Multiple epiphyseal dysplasia type 4

Summary

Multiple epiphyseal dysplasia type 4 (MONDO:0009189) is a disease caused by SLC26A2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: SLC26A2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 763
• Phenotypes (HPO): 58

Clinical features

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0002652	Skeletal dysplasia	Very frequent (80-99%)
HP:0002654	Multiple epiphyseal dysplasia	Very frequent (80-99%)
HP:0002829	Arthralgia	Very frequent (80-99%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0001156	Brachydactyly	Frequent (30-79%)
HP:0001371	Flexion contracture	Frequent (30-79%)
HP:0001376	Limitation of joint mobility	Frequent (30-79%)
HP:0001387	Joint stiffness	Frequent (30-79%)
HP:0001762	Talipes equinovarus	Frequent (30-79%)
HP:0001776	Bilateral talipes equinovarus	Frequent (30-79%)
HP:0002515	Waddling gait	Frequent (30-79%)
HP:0002812	Coxa vara	Frequent (30-79%)
HP:0002857	Genu valgum	Frequent (30-79%)
HP:0002987	Elbow flexion contracture	Frequent (30-79%)
HP:0003071	Flattened epiphysis	Frequent (30-79%)
HP:0003088	Premature osteoarthritis	Frequent (30-79%)
HP:0003365	Arthralgia of the hip	Frequent (30-79%)
HP:0003498	Disproportionate short stature	Frequent (30-79%)
HP:0005616	Accelerated skeletal maturation	Frequent (30-79%)
HP:0008807	Acetabular dysplasia	Frequent (30-79%)
HP:0008848	Moderately short stature	Frequent (30-79%)
HP:0009824	Upper limb undergrowth	Frequent (30-79%)
HP:0030289	Flattened femoral epiphysis	Frequent (30-79%)
HP:0031174	Double-layered patella	Frequent (30-79%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000363	Abnormality of earlobe	Occasional (5-29%)
HP:0000369	Low-set ears	Occasional (5-29%)
HP:0000377	Abnormal pinna morphology	Occasional (5-29%)
HP:0001385	Hip dysplasia	Occasional (5-29%)
HP:0001440	Metatarsal synostosis	Occasional (5-29%)
HP:0001769	Broad foot	Occasional (5-29%)
HP:0001831	Short toe	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002947	Cervical kyphosis	Occasional (5-29%)
HP:0002986	Radial bowing	Occasional (5-29%)
HP:0003016	Metaphyseal widening	Occasional (5-29%)
HP:0003031	Ulnar bowing	Occasional (5-29%)
HP:0004002	Flattened radial epiphyses	Occasional (5-29%)
HP:0004037	Abnormality of the ulnar epiphyses	Occasional (5-29%)
HP:0005922	Abnormal hand morphology	Occasional (5-29%)
HP:0006429	Broad femoral neck	Occasional (5-29%)
HP:0008434	Hypoplastic cervical vertebrae	Occasional (5-29%)
HP:0008829	Delayed femoral head ossification	Occasional (5-29%)
HP:0008905	Rhizomelia	Occasional (5-29%)
HP:0009381	Short finger	Occasional (5-29%)
HP:0009471	Contracture of the proximal interphalangeal joint of the 3rd finger	Occasional (5-29%)
HP:0009487	Ulnar deviation of the hand	Occasional (5-29%)
HP:0009778	Short thumb	Occasional (5-29%)
HP:0010049	Short metacarpal	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple epiphyseal dysplasia type 4
Mondo ID	MONDO:0009189
MeSH	C535504
OMIM	226900
Orphanet	93307
DOID	DOID:0070300
ICD-11	1927114777
SNOMED CT	715672007
UMLS	C1847593
MedGen	376164
GARD	0009793
NORD	1881
Is cancer (heuristic)	no

Also known as: autosomal recessive multiple epiphyseal dysplasia · EDM4 · epiphyseal dysplasia multiple 4 · epiphyseal dysplasia, multiple, 4 · epiphyseal dysplasia, multiple, type 4 · MED4 · multiple epiphyseal dysplasia (disease) caused by mutation in SLC26A2 · multiple epiphyseal dysplasia 4 · multiple epiphyseal dysplasia with double-layered patella · Polyepiphyseal dysplasia type 4 · Recessive Multiple Epiphyseal Dysplasia · rMED · SLC26A2 multiple epiphyseal dysplasia (disease)

