Ehlers-Danlos syndrome, vascular type

Summary

Ehlers-Danlos syndrome, vascular type (MONDO:0017314) is a disease with 2 cohort genes and 12 clinical trials. Top therapeutic interventions include irbesartan and enzastaurin.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 2,964
• Phenotypes (HPO): 95
• Clinical trials: 12

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000015	Bladder diverticulum	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Very frequent (80-99%)
HP:0000190	Abnormal oral frenulum morphology	Very frequent (80-99%)
HP:0000271	Abnormality of the face	Very frequent (80-99%)
HP:0000286	Epicanthus	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000411	Protruding ear	Very frequent (80-99%)
HP:0000499	Abnormal eyelash morphology	Very frequent (80-99%)
HP:0000506	Telecanthus	Very frequent (80-99%)
HP:0000670	Carious teeth	Very frequent (80-99%)
HP:0000767	Pectus excavatum	Very frequent (80-99%)
HP:0000822	Hypertension	Very frequent (80-99%)
HP:0000912	Sprengel anomaly	Very frequent (80-99%)
HP:0000951	Abnormality of the skin	Very frequent (80-99%)
HP:0000963	Thin skin	Very frequent (80-99%)
HP:0000978	Bruising susceptibility	Very frequent (80-99%)
HP:0000995	Melanocytic nevus	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001634	Mitral valve prolapse	Very frequent (80-99%)
HP:0001654	Abnormal heart valve morphology	Very frequent (80-99%)
HP:0001892	Abnormal bleeding	Very frequent (80-99%)
HP:0002107	Pneumothorax	Very frequent (80-99%)
HP:0002617	Dilatation	Very frequent (80-99%)
HP:0002647	Aortic dissection	Very frequent (80-99%)
HP:0002900	Hypokalemia	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0005244	Gastrointestinal infarctions	Very frequent (80-99%)
HP:0007495	Prematurely aged appearance	Very frequent (80-99%)
HP:0009906	Aplasia/Hypoplasia of the earlobes	Very frequent (80-99%)
HP:0010648	Dermal translucency	Very frequent (80-99%)
HP:0011029	Internal hemorrhage	Very frequent (80-99%)
HP:0012733	Macule	Very frequent (80-99%)
HP:0100543	Cognitive impairment	Very frequent (80-99%)
HP:0100784	Peripheral arteriovenous fistula	Very frequent (80-99%)
HP:0100840	Aplasia/Hypoplasia of the eyebrow	Very frequent (80-99%)
HP:0000233	Thin vermilion border	Frequent (30-79%)
HP:0000501	Glaucoma	Frequent (30-79%)
HP:0000520	Proptosis	Frequent (30-79%)
HP:0001622	Premature birth	Frequent (30-79%)
HP:0001762	Talipes equinovarus	Frequent (30-79%)
HP:0002093	Respiratory insufficiency	Frequent (30-79%)
HP:0002619	Varicose veins	Frequent (30-79%)
HP:0002642	Arteriovenous fistulas of celiac and mesenteric vessels	Frequent (30-79%)
HP:0004947	Arteriovenous fistula	Frequent (30-79%)
HP:0005294	Arterial dissection	Frequent (30-79%)
HP:0012368	Flat face	Frequent (30-79%)
HP:0100585	Telangiectasia of the skin	Frequent (30-79%)
HP:0000023	Inguinal hernia	Occasional (5-29%)
HP:0000047	Hypospadias	Occasional (5-29%)
HP:0000139	Uterine prolapse	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Ehlers-Danlos syndrome, vascular type
Mondo ID	MONDO:0017314
Orphanet	286
ICD-11	1202686415
NCIT	C125699
SNOMED CT	17025000
UMLS	C0268338
MedGen	82790
GARD	0002082
Is cancer (heuristic)	no

Also known as: EDS IV · EDS IV (formerly) · EDS type 4 · EDS type 4 (formerly) · EDS4 (formerly) · Ehlers Danlos syndrome, arterial type · Ehlers Danlos syndrome, ecchymotic type · Ehlers Danlos syndrome, sack-Barabas type · Ehlers-Danlos syndrome type 4 · Ehlers-Danlos syndrome type 4 (formerly) · Ehlers-Danlos syndrome type IV · Ehlers-Danlos syndrome type IV (formerly) · Ehlers-Danlos syndrome, type IV · Ehlers-Danlos syndrome, vascular type · sack-Barabas syndrome · vascular EDS · vascular Ehlers-Danlos syndrome · vEDS

