Wrinkly skin syndrome

Summary

Wrinkly skin syndrome (MONDO:0010208) is a disease caused by ATP6V0A2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ATP6V0A2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 44
• Phenotypes (HPO): 61

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0007407	Excessive skin wrinkling on dorsum of hands and fingers	Obligate (100%)
HP:0000023	Inguinal hernia	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Very frequent (80-99%)
HP:0000218	High palate	Very frequent (80-99%)
HP:0000253	Progressive microcephaly	Very frequent (80-99%)
HP:0000286	Epicanthus	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000319	Smooth philtrum	Very frequent (80-99%)
HP:0000343	Long philtrum	Very frequent (80-99%)
HP:0000369	Low-set ears	Very frequent (80-99%)
HP:0000455	Broad nasal tip	Very frequent (80-99%)
HP:0000494	Downslanted palpebral fissures	Very frequent (80-99%)
HP:0000670	Carious teeth	Very frequent (80-99%)
HP:0000684	Delayed eruption of teeth	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0000767	Pectus excavatum	Very frequent (80-99%)
HP:0000938	Osteopenia	Very frequent (80-99%)
HP:0000973	Cutis laxa	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001374	Congenital hip dislocation	Very frequent (80-99%)
HP:0001476	Delayed closure of the anterior fontanelle	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001511	Intrauterine growth retardation	Very frequent (80-99%)
HP:0001537	Umbilical hernia	Very frequent (80-99%)
HP:0001611	Hypernasal speech	Very frequent (80-99%)
HP:0001763	Pes planus	Very frequent (80-99%)
HP:0001788	Premature rupture of membranes	Very frequent (80-99%)
HP:0001869	Deep plantar creases	Very frequent (80-99%)
HP:0002645	Wormian bones	Very frequent (80-99%)
HP:0002751	Kyphoscoliosis	Very frequent (80-99%)
HP:0002761	Generalized joint laxity	Very frequent (80-99%)
HP:0002812	Coxa vara	Very frequent (80-99%)
HP:0003160	Abnormal isoelectric focusing of serum transferrin	Very frequent (80-99%)
HP:0003199	Decreased muscle mass	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0004426	Abnormality of the cheek	Very frequent (80-99%)
HP:0004993	Slender long bones with narrow diaphyses	Very frequent (80-99%)
HP:0005272	Prominent nasolabial fold	Very frequent (80-99%)
HP:0005425	Recurrent sinopulmonary infections	Very frequent (80-99%)
HP:0006114	Multiple palmar creases	Very frequent (80-99%)
HP:0006191	Deep palmar crease	Very frequent (80-99%)
HP:0006891	Thick cerebral cortex	Very frequent (80-99%)
HP:0007392	Excessive wrinkled skin	Very frequent (80-99%)
HP:0007457	Prominent veins on trunk	Very frequent (80-99%)
HP:0008070	Sparse hair	Very frequent (80-99%)
HP:0008113	Multiple plantar creases	Very frequent (80-99%)
HP:0008897	Postnatal growth retardation	Very frequent (80-99%)
HP:0008947	Floppy infant	Very frequent (80-99%)
HP:0009125	Lipodystrophy	Very frequent (80-99%)
HP:0010838	High nonceruloplasmin-bound serum copper	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	wrinkly skin syndrome
Mondo ID	MONDO:0010208
MeSH	C536750
OMIM	278250
Orphanet	2834
DOID	DOID:0112171
ICD-11	638767040
SNOMED CT	238875009
UMLS	C0406587
MedGen	98030
GARD	0000273
Is cancer (heuristic)	no

Also known as: wrinkled skin syndrome · wrinkly skin syndrome · WSS

Data availability: 44 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 › autosomal genetic disease › autosomal recessive disease › autosomal recessive cutis laxa type 2 › autosomal recessive cutis laxa type 2A › wrinkly skin 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

44 retrieved; paginated sample, class counts are floors:

