Ehlers-Danlos syndrome, dermatosparaxis type

Summary

Ehlers-Danlos syndrome, dermatosparaxis type (MONDO:0009161) is a disease caused by ADAMTS2 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ADAMTS2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 1,774
• Phenotypes (HPO): 35

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		15	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

35 HPO clinical features (Orphanet curated; top 35 by frequency):

HPO ID	Term	Frequency
HP:0000938	Osteopenia	Very frequent (80-99%)
HP:0000939	Osteoporosis	Very frequent (80-99%)
HP:0000963	Thin skin	Very frequent (80-99%)
HP:0000974	Hyperextensible skin	Very frequent (80-99%)
HP:0001001	Abnormality of subcutaneous fat tissue	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001367	Abnormal joint morphology	Very frequent (80-99%)
HP:0001373	Joint dislocation	Very frequent (80-99%)
HP:0001385	Hip dysplasia	Very frequent (80-99%)
HP:0001387	Joint stiffness	Very frequent (80-99%)
HP:0002020	Gastroesophageal reflux	Very frequent (80-99%)
HP:0002036	Hiatus hernia	Very frequent (80-99%)
HP:0002300	Mutism	Very frequent (80-99%)
HP:0002381	Aphasia	Very frequent (80-99%)
HP:0002673	Coxa valga	Very frequent (80-99%)
HP:0002748	Rickets	Very frequent (80-99%)
HP:0002749	Osteomalacia	Very frequent (80-99%)
HP:0002812	Coxa vara	Very frequent (80-99%)
HP:0002827	Hip dislocation	Very frequent (80-99%)
HP:0003010	Prolonged bleeding time	Very frequent (80-99%)
HP:0003510	Severe short stature	Very frequent (80-99%)
HP:0005743	Avascular necrosis of the capital femoral epiphysis	Very frequent (80-99%)
HP:0007392	Excessive wrinkled skin	Very frequent (80-99%)
HP:0010529	Echolalia	Very frequent (80-99%)
HP:0100633	Esophagitis	Very frequent (80-99%)
HP:0100699	Scarring	Very frequent (80-99%)
HP:0100790	Hernia	Very frequent (80-99%)
HP:0001382	Joint hypermobility	Very frequent (80-99%)
HP:0000023	Inguinal hernia	Frequent (30-79%)
HP:0000278	Retrognathia	Frequent (30-79%)
HP:0000286	Epicanthus	Frequent (30-79%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)
HP:0100541	Femoral hernia	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Ehlers-Danlos syndrome, dermatosparaxis type
Mondo ID	MONDO:0009161
MeSH	C567527
OMIM	225410
Orphanet	1901
DOID	DOID:0080733
ICD-11	445808781
SNOMED CT	55711009
UMLS	C2700425
MedGen	397792
GARD	0002089
Is cancer (heuristic)	no

Also known as: dEDS · dermatosparaxis EDS · dermatosparaxis Ehlers-Danlos syndrome · EDS VIIC · EDS7C · EDSDERMS · Ehlers-Danlos syndrome type 7C · Ehlers-Danlos syndrome type 7C (formerly) · Ehlers-Danlos syndrome, dermatosparaxis type

Data availability: 1,774 ClinVar variants · 7 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Ehlers-Danlos syndrome › Ehlers-Danlos syndrome, dermatosparaxis type

Related subtypes (24): Ehlers-Danlos syndrome, classic type, Ehlers-Danlos syndrome, hypermobility type, Ehlers-Danlos syndrome, arthrochalasia type, Ehlers-Danlos syndrome, spondylodysplastic type, Ehlers-Danlos syndrome, periodontitis type, Ehlers-Danlos syndrome, autosomal dominant, type unspecified, joint laxity, familial, Ehlers-Danlos syndrome, fibronectinemic type, brittle cornea syndrome, X-linked Ehlers-Danlos syndrome, Ehlers-Danlos syndrome, musculocontractural type, Ehlers-Danlos syndrome due to tenascin-X deficiency, Ehlers-Danlos syndrome, Beasley-Cohen type, Ehlers-Danlos syndrome, kyphoscoliotic type, 2, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Ehlers-Danlos syndrome, vascular-like type, Ehlers-Danlos/osteogenesis imperfecta syndrome, Ehlers-Danlos syndrome, vascular type, spondylodysplastic Ehlers-Danlos syndrome, Bethlem myopathy 2, Ehlers-Danlos syndrome, classic-like, 2, COL1A1-related Ehlers-Danlos syndrome, COL1A2-related Ehlers-Danlos syndrome, Ehlers-Danlos syndrome, classic-like, 3

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

600 retrieved; paginated sample, class counts are floors:

