Ehlers-Danlos syndrome due to tenascin-X deficiency

Summary

Ehlers-Danlos syndrome due to tenascin-X deficiency (MONDO:0011670) is a disease caused by TNXB (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TNXB (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 275
• Phenotypes (HPO): 20

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		17	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0001382	Joint hypermobility	Very frequent (80-99%)
HP:0000763	Sensory neuropathy	Frequent (30-79%)
HP:0000963	Thin skin	Frequent (30-79%)
HP:0000974	Hyperextensible skin	Frequent (30-79%)
HP:0000978	Bruising susceptibility	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0002829	Arthralgia	Frequent (30-79%)
HP:0003202	Skeletal muscle atrophy	Frequent (30-79%)
HP:0003326	Myalgia	Frequent (30-79%)
HP:0003701	Proximal muscle weakness	Frequent (30-79%)
HP:0009830	Peripheral neuropathy	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0000835	Adrenal hypoplasia	Occasional (5-29%)
HP:0001297	Stroke	Occasional (5-29%)
HP:0001634	Mitral valve prolapse	Occasional (5-29%)
HP:0002239	Gastrointestinal hemorrhage	Occasional (5-29%)
HP:0003298	Spina bifida occulta	Occasional (5-29%)
HP:0004416	Precocious atherosclerosis	Occasional (5-29%)
HP:0011675	Arrhythmia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Ehlers-Danlos syndrome due to tenascin-X deficiency
Mondo ID	MONDO:0011670
MeSH	C536193
OMIM	606408
Orphanet	230839
DOID	DOID:0080731
ICD-11	1840696236
UMLS	C1848029
MedGen	336244
GARD	0008507
Is cancer (heuristic)	no

Also known as: classical-like EDS · classical-like Ehlers-Danlos syndrome · clEDS · EDS due to TNX deficiency · EDS, classic-like type · EDSCLL · Ehlers-Danlos syndrome due to tenascin-X deficiency · Ehlers-Danlos syndrome, classic-like type · Ehlers-Danlos syndrome, classic-like, 1 · Ehlers-Danlos-like syndrome due to tenascin-X deficiency · TNX deficiency

Data availability: 275 ClinVar variants · 5 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 due to tenascin-X deficiency

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, Ehlers-Danlos syndrome, dermatosparaxis type, brittle cornea syndrome, X-linked Ehlers-Danlos syndrome, Ehlers-Danlos syndrome, musculocontractural type, 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

275 retrieved; paginated sample, class counts are floors:

92 uncertain significance, 53 conflicting classifications of pathogenicity, 47 likely pathogenic, 28 pathogenic, 20 benign/likely benign, 18 pathogenic/likely pathogenic, 11 benign, 4 likely benign, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
3593443	NM_001365276.2(TNXB):c.12559C>T (p.Arg4187Ter)	LOC106780803	Pathogenic	criteria provided, single submitter
2434194	NM_001365276.2(TNXB):c.10291C>T (p.Arg3431Ter)	LOC126859654	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1196848	NM_001365276.2(TNXB):c.6805C>T (p.Gln2269Ter)	TNXB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1209904	NM_001365276.2(TNXB):c.2590C>T (p.Gln864Ter)	TNXB	Pathogenic/Likely pathogenic	no assertion criteria provided
1323700	NM_001365276.2(TNXB):c.7826-1G>C	TNXB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1326137	NM_001365276.2(TNXB):c.6293dup (p.Glu2100fs)	TNXB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
144112	NM_001365276.2(TNXB):c.12220C>T (p.Arg4074Cys)	TNXB	Pathogenic	no assertion criteria provided
1702327	NM_001365276.2(TNXB):c.3942dup (p.Thr1315fs)	TNXB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1763690	NM_001365276.2(TNXB):c.8516_8517del (p.Pro2839fs)	TNXB	Pathogenic	criteria provided, multiple submitters, no conflicts
1805011	NM_001365276.2(TNXB):c.3763dup (p.Arg1255fs)	TNXB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2392339	NM_001365276.2(TNXB):c.8613del (p.Phe2871fs)	TNXB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2632069	NM_001365276.2(TNXB):c.8995del (p.Arg2999fs)	TNXB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2691676	NM_001365276.2(TNXB):c.3908del (p.Gln1303fs)	TNXB	Pathogenic	criteria provided, single submitter
3255080	NM_001365276.2(TNXB):c.9589del (p.Thr3197fs)	TNXB	Pathogenic	criteria provided, single submitter
3338902	NM_001365276.2(TNXB):c.510dup (p.Thr171fs)	TNXB	Pathogenic	criteria provided, single submitter
3374955	NM_001365276.2(TNXB):c.10442dup (p.Gln3482fs)	TNXB	Pathogenic	criteria provided, single submitter
3376963	NM_001365276.2(TNXB):c.1136del (p.Gly379fs)	TNXB	Pathogenic	criteria provided, single submitter
3382154	NM_001365276.2(TNXB):c.5451_5476del (p.Val1819fs)	TNXB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3384708	NM_001365276.2(TNXB):c.3907C>T (p.Gln1303Ter)	TNXB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3593460	NM_001365276.2(TNXB):c.7505del (p.Asp2502fs)	TNXB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3593470	NM_001365276.2(TNXB):c.4706_4707del (p.Thr1569fs)	TNXB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3593471	NM_001365276.2(TNXB):c.4411del (p.Ser1471fs)	TNXB	Pathogenic	criteria provided, single submitter
3593481	NM_001365276.2(TNXB):c.703_704dup (p.Arg236fs)	TNXB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
373424	NM_001365276.2(TNXB):c.2461C>T (p.Arg821Ter)	TNXB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3768456	NM_001365276.2(TNXB):c.7056_7063del (p.His2352fs)	TNXB	Pathogenic	criteria provided, single submitter
3768974	NM_001365276.2(TNXB):c.2086dup (p.Glu696fs)	TNXB	Pathogenic	criteria provided, single submitter
3769358	NM_001365276.2(TNXB):c.3372dup (p.Lys1125fs)	TNXB	Pathogenic	criteria provided, single submitter
3899274	NM_001365276.2(TNXB):c.6454_6460dup (p.Glu2154fs)	TNXB	Pathogenic	criteria provided, single submitter
3902286	NM_001365276.2(TNXB):c.2539C>T (p.Arg847Ter)	TNXB	Pathogenic	criteria provided, single submitter
4081807	NM_001365276.2(TNXB):c.4296dup (p.Gly1433fs)	TNXB	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 4 · 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
TNXB	Definitive	Autosomal recessive	Ehlers-Danlos syndrome due to tenascin-X deficiency	8

