X-linked spondyloepimetaphyseal dysplasia

Summary

X-linked spondyloepimetaphyseal dysplasia (MONDO:0010248) is a disease caused by BGN (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: BGN (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 22

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked spondyloepimetaphyseal dysplasia
Mondo ID	MONDO:0010248
MeSH	C564714
OMIM	300106
Orphanet	93349
DOID	DOID:0112150
UMLS	C1848097
MedGen	376281
GARD	0004979
Is cancer (heuristic)	no

Also known as: SEMD X-linked · SEMDX · spondylo-epimetaphyseal dysplasia · spondyloepimetaphyseal dysplasia X-linked · spondyloepimetaphyseal dysplasia, X-linked · spondyloepimetaphyseal dysplasia, X-linked, X-linked recessive

Data availability: 22 ClinVar variants · 5 GenCC gene-disease records · 2 cell lines.

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 › spondyloepiphyseal dysplasia › X-linked spondyloepimetaphyseal dysplasia

Related subtypes (43): hip dysplasia, Beukes type, spondyloepiphyseal dysplasia with congenital joint dislocations, Marshall syndrome, metatropic dysplasia, spondyloepiphyseal dysplasia with punctate corneal dystrophy, spondyloepiphyseal dysplasia, MacDermot type, progressive pseudorheumatoid arthropathy of childhood, otospondylomegaepiphyseal dysplasia, Dyggve-Melchior-Clausen disease, dyssegmental dysplasia, Rolland-Desbuquois type, Silverman-Handmaker type dyssegmental dysplasia, Wolcott-Rallison syndrome, Schimke immuno-osseous dysplasia, Richieri Costa-da Silva syndrome, Schwartz-Jampel syndrome, CODAS syndrome, spondyloepiphyseal dysplasia, Reardon type, brachyolmia-amelogenesis imperfecta syndrome, spondyloepiphyseal dysplasia with coronal craniosynostosis, cataracts, cleft palate, and intellectual disability, anauxetic dysplasia, spondyloepiphyseal dysplasia, Kimberley type, spondyloepiphyseal dysplasia, Cantu type, Ehlers-Danlos syndrome, spondylocheirodysplastic type, spondylo-megaepiphyseal-metaphyseal dysplasia, brachydactylous dwarfism, Mseleni type, TMEM165-congenital disorder of glycosylation, Steel syndrome, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, Roifman syndrome, progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome, even-plus syndrome, Smith-McCort dysplasia, cono-spondylar dysplasia, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, Stickler syndrome, spondyloepiphyseal dysplasia tarda, spondyloepiphyseal dysplasia, kondo-fu type, spondyloepiphyseal dysplasia, nishimura type, immunoskeletal dysplasia with neurodevelopmental abnormalities, COL2A1-related spondyloepiphyseal dysplasia, MIR140-related spondyloepiphyseal dysplasia, MGP-related spondyloepiphyseal dysplasia, spondyloepiphyseal dysplasia, Holling 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