400 likely benign, 131 uncertain significance, 28 likely pathogenic, 16 benign, 10 conflicting classifications of pathogenicity, 8 pathogenic/likely pathogenic, 7 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069859	NC_000005.9:g.(?178699902)(178772339_?)del	ADAMTS2	Pathogenic	criteria provided, single submitter
1070257	NM_014244.5(ADAMTS2):c.227C>A (p.Ser76Ter)	ADAMTS2	Pathogenic	criteria provided, single submitter
1071129	NM_014244.5(ADAMTS2):c.2938C>T (p.Arg980Ter)	ADAMTS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072866	NM_014244.5(ADAMTS2):c.137del (p.Pro46fs)	ADAMTS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1194897	NM_014244.5(ADAMTS2):c.1822C>T (p.Gln608Ter)	ADAMTS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1369667	NM_014244.5(ADAMTS2):c.21del (p.Ala8fs)	ADAMTS2	Pathogenic	criteria provided, single submitter
1391219	NM_014244.5(ADAMTS2):c.2372del (p.Met791fs)	ADAMTS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1394405	NM_014244.5(ADAMTS2):c.102_123dup (p.Ala42fs)	ADAMTS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453000	NM_014244.5(ADAMTS2):c.274del (p.Val92fs)	ADAMTS2	Pathogenic	criteria provided, single submitter
1455817	NM_014244.5(ADAMTS2):c.591dup (p.Leu198fs)	ADAMTS2	Pathogenic	criteria provided, single submitter
1456924	NM_014244.5(ADAMTS2):c.310dup (p.Glu104fs)	ADAMTS2	Pathogenic	criteria provided, single submitter
1458940	NM_014244.5(ADAMTS2):c.2716A>T (p.Arg906Ter)	ADAMTS2	Pathogenic	criteria provided, single submitter
1725091	NM_014244.5(ADAMTS2):c.1701G>A (p.Trp567Ter)	ADAMTS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1726297	NM_014244.5(ADAMTS2):c.265del (p.Ala89fs)	ADAMTS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1936753	NM_014244.5(ADAMTS2):c.100_130del (p.Pro34fs)	ADAMTS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065161	NM_014244.5(ADAMTS2):c.2422del (p.Thr808fs)	ADAMTS2	Likely pathogenic	criteria provided, single submitter
1066627	NC_000005.9:g.(?178554950)(178564955_?)dup	ADAMTS2	Likely pathogenic	criteria provided, single submitter
1068382	NM_014244.5(ADAMTS2):c.689-9_695del	ADAMTS2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1199244	NM_014244.5(ADAMTS2):c.1701G>T (p.Trp567Cys)	ADAMTS2	Likely pathogenic	criteria provided, single submitter
1481564	NM_014244.5(ADAMTS2):c.688+1G>A	ADAMTS2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1503058	NM_014244.5(ADAMTS2):c.688+2T>C	ADAMTS2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1510020	NM_014244.5(ADAMTS2):c.2457+1G>A	ADAMTS2	Likely pathogenic	criteria provided, single submitter
1518873	NC_000005.9:g.(?178548652)(178700075_?)dup	ADAMTS2	Likely pathogenic	criteria provided, single submitter
1723970	NM_014244.5(ADAMTS2):c.460_461insAAACTGCAGTGGCCTCT (p.Ser154fs)	ADAMTS2	Likely pathogenic	criteria provided, single submitter
1724166	NM_014244.5(ADAMTS2):c.1175del (p.Cys392fs)	ADAMTS2	Likely pathogenic	criteria provided, single submitter
1724168	NM_014244.5(ADAMTS2):c.693del (p.Ser232fs)	ADAMTS2	Likely pathogenic	criteria provided, single submitter
1724314	NM_014244.5(ADAMTS2):c.2486C>A (p.Ser829Ter)	ADAMTS2	Likely pathogenic	criteria provided, single submitter
1724357	NM_014244.5(ADAMTS2):c.153dup (p.His52fs)	ADAMTS2	Likely pathogenic	criteria provided, single submitter
1724612	NM_014244.5(ADAMTS2):c.27_28insTCTTATACACATCTGTG (p.Arg10fs)	ADAMTS2	Likely pathogenic	criteria provided, single submitter
1724827	NM_014244.5(ADAMTS2):c.46del (p.Leu16fs)	ADAMTS2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 3 · 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
ADAMTS2	Definitive	Autosomal recessive	Ehlers-Danlos syndrome, dermatosparaxis type	6
ADAMTSL2	Moderate	Autosomal dominant	Ehlers-Danlos syndrome, dermatosparaxis type	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ADAMTS2	Orphanet:1901	Dermatosparaxis Ehlers-Danlos syndrome
ADAMTSL2	Orphanet:1901	Dermatosparaxis Ehlers-Danlos syndrome
ADAMTSL2	Orphanet:2623	Geleophysic dysplasia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ADAMTS2	HGNC:218	ENSG00000087116	O95450	A disintegrin and metalloproteinase with thrombospondin motifs 2	gencc,clinvar
ADAMTSL2	HGNC:14631	ENSG00000197859	Q86TH1	ADAMTS-like protein 2	gencc
ZNF354C	HGNC:16736	ENSG00000177932	Q86Y25	Zinc finger protein 354C	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ADAMTS2	A disintegrin and metalloproteinase with thrombospondin motifs 2	Cleaves the propeptides of type I and II collagen prior to fibril assembly.
ZNF354C	Zinc finger protein 354C	Transcriptional repressor that inhibits endothelial angiogenic sprouting.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Protease	1	12.2×	0.239
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ADAMTS2	Protease	yes	3.4.24.14	TSP1_rpt, Peptidase_M12B, Peptidase_M12B_N
ADAMTSL2	Other/Unknown	no		TSP1_rpt, ADAMTS_spacer1, PLAC
ZNF354C	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adipose tissue	1
stromal cell of endometrium	1
subcutaneous adipose tissue	1
cardiac atrium	1
metanephros cortex	1
right atrium auricular region	1
cardiac muscle of right atrium	1
cortical plate	1
left ventricle myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADAMTS2	139	ubiquitous	marker	stromal cell of endometrium, subcutaneous adipose tissue, adipose tissue
ADAMTSL2	159	broad	marker	right atrium auricular region, metanephros cortex, cardiac atrium
ZNF354C	195	ubiquitous	marker	cardiac muscle of right atrium, left ventricle myocardium, cortical plate

