Ehlers-Danlos syndrome, hypermobility type

Summary

Ehlers-Danlos syndrome, hypermobility type (MONDO:0007523) is a disease with 3 cohort genes and 17 clinical trials. Top therapeutic interventions include oxytocin.

At a glance

• Prevalence: 1-5 / 10 000 (Europe)
• Cohort genes: 3
• ClinVar variants: 6
• Phenotypes (HPO): 70
• Clinical trials: 17

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	12.5	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000974	Hyperextensible skin	Very frequent (80-99%)
HP:0001063	Acrocyanosis	Very frequent (80-99%)
HP:0001373	Joint dislocation	Very frequent (80-99%)
HP:0001382	Joint hypermobility	Very frequent (80-99%)
HP:0001760	Abnormal foot morphology	Very frequent (80-99%)
HP:0002321	Vertigo	Very frequent (80-99%)
HP:0002360	Sleep abnormality	Very frequent (80-99%)
HP:0002645	Wormian bones	Very frequent (80-99%)
HP:0002827	Hip dislocation	Very frequent (80-99%)
HP:0002829	Arthralgia	Very frequent (80-99%)
HP:0003042	Elbow dislocation	Very frequent (80-99%)
HP:0003326	Myalgia	Very frequent (80-99%)
HP:0012378	Fatigue	Very frequent (80-99%)
HP:0000678	Dental crowding	Frequent (30-79%)
HP:0000716	Depression	Frequent (30-79%)
HP:0000739	Anxiety	Frequent (30-79%)
HP:0000762	Decreased nerve conduction velocity	Frequent (30-79%)
HP:0000963	Thin skin	Frequent (30-79%)
HP:0000977	Soft skin	Frequent (30-79%)
HP:0000978	Bruising susceptibility	Frequent (30-79%)
HP:0001065	Striae distensae	Frequent (30-79%)
HP:0001166	Arachnodactyly	Frequent (30-79%)
HP:0001634	Mitral valve prolapse	Frequent (30-79%)
HP:0001763	Pes planus	Frequent (30-79%)
HP:0002017	Nausea and vomiting	Frequent (30-79%)
HP:0002019	Constipation	Frequent (30-79%)
HP:0002024	Malabsorption	Frequent (30-79%)
HP:0002035	Rectal prolapse	Frequent (30-79%)
HP:0002076	Migraine	Frequent (30-79%)
HP:0002758	Osteoarthritis	Frequent (30-79%)
HP:0011675	Arrhythmia	Frequent (30-79%)
HP:0012532	Chronic pain	Frequent (30-79%)
HP:0031607	Pelvic organ prolapse	Frequent (30-79%)
HP:0000023	Inguinal hernia	Occasional (5-29%)
HP:0000144	Decreased fertility	Occasional (5-29%)
HP:0000212	Gingival overgrowth	Occasional (5-29%)
HP:0000230	Gingivitis	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000421	Epistaxis	Occasional (5-29%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0000563	Keratoconus	Occasional (5-29%)
HP:0000691	Microdontia	Occasional (5-29%)
HP:0000987	Atypical scarring of skin	Occasional (5-29%)
HP:0001097	Keratoconjunctivitis sicca	Occasional (5-29%)
HP:0001376	Limitation of joint mobility	Occasional (5-29%)
HP:0001482	Subcutaneous nodule	Occasional (5-29%)
HP:0001537	Umbilical hernia	Occasional (5-29%)
HP:0002020	Gastroesophageal reflux	Occasional (5-29%)
HP:0002104	Apnea	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Ehlers-Danlos syndrome, hypermobility type
Mondo ID	MONDO:0007523
MeSH	C536196
OMIM	130020
Orphanet	285
DOID	DOID:14757
NCIT	C125698
SNOMED CT	30652003
UMLS	C0268337
MedGen	75670
GARD	0002081
Is cancer (heuristic)	no

Also known as: EDS III · EDS3 (formerly) · EDSHMB · Ehlers-Danlos syndrome type 3 · Ehlers-Danlos syndrome type 3 (formerly) · Ehlers-Danlos syndrome, hypermobile type · Ehlers-Danlos syndrome, hypermobility type · Ehlers-Danlos syndrome, type 3 · Ehlers-Danlos syndrome, type III · hEDS · HT-EDS · hypermobile EDS · hypermobile Ehlers-Danlos syndrome

Data availability: 6 ClinVar variants · 28 cell lines.