15 uncertain significance, 10 likely pathogenic, 7 benign, 4 conflicting classifications of pathogenicity, 4 pathogenic, 3 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2137448	NM_012463.4(ATP6V0A2):c.390_397dup (p.Arg133delinsThrCysTer)	ATP6V0A2	Pathogenic	criteria provided, multiple submitters, no conflicts
21499	NM_012463.4(ATP6V0A2):c.294+1G>A	ATP6V0A2	Pathogenic	no assertion criteria provided
3574387	NM_012463.4(ATP6V0A2):c.130del (p.Asn43_Val44insTer)	ATP6V0A2	Pathogenic	criteria provided, multiple submitters, no conflicts
3574388	NM_012463.4(ATP6V0A2):c.208C>T (p.Gln70Ter)	ATP6V0A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
845	NM_012463.4(ATP6V0A2):c.187C>T (p.Arg63Ter)	ATP6V0A2	Pathogenic	criteria provided, multiple submitters, no conflicts
95519	NM_012463.4(ATP6V0A2):c.1514+1G>A	ATP6V0A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
286400	NM_012463.4(ATP6V0A2):c.78dup (p.Ser27fs)	LOC130009117	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2735988	NM_012463.4(ATP6V0A2):c.117+1del	ATP6V0A2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2740713	NM_012463.4(ATP6V0A2):c.1189G>C (p.Ala397Pro)	ATP6V0A2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3574386	NM_012463.4(ATP6V0A2):c.124C>T (p.Gln42Ter)	ATP6V0A2	Likely pathogenic	criteria provided, single submitter
3574389	NM_012463.4(ATP6V0A2):c.726T>A (p.Cys242Ter)	ATP6V0A2	Likely pathogenic	criteria provided, single submitter
3574391	NM_012463.4(ATP6V0A2):c.1418C>G (p.Ser473Ter)	ATP6V0A2	Likely pathogenic	criteria provided, single submitter
3574392	NM_012463.4(ATP6V0A2):c.1724+2T>C	ATP6V0A2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3574393	NM_012463.4(ATP6V0A2):c.2137C>T (p.Gln713Ter)	ATP6V0A2	Likely pathogenic	criteria provided, single submitter
3574394	NM_012463.4(ATP6V0A2):c.2442del (p.Leu815fs)	ATP6V0A2	Likely pathogenic	criteria provided, single submitter
3779384	NM_012463.4(ATP6V0A2):c.197-1G>A	ATP6V0A2	Likely pathogenic	criteria provided, single submitter
3779385	NM_012463.4(ATP6V0A2):c.1501_1514+15del	ATP6V0A2	Likely pathogenic	criteria provided, single submitter
1677219	NM_012463.4(ATP6V0A2):c.1214C>T (p.Pro405Leu)	ATP6V0A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2069270	NM_012463.4(ATP6V0A2):c.976G>T (p.Ala326Ser)	ATP6V0A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
307580	NM_012463.4(ATP6V0A2):c.614C>T (p.Ala205Val)	ATP6V0A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
390767	NM_012463.4(ATP6V0A2):c.422G>T (p.Arg141Leu)	ATP6V0A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1190639	NM_012463.4(ATP6V0A2):c.539T>C (p.Ile180Thr)	ATP6V0A2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1303408	NM_012463.4(ATP6V0A2):c.422G>A (p.Arg141His)	ATP6V0A2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1309768	NM_012463.4(ATP6V0A2):c.883G>A (p.Val295Ile)	ATP6V0A2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1368713	NM_012463.4(ATP6V0A2):c.28A>G (p.Met10Val)	ATP6V0A2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1462973	NM_012463.4(ATP6V0A2):c.2327G>A (p.Arg776His)	ATP6V0A2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2186320	NM_012463.4(ATP6V0A2):c.1157A>G (p.Tyr386Cys)	ATP6V0A2	Uncertain significance	criteria provided, multiple submitters, no conflicts
307578	NM_012463.4(ATP6V0A2):c.309G>T (p.Lys103Asn)	ATP6V0A2	Uncertain significance	criteria provided, multiple submitters, no conflicts
307587	NM_012463.4(ATP6V0A2):c.1565C>T (p.Pro522Leu)	ATP6V0A2	Uncertain significance	criteria provided, multiple submitters, no conflicts
307595	NM_012463.4(ATP6V0A2):c.2072T>C (p.Ile691Thr)	ATP6V0A2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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
ATP6V0A2	Definitive	Autosomal recessive	wrinkly skin syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP6V0A2	Orphanet:2834	Wrinkly skin syndrome
ATP6V0A2	Orphanet:357074	Autosomal recessive cutis laxa type 2, classic type

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
ATP6V0A2	HGNC:18481	ENSG00000185344	Q9Y487	V-type proton ATPase 116 kDa subunit a 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP6V0A2	V-type proton ATPase 116 kDa subunit a 2	Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATP6V0A2	Enzyme (other)	yes	7.1.2.1	V-ATPase_116kDa_su, V-type_ATPase_116kDa_su_euka

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
skin of leg	1
stromal cell of endometrium	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP6V0A2	239	ubiquitous	marker	skin of leg, sural nerve, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP6V0A2	2,076

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATP6V0A2	Q9Y487	81.94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Insulin receptor recycling	1	380.7×	0.004	ATP6V0A2
Transferrin endocytosis and recycling	1	368.4×	0.004	ATP6V0A2
ROS and RNS production in phagocytes	1	335.9×	0.004	ATP6V0A2
Ion channel transport	1	96.0×	0.010	ATP6V0A2

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
cellular response to increased oxygen levels	1	2106.5×	0.002	ATP6V0A2
Golgi lumen acidification	1	1685.2×	0.002	ATP6V0A2
vacuolar acidification	1	732.7×	0.003	ATP6V0A2
proton transmembrane transport	1	312.1×	0.005	ATP6V0A2
regulation of macroautophagy	1	295.6×	0.005	ATP6V0A2
intracellular iron ion homeostasis	1	244.2×	0.005	ATP6V0A2
immune response	1	47.1×	0.021	ATP6V0A2

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
ATP6V0A2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATP6V0A2	7.1.2.1	P-type H+-exporting transporter

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	1	ATP6V0A2
E	Difficult family or no structure, no drug	0

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)
ATP6V0A2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.