Gordon syndrome

Summary

Gordon syndrome (MONDO:0007252) is a disease caused by PIEZO2 (GenCC Definitive), with 1 cohort gene and 2 clinical trials.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: PIEZO2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 71
• Phenotypes (HPO): 14
• Clinical trials: 2

Clinical features

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0001883	Talipes	Very frequent (80-99%)
HP:0100490	Camptodactyly of finger	Very frequent (80-99%)
HP:0000218	High palate	Frequent (30-79%)
HP:0003199	Decreased muscle mass	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000324	Facial asymmetry	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000767	Pectus excavatum	Occasional (5-29%)
HP:0001376	Limitation of joint mobility	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0004209	Clinodactyly of the 5th finger	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0006101	Finger syndactyly	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Gordon syndrome
Mondo ID	MONDO:0007252
MeSH	C537288
OMIM	114300
Orphanet	376
DOID	DOID:0111607
SNOMED CT	237850008
UMLS	C0220666
MedGen	66314
GARD	0002553
NORD	1199
Is cancer (heuristic)	no

Also known as: arthrogryposis distal type 3 · arthrogryposis, distal, type 3 · camptodactyly-cleft palate-clubfoot syndrome · DA3 · distal arthrogryposis type 3 · distal arthrogryposis type IIA · Gordon syndrome

Data availability: 71 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › multiple congenital anomalies/dysmorphic syndrome › multiple congenital anomalies/dysmorphic syndrome without intellectual disability › Gordon syndrome

