Steel syndrome

Summary

Steel syndrome (MONDO:0014061) is a disease caused by COL27A1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: COL27A1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 105

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		40	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Steel syndrome
Mondo ID	MONDO:0014061
OMIM	615155
Orphanet	438117
UMLS	C3554594
MedGen	767508
GARD	0017735
Is cancer (heuristic)	no

Also known as: bilateral hip and radial head dislocations-short stature-scoliosis-carpal coalitions-pes cavus-facial dysmorphism syndrome · steel syndrome · STLS

Data availability: 105 ClinVar variants · 3 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 › spondyloepiphyseal dysplasia › Steel syndrome

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, X-linked spondyloepimetaphyseal dysplasia, 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, 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

105 retrieved; paginated sample, class counts are floors:

43 benign, 20 likely pathogenic, 17 uncertain significance, 13 pathogenic, 6 pathogenic/likely pathogenic, 2 conflicting classifications of pathogenicity, 2 benign/likely benign, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1027381	NM_032888.4(COL27A1):c.4519C>T (p.Arg1507Ter)	COL27A1	Pathogenic	criteria provided, single submitter
1031005	NM_032888.4(COL27A1):c.3439G>T (p.Gly1147Ter)	COL27A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073679	NM_032888.4(COL27A1):c.1216C>T (p.Gln406Ter)	COL27A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322126	NM_032888.4(COL27A1):c.3294+1G>C	COL27A1	Pathogenic	criteria provided, single submitter
1334897	NM_032888.4(COL27A1):c.4060C>T (p.Arg1354Ter)	COL27A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1360123	NM_032888.4(COL27A1):c.3083dup (p.Met1029fs)	COL27A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1365471	NM_032888.4(COL27A1):c.3616del (p.Arg1206fs)	COL27A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
143245	NM_032888.4(COL27A1):c.2089G>C (p.Gly697Arg)	COL27A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1683731	NM_032888.4(COL27A1):c.2320C>T (p.Arg774Ter)	COL27A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2439337	NM_032888.4(COL27A1):c.4357dup (p.Ala1453fs)	COL27A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3220911	NM_032888.4(COL27A1):c.4261-1G>A	COL27A1	Pathogenic	criteria provided, single submitter
3233479	NM_032888.4(COL27A1):c.1895del (p.Asp632fs)	COL27A1	Pathogenic	criteria provided, single submitter
4535830	NM_032888.4(COL27A1):c.25del (p.Ala9fs)	COL27A1	Pathogenic	criteria provided, single submitter
559387	NM_032888.4(COL27A1):c.2119C>T (p.Arg707Ter)	COL27A1	Pathogenic	criteria provided, multiple submitters, no conflicts
559388	NM_032888.4(COL27A1):c.521_528del (p.Cys174fs)	COL27A1	Pathogenic	no assertion criteria provided
559511	NM_032888.4(COL27A1):c.3556-2A>G	COL27A1	Pathogenic	criteria provided, single submitter
807556	NM_032888.4(COL27A1):c.93del (p.Phe32fs)	COL27A1	Pathogenic	criteria provided, single submitter
807557	NM_032888.4(COL27A1):c.3075del (p.Lys1026fs)	COL27A1	Pathogenic	criteria provided, single submitter
870446	NM_032888.4(COL27A1):c.2405G>A (p.Gly802Glu)	COL27A1	Pathogenic	criteria provided, single submitter
1066232	NM_032888.4(COL27A1):c.4152+1G>A	COL27A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339013	NM_032888.4(COL27A1):c.62+1G>T	COL27A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1347444	NM_032888.4(COL27A1):c.2367G>A (p.Pro789=)	COL27A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1679341	NM_032888.4(COL27A1):c.4020del (p.Pro1342fs)	COL27A1	Likely pathogenic	criteria provided, single submitter
1802266	NM_032888.4(COL27A1):c.4854del (p.Gly1620fs)	COL27A1	Likely pathogenic	criteria provided, single submitter
1805797	NM_032888.4(COL27A1):c.211del (p.Gln71fs)	COL27A1	Likely pathogenic	criteria provided, single submitter
2439329	NM_032888.4(COL27A1):c.358C>T (p.Gln120Ter)	COL27A1	Likely pathogenic	criteria provided, single submitter
3596334	NM_032888.4(COL27A1):c.600del (p.Lys201fs)	COL27A1	Likely pathogenic	criteria provided, single submitter
3596335	NM_032888.4(COL27A1):c.1734_1737dup (p.Pro580fs)	COL27A1	Likely pathogenic	criteria provided, single submitter
3596336	NM_032888.4(COL27A1):c.2728-1G>A	COL27A1	Likely pathogenic	criteria provided, single submitter
3596338	NM_032888.4(COL27A1):c.3010G>T (p.Glu1004Ter)	COL27A1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
COL27A1	Definitive	Autosomal recessive	Steel syndrome	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL27A1	Orphanet:438117	Steel 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
COL27A1	HGNC:22986	ENSG00000196739	Q8IZC6	Collagen alpha-1(XXVII) chain	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL27A1	Collagen alpha-1(XXVII) chain	Plays a role during the calcification of cartilage and the transition of cartilage to bone.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL27A1	Other/Unknown	no		Fib_collagen_C, Collagen, ConA-like_dom_sf

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
cerebellar vermis	1
pancreatic ductal cell	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL27A1	252	ubiquitous	marker	tibia, cerebellar vermis, pancreatic ductal cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL27A1	1,252

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COL27A1	Q8IZC6	49.13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
MET activates PTK2 signaling	1	380.7×	0.006	COL27A1
Collagen chain trimerization	1	259.6×	0.006	COL27A1
Developmental Lineage of Pancreatic Ductal Cells	1	228.4×	0.006	COL27A1
Assembly of collagen fibrils and other multimeric structures	1	200.3×	0.006	COL27A1
Collagen biosynthesis and modifying enzymes	1	170.4×	0.006	COL27A1

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
growth plate cartilage chondrocyte development	1	5617.3×	5e-04	COL27A1
skeletal system development	1	125.8×	0.008	COL27A1
extracellular matrix organization	1	122.1×	0.008	COL27A1

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
COL27A1	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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	COL27A1

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)
COL27A1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.