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ADAMTS2	1,478
ADAMTSL2	600
ZNF354C	458

Intra-cohort edges

A	B	Sources
ADAMTS2	ADAMTSL2	string_interaction

Structural data

PDB: 0 · AlphaFold-only: 3 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADAMTS2	O95450	71.59
ADAMTSL2	Q86TH1	67.10
ZNF354C	Q86Y25	66.18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective B3GALTL causes PpS	2	205.8×	2e-04	ADAMTS2, ADAMTSL2
O-glycosylation of TSR domain-containing proteins	2	200.3×	2e-04	ADAMTS2, ADAMTSL2
Diseases associated with O-glycosylation of proteins	2	143.7×	3e-04	ADAMTS2, ADAMTSL2
O-linked glycosylation	2	96.4×	4e-04	ADAMTS2, ADAMTSL2
Diseases of glycosylation	2	87.5×	4e-04	ADAMTS2, ADAMTSL2
Diseases of metabolism	2	53.6×	1e-03	ADAMTS2, ADAMTSL2
Collagen formation	1	152.3×	0.012	ADAMTS2
Post-translational protein modification	2	12.8×	0.013	ADAMTS2, ADAMTSL2
Collagen biosynthesis and modifying enzymes	1	56.8×	0.022	ADAMTS2
Disease	2	8.7×	0.022	ADAMTS2, ADAMTSL2
Metabolism of proteins	2	8.2×	0.022	ADAMTS2, ADAMTSL2
Extracellular matrix organization	1	21.0×	0.051	ADAMTS2
Generic Transcription Pathway	1	5.0×	0.186	ZNF354C

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
lobar bronchus epithelium development	1	5617.3×	0.001	ADAMTSL2
extracellular matrix organization	2	81.4×	0.001	ADAMTS2, ADAMTSL2
negative regulation of sprouting angiogenesis	1	432.1×	0.010	ZNF354C
skin development	1	147.8×	0.020	ADAMTS2
collagen catabolic process	1	130.6×	0.020	ADAMTS2
collagen fibril organization	1	74.9×	0.025	ADAMTS2
lung development	1	66.1×	0.025	ADAMTS2
negative regulation of transforming growth factor beta receptor signaling pathway	1	57.9×	0.025	ADAMTSL2
protein processing	1	56.7×	0.025	ADAMTS2
angiogenesis	1	20.8×	0.061	ZNF354C
spermatogenesis	1	11.7×	0.092	ADAMTS2
proteolysis	1	11.4×	0.092	ADAMTS2
regulation of transcription by RNA polymerase II	1	3.9×	0.236	ZNF354C

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
ADAMTS2	0	0
ADAMTSL2	0	0
ZNF354C	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADAMTS2	3.4.24.14	procollagen N-endopeptidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	ADAMTS2
E	Difficult family or no structure, no drug	2	ADAMTSL2, ZNF354C

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ADAMTS2	0	—
ADAMTSL2	0	—
ZNF354C	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.