Ehlers-Danlos syndrome, musculocontractural type

Summary

Ehlers-Danlos syndrome, musculocontractural type (MONDO:0011142) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 186
• Phenotypes (HPO): 64

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		34	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000028	Cryptorchidism	Very frequent (80-99%)
HP:0000160	Narrow mouth	Very frequent (80-99%)
HP:0000218	High palate	Very frequent (80-99%)
HP:0000219	Thin upper lip vermilion	Very frequent (80-99%)
HP:0000239	Large fontanelles	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000343	Long philtrum	Very frequent (80-99%)
HP:0000400	Macrotia	Very frequent (80-99%)
HP:0000411	Protruding ear	Very frequent (80-99%)
HP:0000494	Downslanted palpebral fissures	Very frequent (80-99%)
HP:0000592	Blue sclerae	Very frequent (80-99%)
HP:0000766	Abnormal sternum morphology	Very frequent (80-99%)
HP:0000974	Hyperextensible skin	Very frequent (80-99%)
HP:0000978	Bruising susceptibility	Very frequent (80-99%)
HP:0001075	Atrophic scars	Very frequent (80-99%)
HP:0001238	Slender finger	Very frequent (80-99%)
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0001519	Disproportionate tall stature	Very frequent (80-99%)
HP:0001892	Abnormal bleeding	Very frequent (80-99%)
HP:0001933	Subcutaneous hemorrhage	Very frequent (80-99%)
HP:0002194	Delayed gross motor development	Very frequent (80-99%)
HP:0002650	Scoliosis	Very frequent (80-99%)
HP:0002761	Generalized joint laxity	Very frequent (80-99%)
HP:0002804	Arthrogryposis multiplex congenita	Very frequent (80-99%)
HP:0003196	Short nose	Very frequent (80-99%)
HP:0003199	Decreased muscle mass	Very frequent (80-99%)
HP:0003319	Abnormality of the cervical spine	Very frequent (80-99%)
HP:0005272	Prominent nasolabial fold	Very frequent (80-99%)
HP:0006184	Decreased palmar creases	Very frequent (80-99%)
HP:0012534	Dysesthesia	Very frequent (80-99%)
HP:0031869	Recurrent joint dislocation	Very frequent (80-99%)
HP:0000358	Posteriorly rotated ears	Very frequent (80-99%)
HP:0000377	Abnormal pinna morphology	Very frequent (80-99%)
HP:0000308	Microretrognathia	Frequent (30-79%)
HP:0000483	Astigmatism	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000541	Retinal detachment	Frequent (30-79%)
HP:0000545	Myopia	Frequent (30-79%)
HP:0001182	Tapered finger	Frequent (30-79%)
HP:0001581	Recurrent skin infections	Frequent (30-79%)
HP:0001582	Redundant skin	Frequent (30-79%)
HP:0002019	Constipation	Frequent (30-79%)
HP:0002751	Kyphoscoliosis	Frequent (30-79%)
HP:0002947	Cervical kyphosis	Frequent (30-79%)
HP:0003198	Myopathy	Frequent (30-79%)
HP:0007906	Ocular hypertension	Frequent (30-79%)
HP:0430043	Thoracic lordosis	Frequent (30-79%)
HP:0000009	Functional abnormality of the bladder	Occasional (5-29%)
HP:0000126	Hydronephrosis	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Ehlers-Danlos syndrome, musculocontractural type
Mondo ID	MONDO:0011142
MeSH	C000600608
Orphanet	2953
SNOMED CT	720860004
UMLS	C1866294
MedGen	356497
GARD	0008486
Is cancer (heuristic)	no

Also known as: adducted thumb clubfoot syndrome · adducted thumb, clubfoot, and progressive joint and skin laxity syndrome · adducted thumb-club foot syndrome · adducted thumb-clubfoot syndrome · adducted thumbs Dundar type · adducted thumbs-arthrogryposis syndrome, Dundar type · arthrogryposis, distal, with peculiar facies and hydronephrosis · ATCS · autosomal recessive adducted thumb-club foot syndrome · CHST14-related EDS · CHST14-related Ehlers-Danlos syndrome · D4ST1-deficient EDS · D4ST1-deficient Ehlers-Danlos syndrome · Dundar syndrome · EDS, arthrogryposic type · EDS, Kosho type · EDS, musculocontractural type · EDS6B, formerly · EDSMC · EDSMC1 (+8 more)