Data availability: 2,964 ClinVar variants · 1 GenCC gene-disease record · 68 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › vascular disorder › Ehlers-Danlos syndrome, vascular type

Related subtypes (59): arterial disorder, ischemic colitis, thrombotic disease, capillary disorder, angiodysplasia, hepatic vascular disorder, vascular hemostatic disease, vein disorder, ischemic disease, peripheral vascular disease, venous thromboembolism, ocular vascular disorder, cholesterol embolism, thoracic outlet syndrome, idiopathic spontaneous coronary artery dissection, cerebral arteriopathy with subcortical infarcts and leukoencephalopathy, angioosteohypertrophic syndrome, Bannayan-Riley-Ruvalcaba syndrome, arterial tortuosity syndrome, hereditary arterial and articular multiple calcification syndrome, pulmonary venoocclusive disease, multiple cutaneous and mucosal venous malformations, arterial dissection-lentiginosis syndrome, patent ductus arteriosus, multisystemic smooth muscle dysfunction syndrome, STING-associated vasculopathy with onset in infancy, capillary malformation, Ehlers-Danlos syndrome, vascular-like type, calciphylaxis, neonatal Marfan syndrome, lethal arteriopathy syndrome due to fibulin-4 deficiency, congenital portosystemic shunt, arterial calcification of infancy, vasculitis, Loeys-Dietz syndrome, skin vascular disease, lymphatic malformation, familial thoracic aortic aneurysm and aortic dissection, congenital anomaly of superior vena cava, congenital anomaly of the inferior vena cava, congenital anomaly of hepatic vein, congenital renal artery stenosis, internal carotid agenesis, coronary sinus stenosis, coronary sinus atresia, vascular occlusion disorder, vascular insufficiency disorder, blood vessel neoplasm, vascular ectasia, vascular disorder of penis, fibrocartilaginous embolism, vascular malformation, lymphatic vessel neoplasm, neurovascular disorder, superior vena cava syndrome, coronary microvascular disorder, segmental arterial mediolysis, bleeding disorder, vascular-type, arterial tortuosity-bone fragility syndrome

Subtypes (2): autosomal recessive Ehlers-Danlos syndrome, vascular type, autosomal dominant Ehlers-Danlos syndrome, vascular type

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:

