.005	PIEZO2
cellular response to mechanical stimulus	1	216.1×	0.005	PIEZO2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIEZO2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	1	PIEZO2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PIEZO2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: PIEZO2