Data availability: 186 ClinVar variants · 2 GenCC gene-disease records · 1 cell line.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › congenital disorder of glycosylation › Ehlers-Danlos syndrome, musculocontractural type

Related subtypes (24): congenital disorder of glycosylation type I, congenital disorder of glycosylation type II, Larsen-like syndrome, B3GAT3 type, temtamy preaxial brachydactyly syndrome, progressive myoclonic epilepsy type 3, autosomal recessive limb-girdle muscular dystrophy type 2P, seizures-scoliosis-macrocephaly syndrome, disorder of protein N-glycosylation, disorder of protein O-glycosylation, inborn disorder of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation, disorder of multiple glycosylation, XYLT1-congenital disorder of glycosylation, congenital muscular dystrophy with intellectual disability, congenital disorder of glycosylation syndrome type 4, congenital disorder of glycosylation with defective fucosylation, SLC10A7-congenital disorder of glycosylation, ALG14-congenital disorder of glycosylation, B3GALT6-congenital disorder of glycosylation, A4GALT-congenital disorder of glycosylation, FAM20B-congenital disorder of glycosylation, ALG10-congenital disorder of glycosylation, congenital disorder of glycosylation, type Ibb, congenital disorder of glycosylation, type Iw, autosomal dominant, congenital disorder of glycosylation, type 1DD

Subtypes (2): Ehlers-Danlos syndrome, musculocontractural type 2, Ehlers-Danlos syndrome, musculocontractural type 1

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

186 retrieved; paginated sample, class counts are floors:

84 uncertain significance, 62 likely benign, 15 pathogenic, 12 conflicting classifications of pathogenicity, 7 pathogenic/likely pathogenic, 3 benign/likely benign, 2 likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1071798	NM_130468.4(CHST14):c.171del (p.Leu58fs)	CHST14	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1190749	NM_130468.4(CHST14):c.156_166del (p.Ser53fs)	CHST14	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1937598	NM_130468.4(CHST14):c.486G>A (p.Trp162Ter)	CHST14	Pathogenic	criteria provided, single submitter
1949857	NM_130468.4(CHST14):c.264del (p.Lys89fs)	CHST14	Pathogenic	criteria provided, single submitter
1971283	NM_130468.4(CHST14):c.676_682delinsGCTATGGGGCT (p.Lys226fs)	CHST14	Pathogenic	criteria provided, single submitter
2339	NM_130468.4(CHST14):c.878A>G (p.Tyr293Cys)	CHST14	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2340	NM_130468.4(CHST14):c.842C>T (p.Pro281Leu)	CHST14	Pathogenic	criteria provided, single submitter
2758622	NM_130468.4(CHST14):c.783del (p.Glu262fs)	CHST14	Pathogenic	criteria provided, single submitter
2836581	NM_130468.4(CHST14):c.315del (p.Gln106fs)	CHST14	Pathogenic	criteria provided, single submitter
3631461	NM_130468.4(CHST14):c.88del (p.Ala30fs)	CHST14	Pathogenic	criteria provided, single submitter
3672102	NM_130468.4(CHST14):c.201_202del (p.Glu67fs)	CHST14	Pathogenic	criteria provided, single submitter
3727226	NM_130468.4(CHST14):c.494del (p.Val165fs)	CHST14	Pathogenic	criteria provided, single submitter
3896437	NM_130468.4(CHST14):c.181G>T (p.Glu61Ter)	CHST14	Pathogenic	criteria provided, single submitter
422349	NM_130468.4(CHST14):c.755_851del (p.Ser252fs)	CHST14	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
434766	NM_130468.4(CHST14):c.784G>A (p.Glu262Lys)	CHST14	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4613904	NM_130468.4(CHST14):c.610C>T (p.Gln204Ter)	CHST14	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4777340	NM_130468.4(CHST14):c.597dup (p.Arg200fs)	CHST14	Pathogenic	criteria provided, single submitter
4797381	NM_130468.4(CHST14):c.730del (p.Arg244fs)	CHST14	Pathogenic	criteria provided, single submitter
575403	NM_130468.4(CHST14):c.160dup (p.Ser54fs)	CHST14	Pathogenic	criteria provided, single submitter
653458	NM_130468.4(CHST14):c.527_530delinsGACAG (p.Val176fs)	CHST14	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
816708	NM_130468.4(CHST14):c.797dup (p.Tyr266Ter)	CHST14	Pathogenic	criteria provided, single submitter
3653043	NM_130468.4(CHST14):c.53_57del (p.Leu18fs)	LOC130056851	Pathogenic	criteria provided, single submitter
2337	NM_130468.4(CHST14):c.638G>C (p.Arg213Pro)	CHST14	Likely pathogenic	criteria provided, single submitter
432924	NM_130468.4(CHST14):c.958C>T (p.Arg320Ter)	CHST14	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1411929	NM_130468.4(CHST14):c.692G>A (p.Arg231Gln)	CHST14	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2004232	NM_130468.4(CHST14):c.2T>C (p.Met1Thr)	CHST14	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2336	NM_130468.4(CHST14):c.145del (p.Ala48_Val49insTer)	CHST14	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2447077	NM_130468.4(CHST14):c.78T>C (p.Pro26=)	CHST14	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
262313	NM_130468.4(CHST14):c.807T>C (p.Asp269=)	CHST14	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
287372	NM_130468.4(CHST14):c.941G>A (p.Arg314Gln)	CHST14	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · 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
CHST14	Definitive	Autosomal recessive	Ehlers-Danlos syndrome, musculocontractural type 1	5
DSE	Definitive	Autosomal recessive	Ehlers-Danlos syndrome, musculocontractural type 2	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DSE	Orphanet:2953	Musculocontractural Ehlers-Danlos syndrome
CHST14	Orphanet:2953	Musculocontractural Ehlers-Danlos syndrome