Disease family

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

Related subtypes (24): Ehlers-Danlos syndrome, classic 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, Ehlers-Danlos syndrome, dermatosparaxis 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

6 retrieved; paginated sample, class counts are floors:

3 conflicting classifications of pathogenicity, 2 uncertain significance, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
216910	NM_000090.4(COL3A1):c.4096C>T (p.Gln1366Ter)	COL3A1	Likely pathogenic	criteria provided, single submitter
199744	NM_000090.4(COL3A1):c.3818A>G (p.Lys1273Arg)	COL3A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
222755	NM_017617.5(NOTCH1):c.695C>A (p.Thr232Asn)	NOTCH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
217018	NM_001365276.2(TNXB):c.6074A>T (p.Asp2025Val)	TNXB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
424386	NM_000090.4(COL3A1):c.3462T>G (p.Ser1154Arg)	COL3A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
440954	NM_001365276.2(TNXB):c.2531A>G (p.Gln844Arg)	TNXB	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TNXB	Orphanet:230839	Classical-like Ehlers-Danlos syndrome type 1
TNXB	Orphanet:289365	Familial vesicoureteral reflux
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
NOTCH1	Orphanet:402075	Familial bicuspid aortic valve
NOTCH1	Orphanet:974	Adams-Oliver syndrome

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
TNXB	HGNC:11976	ENSG00000168477	P22105	Tenascin-X	clinvar
COL3A1	HGNC:2201	ENSG00000168542	P02461	Collagen alpha-1(III) chain	clinvar
NOTCH1	HGNC:7881	ENSG00000148400	P46531	Neurogenic locus notch homolog protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNXB	Tenascin-X	Appears to mediate interactions between cells and the extracellular matrix.
COL3A1	Collagen alpha-1(III) chain	Collagen type III occurs in most soft connective tissues along with type I collagen.
NOTCH1	Neurogenic locus notch homolog protein 1	Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination.

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
Antibody/Immunoglobulin	1	9.7×	0.246
Scaffold/PPI	1	5.8×	0.246
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNXB	Antibody/Immunoglobulin	yes		EGF, Fibrinogen_a/b/g_C_dom, FN3_dom
COL3A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
NOTCH1	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom

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
visceral pleura	2
apex of heart	1
right adrenal gland	1
right adrenal gland cortex	1
parietal pleura	1
skin of hip	1
colonic epithelium	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNXB	134	ubiquitous	marker	apex of heart, right adrenal gland cortex, right adrenal gland
COL3A1	281	ubiquitous	marker	skin of hip, parietal pleura, visceral pleura
NOTCH1	272	ubiquitous	marker	ventricular zone, colonic epithelium, visceral pleura

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NOTCH1	7,411
COL3A1	3,629
TNXB	1,335

Intra-cohort edges

A	B	Sources
COL3A1	TNXB	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NOTCH1	P46531	29
COL3A1	P02461	11
TNXB	P22105	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 39. 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
ECM proteoglycans	2	100.2×	0.005	TNXB, COL3A1
Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling	1	761.3×	0.014	NOTCH1
Defective LFNG causes SCDO3	1	761.3×	0.014	NOTCH1
Pre-NOTCH Processing in the Endoplasmic Reticulum	1	634.4×	0.014	NOTCH1
Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	543.8×	0.014	NOTCH1
Regulation of NFE2L2 gene expression	1	475.8×	0.014	NOTCH1
NFE2L2 regulating tumorigenic genes	1	317.2×	0.014	NOTCH1
RUNX3 regulates NOTCH signaling	1	271.9×	0.014	NOTCH1
Constitutive Signaling by NOTCH1 HD Domain Mutants	1	253.8×	0.014	NOTCH1
Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells	1	237.9×	0.014	NOTCH1
Pre-NOTCH Processing in Golgi	1	211.5×	0.014	NOTCH1
Scavenging by Class A Receptors	1	200.3×	0.014	COL3A1
MECP2 regulates neuronal receptors and channels	1	200.3×	0.014	NOTCH1
Fibronectin matrix formation	1	190.3×	0.014	COL3A1
NOTCH4 Intracellular Domain Regulates Transcription	1	190.3×	0.014	NOTCH1
NOTCH3 Intracellular Domain Regulates Transcription	1	146.4×	0.015	NOTCH1
Syndecan interactions	1	141.0×	0.015	COL3A1
Notch-HLH transcription pathway	1	135.9×	0.015	NOTCH1
Formation of paraxial mesoderm	1	135.9×	0.015	NOTCH1
MET activates PTK2 signaling	1	126.9×	0.015	COL3A1
Activated NOTCH1 Transmits Signal to the Nucleus	1	119.0×	0.016	NOTCH1
Nuclear events stimulated by ALK signaling in cancer	1	108.8×	0.016	NOTCH1
Collagen chain trimerization	1	86.5×	0.018	COL3A1
Signaling by PDGF	1	84.6×	0.018	COL3A1
NCAM1 interactions	1	82.8×	0.018	COL3A1
NOTCH1 Intracellular Domain Regulates Transcription	1	79.3×	0.018	NOTCH1
Somitogenesis	1	77.7×	0.018	NOTCH1
Developmental Lineage of Pancreatic Ductal Cells	1	76.1×	0.018	COL3A1
Assembly of collagen fibrils and other multimeric structures	1	66.8×	0.019	COL3A1
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	65.6×	0.019	NOTCH1