Data availability: 763 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › mineral metabolism disease › multiple epiphyseal dysplasia type 4

Related subtypes (12): iron metabolism disease, phosphorus metabolism disease, potassium deficiency disease, calcium metabolic disease, spondyloepiphyseal dysplasia with congenital joint dislocations, diastrophic dysplasia, atelosteogenesis type II, achondrogenesis type IB, chondrodysplasia with joint dislocations, gPAPP type, spondyloepimetaphyseal dysplasia, PAPSS2 type, acquired mineral metabolism disease, sulfur metabolism disease

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:

250 likely benign, 170 uncertain significance, 59 pathogenic, 37 conflicting classifications of pathogenicity, 35 pathogenic/likely pathogenic, 26 likely pathogenic, 12 benign/likely benign, 11 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3780616	NC_000007.14:g.149663085_149663087del		Pathogenic	criteria provided, single submitter
1067905	NM_000112.4(SLC26A2):c.2065_2066del (p.Thr689fs)	SLC26A2	Pathogenic	criteria provided, single submitter
1070109	NM_000112.4(SLC26A2):c.1714del (p.Leu572fs)	SLC26A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070678	NM_000112.4(SLC26A2):c.1441dup (p.Ser481fs)	SLC26A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071456	NM_000112.4(SLC26A2):c.1246C>T (p.Gln416Ter)	SLC26A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1285445	NM_000112.4(SLC26A2):c.1994dup (p.His665fs)	SLC26A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1326262	NM_000112.4(SLC26A2):c.796dup (p.Thr266fs)	SLC26A2	Pathogenic	criteria provided, single submitter
1374813	NM_000112.4(SLC26A2):c.1203_1204insTTTTTTTTTTTTTTTTTTTNNNNNNNNNNGACGGGGTTTCACCTTGTTAGCCAGGATGGTCTCGATCTCCTGACCTCATGATCCACCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCATTTTCT (p.Glu402delinsPhePhePhePhePhePheXaaXaaXaaXaaThrGlyPheHisLeuValSerGlnAspGlyLeuAspLeuLeuThrSerTer)	SLC26A2	Pathogenic	criteria provided, single submitter
1378416	NM_000112.4(SLC26A2):c.1397dup (p.Leu466fs)	SLC26A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1388388	NM_000112.4(SLC26A2):c.1810_1811del (p.Val604fs)	SLC26A2	Pathogenic	criteria provided, single submitter
1402115	NM_000112.4(SLC26A2):c.1393_1394del (p.Leu465fs)	SLC26A2	Pathogenic	criteria provided, single submitter
1412823	NM_000112.4(SLC26A2):c.1592del (p.Leu531fs)	SLC26A2	Pathogenic	criteria provided, single submitter
1419742	NM_000112.4(SLC26A2):c.2004_2007del (p.Glu669fs)	SLC26A2	Pathogenic	criteria provided, single submitter
1436633	NM_000112.4(SLC26A2):c.1155del (p.Asp385fs)	SLC26A2	Pathogenic	criteria provided, single submitter
1452842	NM_000112.4(SLC26A2):c.1147_1150del (p.Val382_Ala383insTer)	SLC26A2	Pathogenic	criteria provided, single submitter
1452846	NM_000112.4(SLC26A2):c.1772del (p.Asn591fs)	SLC26A2	Pathogenic	criteria provided, single submitter
1453452	NM_000112.4(SLC26A2):c.100del (p.Glu34fs)	SLC26A2	Pathogenic	criteria provided, multiple submitters, no conflicts
1453498	NM_000112.4(SLC26A2):c.58_62dup (p.Asp21fs)	SLC26A2	Pathogenic	criteria provided, single submitter
1453606	NM_000112.4(SLC26A2):c.218del (p.Lys73fs)	SLC26A2	Pathogenic	criteria provided, multiple submitters, no conflicts
1453912	NM_000112.4(SLC26A2):c.1720del (p.Ile574fs)	SLC26A2	Pathogenic	criteria provided, single submitter
1454165	NM_000112.4(SLC26A2):c.78_88dup (p.Glu30fs)	SLC26A2	Pathogenic	criteria provided, single submitter
1456395	NM_000112.4(SLC26A2):c.1272dup (p.Asn425Ter)	SLC26A2	Pathogenic	criteria provided, single submitter
1456546	NM_000112.4(SLC26A2):c.1306del (p.Thr436fs)	SLC26A2	Pathogenic	criteria provided, single submitter
1456961	NM_000112.4(SLC26A2):c.1064_1065insAAAAA (p.Asn355fs)	SLC26A2	Pathogenic	criteria provided, single submitter
1458581	NM_000112.4(SLC26A2):c.1639C>T (p.Gln547Ter)	SLC26A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1683435	NM_000112.4(SLC26A2):c.306C>G (p.Tyr102Ter)	SLC26A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1702483	NM_000112.4(SLC26A2):c.1487_1488insGGCG (p.Lys497fs)	SLC26A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189077	NM_000112.4(SLC26A2):c.451del (p.Tyr151fs)	SLC26A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1995802	NM_000112.4(SLC26A2):c.909T>A (p.Cys303Ter)	SLC26A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1999769	NM_000112.4(SLC26A2):c.2095del (p.Tyr699fs)	SLC26A2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · 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
SLC26A2	Definitive	Autosomal recessive	SLC26A2-related skeletal dysplasia	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC26A2	Orphanet:56304	Atelosteogenesis type II
SLC26A2	Orphanet:628	Diastrophic dysplasia
SLC26A2	Orphanet:93298	Achondrogenesis type 1B
SLC26A2	Orphanet:93307	Multiple epiphyseal dysplasia type 4

