spondylometaphyseal dysplasia, Sedaghatian type

Summary

spondylometaphyseal dysplasia, Sedaghatian type (MONDO:0009593) is a disease caused by GPX4 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GPX4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 10
• Phenotypes (HPO): 25

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		9	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0000772	Abnormal rib morphology	Very frequent (80-99%)
HP:0000782	Abnormality of the scapula	Very frequent (80-99%)
HP:0000926	Platyspondyly	Very frequent (80-99%)
HP:0001678	Atrioventricular block	Very frequent (80-99%)
HP:0002657	Spondylometaphyseal dysplasia	Very frequent (80-99%)
HP:0002750	Delayed skeletal maturation	Very frequent (80-99%)
HP:0003085	Long fibula	Very frequent (80-99%)
HP:0003498	Disproportionate short stature	Very frequent (80-99%)
HP:0004279	Short palm	Very frequent (80-99%)
HP:0004991	Rhizomelic arm shortening	Very frequent (80-99%)
HP:0005871	Metaphyseal chondrodysplasia	Very frequent (80-99%)
HP:0006543	Cardiorespiratory arrest	Very frequent (80-99%)
HP:0008786	Iliac crest serration	Very frequent (80-99%)
HP:0010049	Short metacarpal	Very frequent (80-99%)
HP:0011675	Arrhythmia	Very frequent (80-99%)
HP:0000262	Turricephaly	Frequent (30-79%)
HP:0000774	Narrow chest	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001321	Cerebellar hypoplasia	Frequent (30-79%)
HP:0002093	Respiratory insufficiency	Frequent (30-79%)
HP:0001274	Agenesis of corpus callosum	Occasional (5-29%)
HP:0001302	Pachygyria	Occasional (5-29%)
HP:0005616	Accelerated skeletal maturation	Occasional (5-29%)
HP:0010579	Cone-shaped epiphysis	Occasional (5-29%)
HP:0012819	Myocarditis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spondylometaphyseal dysplasia, Sedaghatian type
Mondo ID	MONDO:0009593
MeSH	C535798
OMIM	250220
Orphanet	93317
DOID	DOID:0112298
ICD-11	975738106
UMLS	C1855229
MedGen	340816
GARD	0004993
Is cancer (heuristic)	no

Also known as: lethal metaphyseal dysplasia · SMDS · spondylometaphyseal dysplasia Sedaghatian type · spondylometaphyseal dysplasia, Sedaghatian type

Data availability: 10 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › spondylometaphyseal dysplasia › spondylometaphyseal dysplasia, Sedaghatian type

Related subtypes (18): Kniest dysplasia, spondyloepimetaphyseal dysplasia, Strudwick type, spondylometaphyseal dysplasia, Kozlowski type, spondylometaphyseal dysplasia, Schmidt type, spondylometaphyseal dysplasia, ‘corner fracture’ type, spondylometaphyseal dysplasia, Golden type, axial spondylometaphyseal dysplasia, spondylometaphyseal dysplasia-bowed forearms-facial dysmorphism syndrome, Spondyloenchondrodysplasia with immune dysregulation, spondylometaphyseal dysplasia-cone-rod dystrophy syndrome, spondylometaphyseal dysplasia, A4 type, spondylometaphyseal dysplasia, East African type, autosomal recessive spondylometaphyseal dysplasia, Megarbane type, spondylometaphyseal dysplasia, Czarny-Ratajczak type, regressive spondylometaphyseal dysplasia, spondylometaphyseal dysplasia, pagnamenta type, odontochondrodysplasia, SBDS-related severe neonatal spondylometaphyseal dysplasia

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

10 retrieved; paginated sample, class counts are floors:

5 likely pathogenic, 2 conflicting classifications of pathogenicity, 2 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
140616	NM_002085.5(GPX4):c.477-8_477-4del	GPX4	Pathogenic	no assertion criteria provided
140617	NM_002085.5(GPX4):c.270C>A (p.Tyr90Ter)	GPX4	Pathogenic	no assertion criteria provided
1422567	NM_002085.5(GPX4):c.438_441del (p.Lys145_Trp146insTer)	GPX4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1332848	NM_002085.5(GPX4):c.536G>A (p.Arg179His)	GPX4	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2444499	NM_002085.5(GPX4):c.365del (p.Gly122fs)	GPX4	Likely pathogenic	criteria provided, single submitter
4076406	NM_002085.5(GPX4):c.324+1G>A	GPX4	Likely pathogenic	no assertion criteria provided
451510	NM_002085.5(GPX4):c.502-1del	GPX4	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4849283	NM_002085.5(GPX4):c.48_49del (p.Cys16fs)	GPX4	Likely pathogenic	criteria provided, single submitter
1028980	NM_002085.5(GPX4):c.85-321G>A	GPX4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
140615	NM_002085.5(GPX4):c.476+5G>A	GPX4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
GPX4	Strong	Autosomal recessive	spondylometaphyseal dysplasia, Sedaghatian type	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GPX4	Orphanet:93317	Spondylometaphyseal dysplasia, Sedaghatian type

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
GPX4	HGNC:4556	ENSG00000167468	P36969	Phospholipid hydroperoxide glutathione peroxidase GPX4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GPX4	Phospholipid hydroperoxide glutathione peroxidase GPX4	Essential antioxidant peroxidase that directly reduces phospholipid hydroperoxide even if they are incorporated in membranes and lipoproteins.

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GPX4	Enzyme (other)	yes	1.11.1.12	Glutathione_peroxidase, GPX_AS, GPX_CS

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
adult organism	1
left testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GPX4	293	ubiquitous	marker	left testis, right testis, adult organism

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GPX4	3,036

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GPX4	P36969	23

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Biosynthesis of aspirin-triggered D-series resolvins	1	3806.7×	7e-04	GPX4
Biosynthesis of D-series resolvins	1	2855.0×	7e-04	GPX4
Biosynthesis of E-series 18(R)-resolvins	1	2855.0×	7e-04	GPX4
Biosynthesis of E-series 18(S)-resolvins	1	2284.0×	7e-04	GPX4
Synthesis of 15-eicosatetraenoic acid derivatives	1	1903.3×	7e-04	GPX4
Synthesis of 12-eicosatetraenoic acid derivatives	1	1631.4×	7e-04	GPX4
Synthesis of 5-eicosatetraenoic acids	1	1268.9×	8e-04	GPX4

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
lipoxygenase pathway	1	1532.0×	0.005	GPX4
protein polymerization	1	991.3×	0.005	GPX4
negative regulation of ferroptosis	1	802.5×	0.005	GPX4
arachidonate metabolic process	1	481.5×	0.005	GPX4
long-chain fatty acid biosynthetic process	1	443.5×	0.005	GPX4
dendrite development	1	391.9×	0.005	GPX4
cerebellum development	1	358.6×	0.005	GPX4
phospholipid metabolic process	1	343.9×	0.005	GPX4
response to estradiol	1	198.3×	0.008	GPX4
multicellular organism growth	1	137.0×	0.010	GPX4
response to oxidative stress	1	130.6×	0.010	GPX4
response to lipopolysaccharide	1	124.8×	0.010	GPX4
chromatin organization	1	99.1×	0.012	GPX4
spermatogenesis	1	35.2×	0.030	GPX4
apoptotic process	1	28.7×	0.035	GPX4

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GPX4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
GPX4	176	Binding:176

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GPX4	1.11.1.12	phospholipid-hydroperoxide glutathione peroxidase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GPX4	176

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	GPX4
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)
GPX4	176	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.