298 pathogenic, 89 likely pathogenic, 84 uncertain significance, 54 likely benign, 38 pathogenic/likely pathogenic, 20 conflicting classifications of pathogenicity, 12 benign, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
101229	NM_000090.3(COL3A1):c.[1786C>T;3851G>A]		Pathogenic	no assertion criteria provided
101408	NM_000090.3(COL3A1):c.[=/3426_3452del];[=/3440_3466del]		Pathogenic	no assertion criteria provided
101101	NM_000090.4(COL3A1):c.2977G>T (p.Gly993Cys)	COL3A1	Pathogenic	no assertion criteria provided
101102	NM_000090.4(COL3A1):c.2600G>A (p.Gly867Asp)	COL3A1	Pathogenic	no assertion criteria provided
101104	NM_000090.4(COL3A1):c.1033G>A (p.Gly345Arg)	COL3A1	Pathogenic	no assertion criteria provided
101105	NM_000090.4(COL3A1):c.548G>A (p.Gly183Asp)	COL3A1	Pathogenic	no assertion criteria provided
101106	NM_000090.4(COL3A1):c.2222G>A (p.Gly741Asp)	COL3A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
101107	NM_000090.4(COL3A1):c.1916G>A (p.Gly639Glu)	COL3A1	Pathogenic	no assertion criteria provided
101108	NM_000090.4(COL3A1):c.951+5G>A	COL3A1	Pathogenic	no assertion criteria provided
101109	NM_000090.4(COL3A1):c.951+6T>C	COL3A1	Pathogenic	no assertion criteria provided
101110	NM_000090.4(COL3A1):c.2823+1G>A	COL3A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
101111	NM_000090.4(COL3A1):c.951_951+14del	COL3A1	Pathogenic	no assertion criteria provided
101112	NM_000090.4(COL3A1):c.951+2T>A	COL3A1	Pathogenic	no assertion criteria provided
101113	NM_000090.4(COL3A1):c.800G>T (p.Gly267Val)	COL3A1	Pathogenic	criteria provided, single submitter
101114	NM_000090.4(COL3A1):c.3095G>T (p.Gly1032Val)	COL3A1	Pathogenic	no assertion criteria provided
101115	NM_000090.4(COL3A1):c.2022+2T>C	COL3A1	Pathogenic	criteria provided, single submitter
101116	NM_000090.4(COL3A1):c.1744G>C (p.Gly582Arg)	COL3A1	Pathogenic	no assertion criteria provided
101119	NM_000090.4(COL3A1):c.2780G>A (p.Gly927Asp)	COL3A1	Pathogenic	no assertion criteria provided
101120	NM_000090.4(COL3A1):c.1987G>C (p.Gly663Arg)	COL3A1	Pathogenic	no assertion criteria provided
101121	NM_000090.4(COL3A1):c.2861G>A (p.Gly954Glu)	COL3A1	Pathogenic	no assertion criteria provided
101122	NM_000090.4(COL3A1):c.1915G>C (p.Gly639Arg)	COL3A1	Pathogenic	no assertion criteria provided
101123	NM_000090.4(COL3A1):c.601G>C (p.Gly201Arg)	COL3A1	Pathogenic	no assertion criteria provided
101126	NM_000090.4(COL3A1):c.3301G>A (p.Gly1101Arg)	COL3A1	Pathogenic	no assertion criteria provided
101128	NM_000090.4(COL3A1):c.656G>C (p.Gly219Ala)	COL3A1	Pathogenic	no assertion criteria provided
101132	NM_000090.4(COL3A1):c.3417+1G>A	COL3A1	Pathogenic	criteria provided, multiple submitters, no conflicts
101133	NM_000090.4(COL3A1):c.3347G>T (p.Gly1116Val)	COL3A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
101134	NM_000090.4(COL3A1):c.1456-82_1977+177del	COL3A1	Pathogenic	no assertion criteria provided
101135	NM_000090.4(COL3A1):c.556G>A (p.Gly186Ser)	COL3A1	Pathogenic	no assertion criteria provided
101137	NM_000090.4(COL3A1):c.3417+5G>A	COL3A1	Pathogenic	no assertion criteria provided
101138	NM_000090.4(COL3A1):c.2941G>C (p.Gly981Arg)	COL3A1	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 6 · 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
COL3A1	Definitive	Autosomal dominant	autosomal dominant Ehlers-Danlos syndrome, vascular type	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL3A1	Orphanet:231160	Familial cerebral saccular aneurysm
COL3A1	Orphanet:2500	Acrogeria
COL3A1	Orphanet:286	Vascular Ehlers-Danlos syndrome
COL3A1	Orphanet:636941	Vascular Ehlers-Danlos-polymicrogyria syndrome
COL3A1	Orphanet:86	Familial abdominal aortic aneurysm
FBN2	Orphanet:115	Congenital contractural arachnodactyly

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
COL3A1	HGNC:2201	ENSG00000168542	P02461	Collagen alpha-1(III) chain	gencc,clinvar
FBN2	HGNC:3604	ENSG00000138829	P35556	Fibrillin-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL3A1	Collagen alpha-1(III) chain	Collagen type III occurs in most soft connective tissues along with type I collagen.
FBN2	Fibrillin-2	Fibrillins are structural components of 10-12 nm extracellular calcium-binding microfibrils, which occur either in association with elastin or in elastin-free bundles.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL3A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
FBN2	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom

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
parietal pleura	1
skin of hip	1
visceral pleura	1
adrenal tissue	1
cartilage tissue	1
placenta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL3A1	281	ubiquitous	marker	skin of hip, parietal pleura, visceral pleura
FBN2	194	ubiquitous	marker	cartilage tissue, placenta, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL3A1	3,629
FBN2	2,570

Intra-cohort edges

A	B	Sources
COL3A1	FBN2	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL3A1	P02461	11

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FBN2	P35556

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Scavenging by Class A Receptors	1	300.5×	0.016	COL3A1
Fibronectin matrix formation	1	285.5×	0.016	COL3A1
Syndecan interactions	1	211.5×	0.016	COL3A1
MET activates PTK2 signaling	1	190.3×	0.016	COL3A1
Elastic fibre formation	1	167.9×	0.016	FBN2
Molecules associated with elastic fibres	1	154.3×	0.016	FBN2
Collagen chain trimerization	1	129.8×	0.016	COL3A1
Signaling by PDGF	1	126.9×	0.016	COL3A1
NCAM1 interactions	1	124.1×	0.016	COL3A1
Developmental Lineage of Pancreatic Ductal Cells	1	114.2×	0.016	COL3A1
Assembly of collagen fibrils and other multimeric structures	1	100.2×	0.016	COL3A1
Collagen degradation	1	87.8×	0.016	COL3A1
Collagen biosynthesis and modifying enzymes	1	85.2×	0.016	COL3A1
Non-integrin membrane-ECM interactions	1	77.2×	0.016	COL3A1
ECM proteoglycans	1	75.1×	0.016	COL3A1
Integrin cell surface interactions	1	67.2×	0.017	COL3A1
Degradation of the extracellular matrix	1	58.9×	0.018	FBN2
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	43.6×	0.023	COL3A1