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC26A2	HGNC:10994	ENSG00000155850	P50443	Sulfate transporter	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC26A2	Sulfate transporter	Sulfate transporter which mediates sulfate uptake into chondrocytes in order to maintain adequate sulfation of proteoglycans which is needed for cartilage development.

Protein-family classification

Druggable: 1 · 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
Transporter	1	77.8×	0.013

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC26A2	Transporter	yes		SLC26A/SulP_fam, STAS_dom, SLC26A/SulP_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
colonic mucosa	1
mucosa of sigmoid colon	1
mucosa of transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC26A2	282	ubiquitous	marker	colonic mucosa, mucosa of sigmoid colon, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC26A2	1,793

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC26A2	P50443	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC26A2 causes chondrodysplasias	1	11420.0×	0.002	SLC26A2
Transport and metabolism of PAPS	1	1631.4×	0.005	SLC26A2
Inorganic anion exchange by SLC26 transporters	1	1268.9×	0.005	SLC26A2
Diseases associated with glycosaminoglycan metabolism	1	761.3×	0.006	SLC26A2
Cytosolic sulfonation of small molecules	1	519.1×	0.007	SLC26A2
Phase II - Conjugation of compounds	1	278.5×	0.011	SLC26A2
Glycosaminoglycan metabolism	1	219.6×	0.011	SLC26A2
SLC transporter disorders	1	203.9×	0.011	SLC26A2
Disorders of transmembrane transporters	1	139.3×	0.012	SLC26A2
Diseases of glycosylation	1	131.3×	0.012	SLC26A2
Biological oxidations	1	129.8×	0.012	SLC26A2
R-HSA-425393	1	129.8×	0.012	SLC26A2
Metabolism of carbohydrates and carbohydrate derivatives	1	120.2×	0.012	SLC26A2
Diseases of metabolism	1	80.4×	0.016	SLC26A2
SLC-mediated transmembrane transport	1	59.2×	0.020	SLC26A2
Transport of small molecules	1	25.1×	0.045	SLC26A2
Disease	1	13.1×	0.081	SLC26A2
Metabolism	1	11.6×	0.086	SLC26A2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
oxalate transport	1	2407.4×	0.002	SLC26A2
sulfate transmembrane transport	1	1203.7×	0.002	SLC26A2
chondrocyte proliferation	1	1053.2×	0.002	SLC26A2
chondrocyte differentiation	1	300.9×	0.004	SLC26A2
chloride transmembrane transport	1	237.3×	0.004	SLC26A2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
SLC26A2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	SLC26A2
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)
SLC26A2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.