22 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 5 benign, 2 benign/likely benign, 2 pathogenic, 2 likely pathogenic, 1 pathogenic/likely pathogenic, 1 likely benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
11299	NM_000033.4(ABCD1):c.796G>A (p.Gly266Arg)	ABCD1	Pathogenic	criteria provided, multiple submitters, no conflicts
11307	NM_000033.4(ABCD1):c.1552C>T (p.Arg518Trp)	ABCD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
243090	NM_001711.6(BGN):c.439A>G (p.Lys147Glu)	BGN	Pathogenic	no assertion criteria provided
1723874	NM_001711.6(BGN):c.441G>C (p.Lys147Asn)	BGN	Likely pathogenic	criteria provided, single submitter
243091	NM_001711.6(BGN):c.776G>T (p.Gly259Val)	BGN	Likely pathogenic	criteria provided, single submitter
265798	NM_001711.6(BGN):c.238G>A (p.Gly80Ser)	BGN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029523	NM_001711.6(BGN):c.645C>G (p.Ile215Met)	BGN	Uncertain significance	criteria provided, single submitter
1033440	NM_001711.6(BGN):c.17G>A (p.Arg6His)	BGN	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033441	NM_001711.6(BGN):c.682C>T (p.Pro228Ser)	BGN	Uncertain significance	criteria provided, single submitter
1675114	NM_001711.6(BGN):c.955G>A (p.Asp319Asn)	BGN	Uncertain significance	criteria provided, single submitter
3366963	NM_001711.6(BGN):c.640C>T (p.Arg214Cys)	BGN	Uncertain significance	criteria provided, multiple submitters, no conflicts
3598158	NM_001711.6(BGN):c.185T>C (p.Met62Thr)	BGN	Uncertain significance	criteria provided, multiple submitters, no conflicts
3602591	NM_001711.6(BGN):c.206G>A (p.Cys69Tyr)	BGN	Uncertain significance	criteria provided, single submitter
4292882	NM_001711.6(BGN):c.769A>T (p.Arg257Trp)	BGN	Uncertain significance	criteria provided, single submitter
1098726	NM_001711.6(BGN):c.257A>G (p.Lys86Arg)	BGN	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1165870	NM_001711.6(BGN):c.141G>A (p.Ser47=)	BGN	Benign	criteria provided, multiple submitters, no conflicts
1166521	NM_001711.6(BGN):c.540C>T (p.Ser180=)	BGN	Benign	criteria provided, multiple submitters, no conflicts
1192382	NM_001711.6(BGN):c.238+75A>G	BGN	Benign	criteria provided, multiple submitters, no conflicts
1192383	NM_001711.6(BGN):c.771-32C>T	BGN	Benign	criteria provided, multiple submitters, no conflicts
1192384	NM_001711.6(BGN):c.909+115T>C	BGN	Benign	criteria provided, multiple submitters, no conflicts
1316894	NM_001711.6(BGN):c.954C>T (p.Asn318=)	BGN	Likely benign	criteria provided, multiple submitters, no conflicts
774542	NM_001711.6(BGN):c.111C>T (p.Asn37=)	BGN	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 6 · 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
BGN	Strong	X-linked	X-linked spondyloepimetaphyseal dysplasia	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BGN	Orphanet:622925	X-linked severe syndromic thoracic aortic aneurysm and dissection
BGN	Orphanet:93349	X-linked spondyloepimetaphyseal dysplasia
ABCD1	Orphanet:139396	X-linked cerebral adrenoleukodystrophy
ABCD1	Orphanet:139399	Adrenomyeloneuropathy
ABCD1	Orphanet:369942	CADDS
ABCD1	Orphanet:388	Hirschsprung disease

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
BGN	HGNC:1044	ENSG00000182492	P21810	Biglycan	gencc,clinvar
ABCD1	HGNC:61	ENSG00000101986	P33897	ATP-binding cassette sub-family D member 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BGN	Biglycan	May be involved in collagen fiber assembly.
ABCD1	ATP-binding cassette sub-family D member 1	ATP-dependent transporter of the ATP-binding cassette (ABC) family involved in the transport of very long chain fatty acid (VLCFA)-CoA from the cytosol to the peroxisome lumen.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	38.9×	0.051
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BGN	Other/Unknown	no		LRRNT, Leu-rich_rpt, Leu-rich_rpt_typical-subtyp
ABCD1	Transporter	yes	7.6.2.4	ABC_transporter-like_ATP-bd, AAA+_ATPase, FA_transporter

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
ascending aorta	1
descending thoracic aorta	1
thoracic aorta	1
ileal mucosa	1
left adrenal gland	1
left adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BGN	264	ubiquitous	marker	descending thoracic aorta, ascending aorta, thoracic aorta
ABCD1	201	ubiquitous	marker	ileal mucosa, left adrenal gland cortex, left adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCD1	1,181
BGN	64

