Spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome

Summary

Spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome (MONDO:0010077) is a disease caused by DDR2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DDR2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 74

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		27	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome
Mondo ID	MONDO:0010077
MeSH	C564794
OMIM	271665
Orphanet	93358
DOID	DOID:0112196
UMLS	C1849011
MedGen	338595
GARD	0010616
Is cancer (heuristic)	no

Also known as: Smed short limb-abnormal calcification type · SMED short limb-hand type · SMED type 2 · spondyloepimetaphyseal dysplasia - short limb - abnormal calcification · spondylometaepiphyseal dysplasia short limb-abnormal calcification type · spondylometaepiphyseal dysplasia short limb-hand type

Data availability: 74 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › osteochondrodysplasia › spondyloepimetaphyseal dysplasia › spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome

Related subtypes (22): spondyloepimetaphyseal dysplasia-hypotrichosis syndrome, spondyloepimetaphyseal dysplasia, Maroteaux type, spondyloepimetaphyseal dysplasia, Strudwick type, spondyloepimetaphyseal dysplasia, sponastrime type, spondyloepimetaphyseal dysplasia, Irapa type, spondyloepimetaphyseal dysplasia, Bieganski type, spondyloepimetaphyseal dysplasia-abnormal dentition syndrome, spondyloepimetaphyseal dysplasia, Missouri type, spondyloepimetaphyseal dysplasia, Shohat type, spondyloepimetaphyseal dysplasia, matrilin-3 type, spondyloepimetaphyseal dysplasia, Genevieve type, spondyloepimetaphyseal dysplasia, aggrecan type, spondyloepimetaphyseal dysplasia, Handigodu type, spondyloepimetaphyseal dysplasia, Isidor type, spondyloepimetaphyseal dysplasia, PAPSS2 type, spondyloepimetaphyseal dysplasia with joint laxity, spondyloepimetaphyseal dysplasia, Krakow type, spondyloepimetaphyseal dysplasia, Isidor-Toutain type, spondyloepimetaphyseal dysplasia, di rocco type, COL2A1-related spondyloepiphyseal dysplasia, spondyloepimetaphyseal dysplasia, Guo-Campeau type, spondyloepimetaphyseal dysplasia, Li-Shao-Li 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

74 retrieved; paginated sample, class counts are floors:

39 uncertain significance, 20 conflicting classifications of pathogenicity, 5 pathogenic, 4 likely pathogenic, 4 benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
12314	NM_006182.4(DDR2):c.2177T>G (p.Ile726Arg)	DDR2	Pathogenic	no assertion criteria provided
12315	NM_006182.4(DDR2):c.2138C>T (p.Thr713Ile)	DDR2	Pathogenic	no assertion criteria provided
12316	NM_006182.4(DDR2):c.2283+1G>A	DDR2	Pathogenic	no assertion criteria provided
60759	NM_006182.4(DDR2):c.337G>A (p.Glu113Lys)	DDR2	Pathogenic	criteria provided, single submitter
915984	GRCh37/hg19 1q23.3(chr1:162748370-162748520)	DDR2	Pathogenic	no assertion criteria provided
12313	NM_006182.4(DDR2):c.2254C>T (p.Arg752Cys)	DDR2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1342148	NM_006182.4(DDR2):c.2323G>T (p.Val775Phe)	DDR2	Likely pathogenic	no assertion criteria provided
3906889	NM_006182.4(DDR2):c.2416C>T (p.Arg806Ter)	DDR2	Likely pathogenic	criteria provided, single submitter
4076974	NM_006182.4(DDR2):c.415C>T (p.Gln139Ter)	DDR2	Likely pathogenic	no assertion criteria provided
197782	NM_006182.4(DDR2):c.408T>C (p.His136=)	DDR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
198839	NM_006182.4(DDR2):c.720C>T (p.Asp240=)	DDR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
259933	NM_006182.4(DDR2):c.2481G>T (p.Leu827=)	DDR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
259934	NM_006182.4(DDR2):c.510C>T (p.Thr170=)	DDR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
259935	NM_006182.4(DDR2):c.699C>T (p.Thr233=)	DDR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293376	NM_006182.4(DDR2):c.932G>A (p.Ser311Asn)	DDR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293380	NM_006182.4(DDR2):c.2068A>G (p.Met690Val)	DDR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293382	NM_006182.4(DDR2):c.2253C>T (p.Ile751=)	DDR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3067931	NM_006182.4(DDR2):c.2516G>A (p.Arg839His)	DDR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
501659	NM_006182.4(DDR2):c.1509C>T (p.Cys503=)	DDR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
587431	NM_006182.4(DDR2):c.508A>T (p.Thr170Ser)	DDR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
719940	NM_006182.4(DDR2):c.2031C>T (p.Ser677=)	DDR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
733146	NM_006182.4(DDR2):c.243T>C (p.Asp81=)	DDR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
811602	NM_006182.4(DDR2):c.1323G>A (p.Met441Ile)	DDR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
873757	NM_006182.4(DDR2):c.421C>T (p.Leu141=)	DDR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
874710	NM_006182.4(DDR2):c.549C>T (p.Tyr183=)	DDR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
874711	NM_006182.4(DDR2):c.672-9C>A	DDR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
875649	NM_006182.4(DDR2):c.978C>T (p.Asp326=)	DDR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
875650	NM_006182.4(DDR2):c.1099+12A>C	DDR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
875651	NM_006182.4(DDR2):c.1389T>C (p.Ser463=)	DDR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031024	NM_006182.4(DDR2):c.833T>A (p.Ile278Asn)	DDR2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 1 · 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
DDR2	Definitive	Autosomal recessive	spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DDR2	Orphanet:93358	Spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome

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
DDR2	HGNC:2731	ENSG00000162733	Q16832	Discoidin domain-containing receptor 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DDR2	Discoidin domain-containing receptor 2	Tyrosine kinase involved in the regulation of tissues remodeling.

