Arthrogryposis, distal, with impaired proprioception and touch

Summary

Arthrogryposis, distal, with impaired proprioception and touch (MONDO:0014941) is a disease caused by PIEZO2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: PIEZO2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 138

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	arthrogryposis, distal, with impaired proprioception and touch
Mondo ID	MONDO:0014941
OMIM	617146
UMLS	C4310692
MedGen	934659
GARD	0025036
Is cancer (heuristic)	no

Also known as: arthrogryposis, distal, with impaired proprioception and touch · arthrogryposis, distal, with impaired proprioception and touch; DAIPT · DAIPT

Data availability: 138 ClinVar variants · 6 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, distal, with impaired proprioception and touch

Related subtypes (22): arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome, 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, 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

138 retrieved; paginated sample, class counts are floors:

36 uncertain significance, 26 likely pathogenic, 25 benign, 25 pathogenic, 16 conflicting classifications of pathogenicity, 5 benign/likely benign, 5 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1320154	NM_001378183.1(PIEZO2):c.6828-8_6829del	PIEZO2	Pathogenic	criteria provided, single submitter
1320155	NM_001378183.1(PIEZO2):c.704-2A>G	PIEZO2	Pathogenic	criteria provided, single submitter
1323454	NM_001378183.1(PIEZO2):c.3756_3757+2del	PIEZO2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
137629	NM_001378183.1(PIEZO2):c.8396G>A (p.Arg2799His)	PIEZO2	Pathogenic	criteria provided, multiple submitters, no conflicts
1709561	NM_001378183.1(PIEZO2):c.1549_1550insC (p.Ser517fs)	PIEZO2	Pathogenic	criteria provided, single submitter
1803703	NM_001378183.1(PIEZO2):c.2073C>A (p.Cys691Ter)	PIEZO2	Pathogenic	criteria provided, single submitter
1803704	NM_001378183.1(PIEZO2):c.1882+1G>A	PIEZO2	Pathogenic	criteria provided, single submitter
2431930	NM_001378183.1(PIEZO2):c.4775_4778del (p.Lys1592fs)	PIEZO2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2444167	NM_001378183.1(PIEZO2):c.7186G>T (p.Glu2396Ter)	PIEZO2	Pathogenic	criteria provided, single submitter
265867	NM_001378183.1(PIEZO2):c.5227C>T (p.Arg1743Ter)	PIEZO2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265868	NM_001378183.1(PIEZO2):c.4798C>T (p.Arg1600Ter)	PIEZO2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265869	NM_001378183.1(PIEZO2):c.5228G>C (p.Arg1743Pro)	PIEZO2	Pathogenic	no assertion criteria provided
265870	NM_001378183.1(PIEZO2):c.2783C>G (p.Ser928Ter)	PIEZO2	Pathogenic	no assertion criteria provided
3376643	NM_001378183.1(PIEZO2):c.8161+1G>A	PIEZO2	Pathogenic	criteria provided, single submitter
3376651	NM_001378183.1(PIEZO2):c.1609del (p.Arg537fs)	PIEZO2	Pathogenic	criteria provided, single submitter
374902	NM_001378183.1(PIEZO2):c.5960del (p.Leu1987fs)	PIEZO2	Pathogenic	criteria provided, single submitter
374903	NM_001378183.1(PIEZO2):c.1550_1552delinsCGAA (p.Ser517fs)	PIEZO2	Pathogenic	no assertion criteria provided
374904	NM_001378183.1(PIEZO2):c.3095_3105del (p.Pro1032fs)	PIEZO2	Pathogenic	criteria provided, single submitter
3777098	NM_001378183.1(PIEZO2):c.3627C>A (p.Cys1209Ter)	PIEZO2	Pathogenic	criteria provided, single submitter
3777099	NM_001378183.1(PIEZO2):c.7946_7949dup (p.Gln2650fs)	PIEZO2	Pathogenic	criteria provided, single submitter
3902258	NM_001378183.1(PIEZO2):c.5671G>T (p.Glu1891Ter)	PIEZO2	Pathogenic	criteria provided, single submitter
4293581	NM_001378183.1(PIEZO2):c.1080+1G>C	PIEZO2	Pathogenic	criteria provided, single submitter
4688874	NM_001378183.1(PIEZO2):c.2695_2696del (p.Ala899fs)	PIEZO2	Pathogenic	criteria provided, single submitter
489219	NM_001378183.1(PIEZO2):c.5257-1G>A	PIEZO2	Pathogenic	criteria provided, multiple submitters, no conflicts
632546	NM_001378183.1(PIEZO2):c.1384C>T (p.Arg462Ter)	PIEZO2	Pathogenic	criteria provided, single submitter
638404	NM_001378183.1(PIEZO2):c.2170-2A>C	PIEZO2	Pathogenic	criteria provided, single submitter
800806	NM_001378183.1(PIEZO2):c.4244_4245del (p.Thr1415fs)	PIEZO2	Pathogenic	criteria provided, single submitter
803474	NM_001378183.1(PIEZO2):c.3487C>T (p.Arg1163Ter)	PIEZO2	Pathogenic	criteria provided, single submitter
803475	NM_001378183.1(PIEZO2):c.1924G>T (p.Glu642Ter)	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