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCD1	P33897	14

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BGN	P21810	85.72

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 28. 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 ABCD1 causes ALD	1	2855.0×	0.006	ABCD1
alpha-linolenic (omega3) and linoleic (omega6) acid metabolism	1	951.7×	0.006	ABCD1
Defective CHST3 causes SEDCJD	1	713.8×	0.006	BGN
Defective CHST14 causes EDS, musculocontractural type	1	713.8×	0.006	BGN
Defective CHSY1 causes TPBS	1	713.8×	0.006	BGN
Linoleic acid (LA) metabolism	1	571.0×	0.006	ABCD1
DS-GAG biosynthesis	1	475.8×	0.006	BGN
Beta-oxidation of very long chain fatty acids	1	439.2×	0.006	ABCD1
alpha-linolenic acid (ALA) metabolism	1	356.9×	0.006	ABCD1
Peroxisomal lipid metabolism	1	335.9×	0.006	ABCD1
ABC transporters in lipid homeostasis	1	300.5×	0.006	ABCD1
Defective B4GALT7 causes EDS, progeroid type	1	285.5×	0.006	BGN
Defective B3GAT3 causes JDSSDHD	1	285.5×	0.006	BGN
Defective B3GALT6 causes EDSP2 and SEMDJL1	1	285.5×	0.006	BGN
CS-GAG biosynthesis	1	271.9×	0.006	BGN
CS/DS degradation	1	271.9×	0.006	BGN
Class I peroxisomal membrane protein import	1	259.6×	0.006	ABCD1
ABC transporter disorders	1	219.6×	0.007	ABCD1
Glycosaminoglycan-protein linkage region biosynthesis	1	196.9×	0.007	BGN
Protein localization	1	95.2×	0.015	ABCD1
ECM proteoglycans	1	75.1×	0.018	BGN
Disorders of transmembrane transporters	1	69.6×	0.018	ABCD1
Fatty acid metabolism	1	65.6×	0.018	ABCD1
ABC-family protein mediated transport	1	60.7×	0.019	ABCD1
Metabolism of lipids	1	15.8×	0.070	ABCD1
Transport of small molecules	1	12.6×	0.084	ABCD1
Disease	1	6.5×	0.152	ABCD1
Metabolism	1	5.8×	0.165	ABCD1

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
peroxisomal membrane transport	1	4213.0×	0.002	ABCD1
very long-chain fatty-acyl-CoA catabolic process	1	4213.0×	0.002	ABCD1
positive regulation of unsaturated fatty acid biosynthetic process	1	2808.7×	0.002	ABCD1
sterol homeostasis	1	2106.5×	0.002	ABCD1
long-chain fatty acid import into peroxisome	1	1685.2×	0.002	ABCD1
regulation of fatty acid beta-oxidation	1	1404.3×	0.002	ABCD1
long-chain fatty acid catabolic process	1	1404.3×	0.002	ABCD1
myelin maintenance	1	1404.3×	0.002	ABCD1
regulation of mitochondrial depolarization	1	1404.3×	0.002	ABCD1
fatty acid elongation	1	1203.7×	0.002	ABCD1
very long-chain fatty acid catabolic process	1	1203.7×	0.002	ABCD1
articular cartilage development	1	1203.7×	0.002	BGN
positive regulation of fatty acid beta-oxidation	1	766.0×	0.003	ABCD1
fatty acid derivative biosynthetic process	1	766.0×	0.003	ABCD1
regulation of cellular response to oxidative stress	1	648.1×	0.003	ABCD1
regulation of oxidative phosphorylation	1	601.9×	0.003	ABCD1
neuron projection maintenance	1	561.7×	0.003	ABCD1
negative regulation of reactive oxygen species biosynthetic process	1	495.6×	0.003	ABCD1
fatty acid homeostasis	1	468.1×	0.003	ABCD1
alpha-linolenic acid metabolic process	1	443.5×	0.003	ABCD1
peroxisome organization	1	401.2×	0.003	ABCD1
very long-chain fatty acid metabolic process	1	383.0×	0.003	ABCD1
linoleic acid metabolic process	1	351.1×	0.004	ABCD1
unsaturated fatty acid biosynthetic process	1	324.1×	0.004	ABCD1
long-chain fatty acid biosynthetic process	1	221.7×	0.005	ABCD1
negative regulation of cytokine production involved in inflammatory response	1	210.7×	0.005	ABCD1
blood vessel remodeling	1	191.5×	0.006	BGN
fatty acid beta-oxidation	1	187.2×	0.006	ABCD1
bone development	1	138.1×	0.007	BGN

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
BGN	0	0
ABCD1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ABCD1	7.6.2.4	ABC-type fatty-acyl-CoA transporter

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	ABCD1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	BGN

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)
BGN	0	—
ABCD1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.