Related subtypes (167): Treacher-Collins syndrome, branchio-oto-renal syndrome, acrorenal syndrome, Townes-Brocks syndrome, Ascher syndrome, brachytelephalangy-dysmorphism-Kallmann syndrome, branchiooculofacial syndrome, cataract-aberrant oral frenula-growth delay syndrome, cherubism, Alagille syndrome, cleft palate-lateral synechia syndrome, blepharocheilodontic syndrome, craniofacial-deafness-hand syndrome, cryptomicrotia-brachydactyly-excess fingertip arch syndrome, Beare-Stevenson cutis gyrata syndrome, Cyprus facial-neuromusculoskeletal syndrome, deafness-craniofacial syndrome, short stature-valvular heart disease-characteristic facies syndrome, 3-M syndrome, external auditory canal atresia-vertical talus-hypertelorism syndrome, femoral-facial syndrome, multinodular goiter-cystic kidney-polydactyly syndrome, hand-foot-genital syndrome, Bencze syndrome, oculoauriculovertebral spectrum with radial defects, Holt-Oram syndrome, mullerian duct anomalies-limb anomalies syndrome, Aase-Smith syndrome, LADD syndrome, Noonan syndrome with multiple lentigines, median nodule of the upper lip, Nager acrofacial dysostosis, Marshall syndrome, Binder syndrome, Schilbach-Rott syndrome, nasopalpebral lipoma-coloboma syndrome, autosomal dominant prognathism, short stature-craniofacial anomalies-genital hypoplasia syndrome, radial hypoplasia-triphalangeal thumbs-hypospadias-maxillary diastema syndrome, scalp-ear-nipple syndrome, flat face-microstomia-ear anomaly syndrome, Czeizel-Losonci syndrome, otospondylomegaepiphyseal dysplasia, autosomal dominant, ventricular extrasystoles with syncopal episodes-perodactyly-robin sequence syndrome, posterior fusion of lumbosacral vertebrae-blepharoptosis syndrome, acrofacial dysostosis, Weyers type, Freeman-Sheldon syndrome, Ackerman syndrome, acro-renal-mandibular syndrome, acrocraniofacial dysostosis, PAGOD syndrome, alar cartilages hypoplasia-coloboma-telecanthus syndrome, microcephaly-albinism-digital anomalies syndrome, fetal akinesia deformation sequence, Cooper-Jabs syndrome, Barber-Say syndrome, Beemer-Ertbruggen syndrome, blepharophimosis-ptosis-esotropia-syndactyly-short stature syndrome, camptodactyly syndrome, Guadalajara type 1, camptodactyly syndrome, Guadalajara type 2, heart defects-limb shortening syndrome, Verloove Vanhorick-Brubakk syndrome, Juberg-Hayward syndrome, heart defect - tongue hamartoma - polysyndactyly syndrome, Fraser syndrome, split hand-foot malformation 1 with sensorineural hearing loss, von Voss-Cherstvoy syndrome, autosomal recessive faciodigitogenital syndrome, gingival fibromatosis-facial dysmorphism syndrome, Fibulo-ulnar hypoplasia-renal anomalies syndrome, frontofacionasal dysplasia, genito-palato-cardiac syndrome, Hirschsprung disease-hearing loss-polydactyly syndrome, Holzgreve-Wagner-Rehder syndrome, hydrocephaly-tall stature-joint laxity syndrome, McKusick-Kaufman syndrome, acrofrontofacionasal dysostosis 2, Vici syndrome, Donohue syndrome, Dahlberg-Borer-Newcomer syndrome, macrosomia-microphthalmia-cleft palate syndrome, mesomelic dwarfism-cleft palate-camptodactyly syndrome, Nijmegen breakage syndrome, lethal congenital contracture syndrome 1, Richieri Costa-da Silva syndrome, Keipert syndrome, nephrosis-deafness-urinary tract-digital malformations syndrome, ichthyosis-oral and digital anomalies syndrome, otoonychoperoneal syndrome, PHAVER syndrome, polysyndactyly-cardiac malformation syndrome, postaxial acrofacial dysostosis, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, renal-genital-middle ear anomalies, Richieri Costa-Pereira syndrome, SHORT syndrome, tetraamelia-multiple malformations syndrome, thymic-renal-anal-lung dysplasia, trigonocephaly-bifid nose-acral anomalies syndrome, white forelock with malformations, syndactyly-telecanthus-anogenital and renal malformations syndrome, Abruzzo-Erickson syndrome, CHILD syndrome, pentalogy of Cantrell, atrioventricular defect-blepharophimosis-radial and anal defect syndrome, short tarsus-absence of lower eyelashes syndrome, PARC syndrome, CODAS syndrome, pectus excavatum-macrocephaly-dysplastic nails syndrome, velo-facial-skeletal syndrome, anophthalmia plus syndrome, van den Ende-Gupta syndrome, absent tibia-polydactyly-arachnoid cyst syndrome, diaphragmatic defect-limb deficiency-skull defect syndrome, cleft lip/palate-intestinal malrotation-cardiopathy syndrome, Matthew-Wood syndrome, microcephaly-cardiac defect-lung malsegmentation syndrome, dislocation of the hip-dysmorphism syndrome, short stature-auditory canal atresia-mandibular hypoplasia-skeletal anomalies syndrome, grange syndrome, camptodactyly, myopia, and fibrosis of the medial rectus muscle of eye, arhinia, choanal atresia, and microphthalmia, anonychia-microcephaly syndrome, developmental malformations-deafness-dystonia syndrome, lethal congenital contracture syndrome 2, craniolenticulosutural dysplasia, 8q22.1 microdeletion syndrome, Braddock syndrome, choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome, BNAR syndrome, Frias syndrome, lethal congenital contracture syndrome 3, Fontaine progeroid syndrome, microcephaly-facio-cardio-skeletal syndrome, Hadziselimovic type, Nijmegen breakage syndrome-like disorder, Warsaw breakage syndrome, even-plus syndrome, split-foot malformation-mesoaxial polydactyly syndrome, anophthalmia-megalocornea-cardiopathy-skeletal anomalies syndrome, digitotalar dysmorphism, heart-hand syndrome type 2, night blindness-skeletal anomalies-dysmorphism syndrome, Charlie M syndrome, facial dysmorphism-anorexia-cachexia-eye and skin anomalies syndrome, cleft lip-retinopathy syndrome, Cole-Carpenter syndrome, progressive non-infectious anterior vertebral fusion, dysmorphism-pectus carinatum-joint laxity syndrome, Hirschsprung disease-type D brachydactyly syndrome, mandibuloacral dysplasia, contractures - webbed neck - micrognathia - hypoplastic nipples syndrome, Thomas syndrome, Waardenburg syndrome, Weill-Marchesani syndrome, branchiootic syndrome, auricular abnormalities-cleft lip with or without cleft palate-ocular abnormalities syndrome, Axenfeld-Rieger syndrome, macrostomia-preauricular tags-external ophthalmoplegia syndrome, pelvis syndrome, Fanconi anemia, van der Woude syndrome, hypertrichosis-acromegaloid facial appearance syndrome, 49,XYYYY syndrome, congenital vertebral-cardiac-renal anomalies syndrome, structural heart defects and renal anomalies syndrome, Greig cephalopolysyndactyly-contiguous gene 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