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
CYP21A2	Orphanet:315306	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form
CYP21A2	Orphanet:315311	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form

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
TNXB	HGNC:11976	ENSG00000168477	P22105	Tenascin-X	gencc,clinvar
CYP21A2	HGNC:2600	ENSG00000231852	P08686	Steroid 21-hydroxylase	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.
CYP21A2	Steroid 21-hydroxylase	A cytochrome P450 monooxygenase that plays a major role in adrenal steroidogenesis.

Protein-family classification

Druggable: 2 · 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
Antibody/Immunoglobulin	1	14.6×	0.135
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNXB	Antibody/Immunoglobulin	yes		EGF, Fibrinogen_a/b/g_C_dom, FN3_dom
CYP21A2	Enzyme (other)	yes	1.14.14.16	Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_CS

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
right adrenal gland	2
right adrenal gland cortex	2
apex of heart	1
left adrenal gland	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
CYP21A2	130	tissue_specific	marker	right adrenal gland, left adrenal gland, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TNXB	1,335
CYP21A2	28

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNXB	P22105	3
CYP21A2	P08686	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Defective CYP21A2 causes AH3	1	2855.0×	0.002	CYP21A2
Mineralocorticoid biosynthesis	1	713.8×	0.004	CYP21A2
Glucocorticoid biosynthesis	1	439.2×	0.005	CYP21A2
Endogenous sterols	1	196.9×	0.008	CYP21A2
ECM proteoglycans	1	75.1×	0.016	TNXB
Extracellular matrix organization	1	31.6×	0.031	TNXB

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 cell fate determination	1	8426.0×	0.003	TNXB
mineralocorticoid biosynthetic process	1	2106.5×	0.004	CYP21A2
positive regulation of collagen fibril organization	1	2106.5×	0.004	TNXB
cortisol biosynthetic process	1	1053.2×	0.005	CYP21A2
glucocorticoid biosynthetic process	1	766.0×	0.005	CYP21A2
elastic fiber assembly	1	766.0×	0.005	TNXB
positive regulation of vascular endothelial growth factor signaling pathway	1	561.7×	0.006	TNXB
collagen metabolic process	1	526.6×	0.006	TNXB
regulation of JNK cascade	1	443.5×	0.006	TNXB
sterol metabolic process	1	421.3×	0.006	CYP21A2
steroid biosynthetic process	1	300.9×	0.008	CYP21A2
triglyceride metabolic process	1	221.7×	0.009	TNXB
regulation of cell differentiation	1	216.1×	0.009	TNXB
steroid metabolic process	1	168.5×	0.010	CYP21A2
positive regulation of epithelial to mesenchymal transition	1	159.0×	0.010	TNXB
regulation of cell adhesion	1	153.2×	0.010	TNXB
collagen fibril organization	1	112.3×	0.013	TNXB
fatty acid metabolic process	1	96.8×	0.014	TNXB
cell-matrix adhesion	1	81.8×	0.016	TNXB
regulation of cell migration	1	78.8×	0.016	TNXB
neuron projection development	1	61.1×	0.019	TNXB
cell-cell adhesion	1	50.8×	0.022	TNXB
actin cytoskeleton organization	1	39.6×	0.027	TNXB
cell adhesion	1	18.7×	0.055	TNXB
positive regulation of cell population proliferation	1	16.8×	0.059	TNXB

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
CYP21A2	KETOCONAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CYP21A2	4	4
TNXB	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
KETOCONAZOLE	4	CYP21A2
ABIRATERONE	4	CYP21A2
ORTERONEL	3	CYP21A2
GALETERONE	3	CYP21A2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CYP21A2	15	Binding:10, ADMET:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CYP21A2	1.14.14.16	steroid 21-monooxygenase

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

4 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)
KETOCONAZOLE	4	CYP21A2
ABIRATERONE	4	CYP21A2
ORTERONEL	3	CYP21A2
GALETERONE	3	CYP21A2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CYP21A2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	TNXB
D	Druggable family + AlphaFold only, no drug	0
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)
TNXB	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.