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
DSE	HGNC:21144	ENSG00000111817	Q9UL01	Dermatan-sulfate epimerase	gencc,clinvar
CHST14	HGNC:24464	ENSG00000169105	Q8NCH0	Carbohydrate sulfotransferase 14	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DSE	Dermatan-sulfate epimerase	Converts D-glucuronic acid to L-iduronic acid (IdoUA) residues.
CHST14	Carbohydrate sulfotransferase 14	Catalyzes the transfer of sulfate to position 4 of the N-acetylgalactosamine (GalNAc) residue of dermatan sulfate.

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
Enzyme (other)	2	12.0×	0.007

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DSE	Enzyme (other)	yes	5.1.3.19	Chondroitin_lyas, Dermatan-Sulfate_Isomerase
CHST14	Enzyme (other)	yes	2.8.2.35	Sulfotransferase, Carb_sulfotrans_8-10

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
calcaneal tendon	1
germinal epithelium of ovary	1
parietal pleura	1
ileal mucosa	1
stromal cell of endometrium	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DSE	275	ubiquitous	marker	parietal pleura, calcaneal tendon, germinal epithelium of ovary
CHST14	201	ubiquitous	marker	stromal cell of endometrium, ventricular zone, ileal mucosa

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CHST14	837
DSE	467

Intra-cohort edges

A	B	Sources
CHST14	DSE	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DSE	Q9UL01	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CHST14	Q8NCH0	84.17

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
DS-GAG biosynthesis	2	951.7×	2e-06	DSE, CHST14
Defective CHST14 causes EDS, musculocontractural type	1	713.8×	0.001	CHST14

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
dermatan sulfate proteoglycan metabolic process	2	5617.3×	1e-07	DSE, CHST14
dermatan sulfate proteoglycan biosynthetic process	2	1685.2×	8e-07	DSE, CHST14
chondroitin sulfate proteoglycan metabolic process	1	2106.5×	8e-04	DSE
carbohydrate biosynthetic process	1	766.0×	0.002	CHST14
heparan sulfate proteoglycan biosynthetic process	1	280.9×	0.004	DSE

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
DSE	0	0
CHST14	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
CHST14	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DSE	5.1.3.19	chondroitin-glucuronate 5-epimerase
CHST14	2.8.2.35	dermatan 4-sulfotransferase

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	1	DSE
D	Druggable family + AlphaFold only, no drug	1	CHST14
E	Difficult family or no structure, no drug	0

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)
DSE	0	—
CHST14	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.