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
transforming growth factor beta1 production	1	2808.7×	0.004	COL3A1
limb joint morphogenesis	1	2808.7×	0.004	COL3A1
obsolete sequestering of TGFbeta in extracellular matrix	1	2106.5×	0.004	FBN2
endochondral bone morphogenesis	1	2106.5×	0.004	COL3A1
aorta smooth muscle tissue morphogenesis	1	2106.5×	0.004	COL3A1
bone trabecula formation	1	1053.2×	0.005	FBN2
response to angiotensin	1	936.2×	0.005	COL3A1
embryonic eye morphogenesis	1	766.0×	0.005	FBN2
elastic fiber assembly	1	766.0×	0.005	COL3A1
peptide cross-linking	1	702.2×	0.005	COL3A1
negative regulation of neuron migration	1	702.2×	0.005	COL3A1
response to radiation	1	601.9×	0.005	COL3A1
layer formation in cerebral cortex	1	561.7×	0.005	COL3A1
negative regulation of immune response	1	526.6×	0.005	COL3A1
supramolecular fiber organization	1	526.6×	0.005	COL3A1
positive regulation of Rho protein signal transduction	1	290.6×	0.009	COL3A1
tissue homeostasis	1	280.9×	0.009	COL3A1
digestive tract development	1	263.3×	0.009	COL3A1
basement membrane organization	1	255.3×	0.009	COL3A1
skin development	1	221.7×	0.009	COL3A1
embryonic limb morphogenesis	1	200.6×	0.009	FBN2
positive regulation of bone mineralization	1	195.9×	0.009	FBN2
fibroblast proliferation	1	195.9×	0.009	COL3A1
response to cytokine	1	187.2×	0.009	COL3A1
camera-type eye development	1	179.3×	0.009	FBN2
cellular response to amino acid stimulus	1	153.2×	0.010	COL3A1
chondrocyte differentiation	1	150.5×	0.010	COL3A1
platelet activation	1	133.8×	0.011	COL3A1
glucose metabolic process	1	127.7×	0.011	FBN2
wound healing	1	113.9×	0.012	COL3A1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COL3A1	0	0
FBN2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	2	COL3A1, FBN2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
COL3A1	0	—
FBN2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 12.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	9
PHASE3	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05432466	PHASE3	RECRUITING	Clinical Trial to Compare the Efficacy of Celiprolol to Placebo in Patients With Vascular Ehlers-Danlos Syndrome
NCT02597361	PHASE3	COMPLETED	Angiotensin II Receptor Blockade in Vascular Ehlers Danlos Syndrome (ARCADE)
NCT05463679	PHASE3	SUSPENDED	Investigate Efficacy, Safety, and Pharmacokinetics of Enzastaurin for the Prevention of Arterial Events in Patients With Vascular Ehlers-Danlos Syndrome.
NCT03440697	Not specified	ACTIVE_NOT_RECRUITING	Pathogenetic Basis of Aortopathy and Aortic Valve Disease
NCT05976841	Not specified	ACTIVE_NOT_RECRUITING	SEDVasc (RaDiCo Cohort) (RaDiCo-SEDVasc)
NCT05994664	Not specified	RECRUITING	Heart Coherence Training on Vascular Ehlers-Danlos Syndrome Patients
NCT06546137	Not specified	RECRUITING	National Network for Cardiovascular Genomics: Advancing Cardiovascular Healthcare for Hereditary Diseases in Brazil’s Unified Health System Through a Multicenter Registry
NCT07516496	Not specified	RECRUITING	Metabolic Phenotyping in vEDS
NCT01096264	Not specified	COMPLETED	Non-Invasive Quantitative Imaging of Human Local Arterial Wall Elasticity Using Supersonic Shear Imaging
NCT02165085	Not specified	COMPLETED	Biomarkers in Vascular Ehlers-Danlos Syndrome
NCT05434728	Not specified	UNKNOWN	Characterization of Bleeding Disorders in EDS
NCT05980104	Not specified	COMPLETED	Single-Session Empowered Relief Class for Marfan Syndrome and Related Conditions

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
IRBESARTAN	4	1
ENZASTAURIN	3	1