71 retrieved; paginated sample, class counts are floors:

24 benign, 23 uncertain significance, 7 conflicting classifications of pathogenicity, 6 likely pathogenic, 5 pathogenic, 4 benign/likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1033996	NM_001378183.1(PIEZO2):c.6614del (p.Thr2205fs)	PIEZO2	Pathogenic	criteria provided, multiple submitters, no conflicts
1033997	NM_001378183.1(PIEZO2):c.7807G>T (p.Glu2603Ter)	PIEZO2	Pathogenic	criteria provided, multiple submitters, no conflicts
137628	NM_001378183.1(PIEZO2):c.8577_8584del (p.Trp2859_Glu2862delinsTer)	PIEZO2	Pathogenic	no assertion criteria provided
137629	NM_001378183.1(PIEZO2):c.8396G>A (p.Arg2799His)	PIEZO2	Pathogenic	criteria provided, multiple submitters, no conflicts
137630	NM_001378183.1(PIEZO2):c.8395C>T (p.Arg2799Cys)	PIEZO2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
235839	NM_001378183.1(PIEZO2):c.8514AGA[2] (p.Glu2840del)	PIEZO2	Pathogenic	criteria provided, multiple submitters, no conflicts
973945	NM_001378183.1(PIEZO2):c.8395C>G (p.Arg2799Gly)	PIEZO2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3236261	NM_001378183.1(PIEZO2):c.1484T>G (p.Phe495Cys)	PIEZO2	Likely pathogenic	criteria provided, single submitter
3236262	NM_001378183.1(PIEZO2):c.350_351del (p.Gly117fs)	PIEZO2	Likely pathogenic	criteria provided, single submitter
631524	NM_001378183.1(PIEZO2):c.8492G>A (p.Arg2831Gln)	PIEZO2	Likely pathogenic	criteria provided, single submitter
976307	NM_001378183.1(PIEZO2):c.1741G>T (p.Gly581Ter)	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
998013	NM_001378183.1(PIEZO2):c.771G>A (p.Trp257Ter)	PIEZO2	Likely pathogenic	no assertion criteria provided
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
3212729	NM_001378183.1(PIEZO2):c.5896C>T (p.Arg1966Cys)	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
1028750	NM_001378183.1(PIEZO2):c.8386A>G (p.Lys2796Glu)	PIEZO2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033998	NM_001378183.1(PIEZO2):c.8081+7G>C	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
1696707	NM_001378183.1(PIEZO2):c.71C>T (p.Ala24Val)	PIEZO2	Uncertain significance	criteria provided, single submitter
2387383	NM_001378183.1(PIEZO2):c.2449G>C (p.Asp817His)	PIEZO2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2524509	NM_001378183.1(PIEZO2):c.7037T>G (p.Phe2346Cys)	PIEZO2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2584961	NM_001378183.1(PIEZO2):c.8140C>T (p.Pro2714Ser)	PIEZO2	Uncertain significance	criteria provided, single submitter
2585600	NM_001378183.1(PIEZO2):c.3193G>T (p.Asp1065Tyr)	PIEZO2	Uncertain significance	criteria provided, single submitter
2911813	NM_001378183.1(PIEZO2):c.2725G>C (p.Glu909Gln)	PIEZO2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3376644	NM_001378183.1(PIEZO2):c.4460C>T (p.Ala1487Val)	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	Definitive	Autosomal dominant	Gordon 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: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01144741	Not specified	TERMINATED	Survey Study and Records Review of Treatment Outcomes in Freeman-Sheldon Syndrome
NCT05419245	Not specified	UNKNOWN	Survey Study and Records Review of Treatment Outcomes in Freeman-Sheldon Syndrome