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
elastic fiber assembly	2	1021.3×	2e-04	TNXB, COL3A1
coronary sinus valve morphogenesis	1	5617.3×	0.003	NOTCH1
Notch signaling pathway involved in regulation of secondary heart field cardioblast proliferation	1	5617.3×	0.003	NOTCH1
foregut morphogenesis	1	5617.3×	0.003	NOTCH1
regulation of epithelial cell proliferation involved in prostate gland development	1	5617.3×	0.003	NOTCH1
venous endothelial cell differentiation	1	5617.3×	0.003	NOTCH1
positive regulation of cell fate determination	1	5617.3×	0.003	TNXB
endocardium morphogenesis	1	2808.7×	0.003	NOTCH1
coronary vein morphogenesis	1	2808.7×	0.003	NOTCH1
cardiac right atrium morphogenesis	1	2808.7×	0.003	NOTCH1
growth involved in heart morphogenesis	1	2808.7×	0.003	NOTCH1
obsolete negative regulation of cell proliferation involved in heart valve morphogenesis	1	2808.7×	0.003	NOTCH1
cell differentiation in spinal cord	1	2808.7×	0.003	NOTCH1
positive regulation of aorta morphogenesis	1	2808.7×	0.003	NOTCH1
mitral valve formation	1	1872.4×	0.003	NOTCH1
cardiac chamber formation	1	1872.4×	0.003	NOTCH1
auditory receptor cell fate commitment	1	1872.4×	0.003	NOTCH1
transforming growth factor beta1 production	1	1872.4×	0.003	COL3A1
limb joint morphogenesis	1	1872.4×	0.003	COL3A1
retinal cone cell differentiation	1	1872.4×	0.003	NOTCH1
secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development	1	1872.4×	0.003	NOTCH1
cardiac vascular smooth muscle cell development	1	1872.4×	0.003	NOTCH1
vasculogenesis involved in coronary vascular morphogenesis	1	1872.4×	0.003	NOTCH1
regulation of cell adhesion involved in heart morphogenesis	1	1872.4×	0.003	NOTCH1
distal tubule development	1	1872.4×	0.003	NOTCH1
chemical synaptic transmission, postsynaptic	1	1872.4×	0.003	NOTCH1
apoptotic process involved in embryonic digit morphogenesis	1	1872.4×	0.003	NOTCH1
positive regulation of apoptotic process involved in morphogenesis	1	1872.4×	0.003	NOTCH1
negative regulation of pro-B cell differentiation	1	1872.4×	0.003	NOTCH1
negative regulation of endothelial cell chemotaxis	1	1872.4×	0.003	NOTCH1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NOTCH1	1	2
TNXB	0	0
COL3A1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VAREGACESTAT	2	NOTCH1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NOTCH1	23	Binding:19, ADMET:4

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

1 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)
VAREGACESTAT	2	NOTCH1

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	1	NOTCH1
C	Druggable family + PDB, no drug	1	TNXB
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	COL3A1

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)
TNXB	0	—
COL3A1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 17.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	16
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05405257	PHASE1/PHASE2	TERMINATED	Oxytocin for Hypermobile Ehlers-Danlos Syndrome
NCT05212129	Not specified	RECRUITING	Auricular Vagal Nerve Stimulation for Hypermobile Ehlers-Danlos Syndrome
NCT05757960	Not specified	ENROLLING_BY_INVITATION	TMD-specific Physiotherapy in hEDS Patients Individuals With Hypermobile Ehlers-Danlos Syndrome
NCT07464093	Not specified	NOT_YET_RECRUITING	STABLE Pilates for Hypermobility
NCT04666896	Not specified	TERMINATED	Patient-based Care Versus Standard Care for Patients With hEDS/HSD and Multidirectional Shoulder Instability
NCT04734041	Not specified	COMPLETED	Integrative Medicine for Hypermobility Spectrum Disorder and Ehlers-Danlos Syndromes (IMforHSDandEDS)
NCT04972565	Not specified	COMPLETED	Dyspnea in Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorder
NCT05000151	Not specified	COMPLETED	Lung Volume Perception and Impact of a Cognitive Task on Ventilation in Hypermobile Ehlers-Danlos Syndrome.
NCT05148039	Not specified	COMPLETED	Comprehensive Assessment of Nutrition and Dietary Intervention in Hypermobile Ehlers Danlos Syndrome
NCT05429996	Not specified	UNKNOWN	Ultrastructural Collagen Markers in Ehlers Danlos Syndromes
NCT05434728	Not specified	UNKNOWN	Characterization of Bleeding Disorders in EDS
NCT05633225	Not specified	COMPLETED	Central Sensitization and Physical Activity in Adolescents With HSD/hEDS
NCT05685199	Not specified	TERMINATED	Identifying the Determinants of Bleeding and Hypermobility in Patients With Heavy Menstrual Bleeding
NCT05800262	Not specified	COMPLETED	Dynamic Stability Exercises in Patients With Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorder
NCT06105541	Not specified	COMPLETED	Hypermobile Ehlers-Danlos Syndrome - Transcutaneous Auricular Neuromodulation
NCT06548594	Not specified	COMPLETED	Out of State - tAN hEDS
NCT07118865	Not specified	COMPLETED	Online Pilates Exercise for People With Hypermobility

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
OXYTOCIN	4	1