Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome

Summary

Arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome (MONDO:0007158) is a disease caused by PIEZO2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: PIEZO2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 74
• Phenotypes (HPO): 17

Clinical features

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0000490	Deeply set eye	Very frequent (80-99%)
HP:0000508	Ptosis	Very frequent (80-99%)
HP:0000602	Ophthalmoplegia	Very frequent (80-99%)
HP:0000767	Pectus excavatum	Very frequent (80-99%)
HP:0001387	Joint stiffness	Very frequent (80-99%)
HP:0010751	Chin dimple	Very frequent (80-99%)
HP:0000023	Inguinal hernia	Frequent (30-79%)
HP:0000325	Triangular face	Frequent (30-79%)
HP:0000400	Macrotia	Frequent (30-79%)
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0000512	Abnormal electroretinogram	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0001166	Arachnodactyly	Frequent (30-79%)
HP:0001776	Bilateral talipes equinovarus	Frequent (30-79%)
HP:0004097	Deviation of finger	Frequent (30-79%)
HP:0005879	Congenital finger flexion contractures	Frequent (30-79%)
HP:0010489	Absent palmar crease	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome
Mondo ID	MONDO:0007158
OMIM	108145
Orphanet	1154
DOID	DOID:0111608
SNOMED CT	715217004
UMLS	C1862472
MedGen	350678
GARD	0004047
Is cancer (heuristic)	no

Also known as: Arthogryposis with oculomotor limitation and electroretinal abnormalities · arthrogryposis ophthalmoplegia retinopathy · arthrogryposis with oculomotor limitation and electroretinal abnormalities · arthrogryposis, distal, type 5 · arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome · DA5 · distal arthrogryposis type 5 · distal arthrogryposis type IIB · distal arthrogryposis with ophthalmoplegia · oculomelic amyoplasia

Data availability: 74 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 › distal arthrogryposis › arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome

Related subtypes (22): arthrogryposis-like hand anomaly-sensorineural deafness syndrome, Gordon syndrome, congenital contractural arachnodactyly, arthrogryposis, distal, type 2E, trismus-pseudocamptodactyly syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, Freeman-Sheldon syndrome, Sheldon-hall syndrome, Ehlers-Danlos syndrome, musculocontractural type, arthrogryposis-severe scoliosis syndrome, distal arthrogryposis type 5D, autism spectrum disorder - epilepsy - arthrogryposis syndrome, arthrogryposis, distal, with impaired proprioception and touch, digitotalar dysmorphism, distal arthrogryposis type 10, distal arthrogryposis Moore weaver type, arthrogryposis, distal, type 1C, arthrogryposis, distal, IIa 11, arthrogryposis-ectodermal dysplasia-other anomalies syndrome, ACTC1-related distal arthrogryposis with congenital heart disease, arthrogryposis, distal, type 2B4, arthrogryposis, distal, type 12

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

74 retrieved; paginated sample, class counts are floors:

24 benign, 21 uncertain significance, 12 pathogenic, 7 conflicting classifications of pathogenicity, 4 benign/likely benign, 3 pathogenic/likely pathogenic, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
137629	NM_001378183.1(PIEZO2):c.8396G>A (p.Arg2799His)	PIEZO2	Pathogenic	criteria provided, multiple submitters, no conflicts
137631	NM_001378183.1(PIEZO2):c.8492G>T (p.Arg2831Leu)	PIEZO2	Pathogenic	no assertion criteria provided
137633	NM_001378183.1(PIEZO2):c.2134A>G (p.Met712Val)	PIEZO2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
137634	NM_001378183.1(PIEZO2):c.8554T>C (p.Ser2852Pro)	PIEZO2	Pathogenic	no assertion criteria provided
1686064	NM_001378183.1(PIEZO2):c.5079dup (p.Asp1694fs)	PIEZO2	Pathogenic	criteria provided, single submitter
1686065	NM_001378183.1(PIEZO2):c.2724_2734del (p.Ser908fs)	PIEZO2	Pathogenic	criteria provided, single submitter
1686066	NM_001378183.1(PIEZO2):c.2372T>A (p.Ile791Lys)	PIEZO2	Pathogenic	criteria provided, single submitter
235838	NM_001378183.1(PIEZO2):c.8547del (p.Tyr2850fs)	PIEZO2	Pathogenic	no assertion criteria provided
235839	NM_001378183.1(PIEZO2):c.8514AGA[2] (p.Glu2840del)	PIEZO2	Pathogenic	criteria provided, multiple submitters, no conflicts
235841	NM_001378183.1(PIEZO2):c.7007C>T (p.Ser2336Leu)	PIEZO2	Pathogenic	no assertion criteria provided
235842	NM_001378183.1(PIEZO2):c.7001C>T (p.Thr2334Ile)	PIEZO2	Pathogenic	no assertion criteria provided
235843	NM_001378183.1(PIEZO2):c.3068T>C (p.Met1023Thr)	PIEZO2	Pathogenic	no assertion criteria provided
3340624	NM_001378183.1(PIEZO2):c.3069G>A (p.Met1023Ile)	PIEZO2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
96704	NM_001378183.1(PIEZO2):c.2404A>T (p.Ile802Phe)	PIEZO2	Pathogenic	no assertion criteria provided
973945	NM_001378183.1(PIEZO2):c.8395C>G (p.Arg2799Gly)	PIEZO2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2627045	NM_001378183.1(PIEZO2):c.3450+2T>G	PIEZO2	Likely pathogenic	no assertion criteria provided
4813466	NM_001378183.1(PIEZO2):c.2371A>C (p.Ile791Leu)	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
974867	NM_001378183.1(PIEZO2):c.8555C>T (p.Ser2852Leu)	PIEZO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1310285	NM_001378183.1(PIEZO2):c.86G>T (p.Gly29Val)	PIEZO2	Uncertain significance	criteria provided, multiple submitters, no conflicts
137632	NM_001378183.1(PIEZO2):c.8492G>C (p.Arg2831Pro)	PIEZO2	Uncertain significance	criteria provided, single submitter
1696707	NM_001378183.1(PIEZO2):c.71C>T (p.Ala24Val)	PIEZO2	Uncertain significance	criteria provided, single submitter
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

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 recessive	arthrogryposis, distal, with impaired proprioception and touch	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.