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DDR2	Kinase	yes	2.7.10.1	FA58C, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_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
cauda epididymis	1
tendon of biceps brachii	1
vena cava	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DDR2	270	ubiquitous	marker	cauda epididymis, tendon of biceps brachii, vena cava

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DDR2	1,575

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DDR2	Q16832	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Non-integrin membrane-ECM interactions	1	154.3×	0.006	DDR2

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
positive regulation of hepatic stellate cell proliferation	1	5617.3×	0.003	DDR2
negative regulation of hydrogen peroxide-mediated programmed cell death	1	4213.0×	0.003	DDR2
regulation of extracellular matrix disassembly	1	3370.4×	0.003	DDR2
positive regulation of hepatic stellate cell activation	1	2808.7×	0.003	DDR2
regulation of tissue remodeling	1	2106.5×	0.003	DDR2
endochondral bone growth	1	1685.2×	0.003	DDR2
collagen-activated tyrosine kinase receptor signaling pathway	1	1296.3×	0.003	DDR2
positive regulation of extracellular matrix disassembly	1	1203.7×	0.003	DDR2
positive regulation of fibroblast migration	1	1123.5×	0.003	DDR2
chondrocyte proliferation	1	1053.2×	0.003	DDR2
positive regulation of vascular associated smooth muscle cell migration	1	991.3×	0.003	DDR2
cellular response to angiotensin	1	936.2×	0.003	DDR2
response to muscle stretch	1	766.0×	0.003	DDR2
regulation of bone mineralization	1	732.7×	0.003	DDR2
positive regulation of protein kinase activity	1	674.1×	0.003	DDR2
biomineral tissue development	1	648.1×	0.003	DDR2
positive regulation of collagen biosynthetic process	1	648.1×	0.003	DDR2
obsolete positive regulation of DNA-binding transcription factor activity	1	601.9×	0.003	DDR2
positive regulation of wound healing	1	526.6×	0.004	DDR2
positive regulation of vascular associated smooth muscle cell proliferation	1	432.1×	0.004	DDR2
peptidyl-tyrosine phosphorylation	1	421.3×	0.004	DDR2
positive regulation of G1/S transition of mitotic cell cycle	1	401.2×	0.004	DDR2
positive regulation of fibroblast proliferation	1	295.6×	0.005	DDR2
cellular response to transforming growth factor beta stimulus	1	276.3×	0.005	DDR2
ossification	1	227.7×	0.006	DDR2
collagen fibril organization	1	224.7×	0.006	DDR2
positive regulation of osteoblast differentiation	1	224.7×	0.006	DDR2
cell surface receptor protein tyrosine kinase signaling pathway	1	173.7×	0.007	DDR2
protein autophosphorylation	1	145.3×	0.009	DDR2
positive regulation of neuron projection development	1	137.0×	0.009	DDR2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
DDR2	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DDR2	59	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	DDR2
FEDRATINIB	4	DDR2
TIVOZANIB	4	DDR2
LENVATINIB	4	DDR2
AXITINIB	4	DDR2
SORAFENIB	4	DDR2
DASATINIB ANHYDROUS	4	DDR2
DACTINOMYCIN	4	DDR2
REGORAFENIB	4	DDR2
CABOZANTINIB	4	DDR2
VANDETANIB	4	DDR2
NILOTINIB	4	DDR2
BOSUTINIB	4	DDR2
TOVORAFENIB	4	DDR2
PAZOPANIB	4	DDR2
NINTEDANIB	4	DDR2
SUNITINIB	4	DDR2
DASATINIB	4	DDR2
QUIZARTINIB	4	DDR2
IMATINIB	4	DDR2
MASITINIB	3	DDR2
SARACATINIB	3	DDR2
LINIFANIB	3	DDR2
TESEVATINIB	3	DDR2
NAPORAFENIB	3	DDR2
CEDIRANIB	3	DDR2
DOVITINIB	3	DDR2
LESTAURTINIB	3	DDR2
DORAMAPIMOD	2	DDR2
FORETINIB	2	DDR2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DDR2	389	Binding:386, ADMET:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DDR2	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
DDR2	389

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

30 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)
PONATINIB	4	DDR2
FEDRATINIB	4	DDR2
TIVOZANIB	4	DDR2
LENVATINIB	4	DDR2
AXITINIB	4	DDR2
SORAFENIB	4	DDR2
DASATINIB ANHYDROUS	4	DDR2
DACTINOMYCIN	4	DDR2
REGORAFENIB	4	DDR2
CABOZANTINIB	4	DDR2
VANDETANIB	4	DDR2
NILOTINIB	4	DDR2
BOSUTINIB	4	DDR2
TOVORAFENIB	4	DDR2
PAZOPANIB	4	DDR2
NINTEDANIB	4	DDR2
SUNITINIB	4	DDR2
DASATINIB	4	DDR2
QUIZARTINIB	4	DDR2
IMATINIB	4	DDR2
MASITINIB	3	DDR2
SARACATINIB	3	DDR2
LINIFANIB	3	DDR2
TESEVATINIB	3	DDR2
NAPORAFENIB	3	DDR2
CEDIRANIB	3	DDR2
DOVITINIB	3	DDR2
LESTAURTINIB	3	DDR2
DORAMAPIMOD	2	DDR2
FORETINIB	2	DDR2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	DDR2
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.