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · Orphanet: 5 · 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
STK11	Orphanet:2869	Peutz-Jeghers syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PIEZO2	HGNC:26270	ENSG00000154864	Q9H5I5	Piezo-type mechanosensitive ion channel component 2	gencc,clinvar
STK11	HGNC:11389	ENSG00000118046	Q15831	Serine/threonine-protein kinase STK11	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.
STK11	Serine/threonine-protein kinase STK11	Tumor suppressor serine/threonine-protein kinase that controls the activity of AMP-activated protein kinase (AMPK) family members, thereby playing a role in various processes such as cell metabolism, cell polarity, apoptosis and DNA damage…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PIEZO2	Other/Unknown	no		Piezo, Piezo_cap_dom, Piezo_TM25-28
STK11	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
corpus callosum	1
dorsal root ganglion	1
sural nerve	1
hindlimb stylopod muscle	1
left testis	1
right testis	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
STK11	238	ubiquitous	marker	left testis, right testis, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
STK11	5,146
PIEZO2	1,787

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
STK11	Q15831	4
PIEZO2	Q9H5I5	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 2 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
AMPK inhibits chREBP transcriptional activation activity	1	1427.5×	0.010	STK11
FOXO-mediated transcription of cell death genes	1	713.8×	0.010	STK11
Energy dependent regulation of mTOR by LKB1-AMPK	1	393.8×	0.010	STK11
FOXO-mediated transcription	1	335.9×	0.010	STK11
MTOR signalling	1	265.6×	0.011	STK11
Integration of energy metabolism	1	175.7×	0.013	STK11
Regulation of TP53 Activity	1	132.8×	0.015	STK11
Regulation of TP53 Activity through Phosphorylation	1	117.7×	0.015	STK11
Transcriptional Regulation by TP53	1	62.1×	0.025	STK11
RNA Polymerase II Transcription	1	22.5×	0.062	STK11
Gene expression (Transcription)	1	17.8×	0.071	STK11
Generic Transcription Pathway	1	15.1×	0.077	STK11
Metabolism	1	11.6×	0.093	STK11
Signal Transduction	1	10.2×	0.098	STK11

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of vesicle transport along microtubule	1	8426.0×	0.006	STK11
detection of mechanical stimulus involved in sensory perception	1	1404.3×	0.007	PIEZO2
negative regulation of epithelial cell proliferation involved in prostate gland development	1	1404.3×	0.007	STK11
Golgi localization	1	1053.2×	0.007	STK11
epithelial cell proliferation involved in prostate gland development	1	1053.2×	0.007	STK11
dendrite extension	1	842.6×	0.007	STK11
activation of protein kinase activity	1	766.0×	0.007	STK11
positive thymic T cell selection	1	702.2×	0.007	STK11
G1 to G0 transition	1	702.2×	0.007	STK11
cellular response to UV-B	1	702.2×	0.007	STK11
anoikis	1	648.1×	0.007	STK11
detection of mechanical stimulus	1	601.9×	0.007	PIEZO2
vasculature development	1	561.7×	0.007	STK11
peptidyl-threonine phosphorylation	1	443.5×	0.007	STK11
regulation of Wnt signaling pathway	1	443.5×	0.007	STK11
monoatomic cation transport	1	383.0×	0.008	PIEZO2
regulation of dendrite morphogenesis	1	366.4×	0.008	STK11
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	351.1×	0.008	STK11
positive regulation of axonogenesis	1	290.6×	0.008	STK11
intrinsic apoptotic signaling pathway by p53 class mediator	1	290.6×	0.008	STK11
tissue homeostasis	1	280.9×	0.008	STK11
positive regulation of transforming growth factor beta receptor signaling pathway	1	263.3×	0.008	STK11
response to ionizing radiation	1	205.5×	0.010	STK11
positive regulation of protein localization to nucleus	1	195.9×	0.010	STK11
establishment of cell polarity	1	191.5×	0.010	STK11
regulation of signal transduction by p53 class mediator	1	191.5×	0.010	STK11
protein localization to nucleus	1	175.5×	0.010	STK11
negative regulation of cold-induced thermogenesis	1	172.0×	0.010	STK11
negative regulation of TORC1 signaling	1	162.0×	0.010	STK11
response to mechanical stimulus	1	150.5×	0.011	PIEZO2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
STK11	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
STK11	17	4
PIEZO2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	STK11
PACRITINIB	4	STK11
NINTEDANIB	4	STK11
SUNITINIB	4	STK11
MIDOSTAURIN	4	STK11
DINACICLIB	3	STK11
DOVITINIB	3	STK11
LESTAURTINIB	3	STK11
RUBOXISTAURIN	3	STK11
AZD-1480	2	STK11
SU-014813	2	STK11
R-406	2	STK11
TOZASERTIB	2	STK11
PF-00562271	1	STK11
KW-2449	1	STK11
PF-03758309	1	STK11
XL-228	1	STK11

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
STK11	244	Binding:244

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
STK11	2.7.11.1	non-specific serine/threonine protein kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
STK11	244

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

17 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)
FEDRATINIB	4	STK11
PACRITINIB	4	STK11
NINTEDANIB	4	STK11
SUNITINIB	4	STK11
MIDOSTAURIN	4	STK11
DINACICLIB	3	STK11
DOVITINIB	3	STK11
LESTAURTINIB	3	STK11
RUBOXISTAURIN	3	STK11
AZD-1480	2	STK11
SU-014813	2	STK11
R-406	2	STK11
TOZASERTIB	2	STK11
PF-00562271	1	STK11
KW-2449	1	STK11
PF-03758309	1	STK11
XL-228	1	STK11

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	STK11
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.