Skeletal system disorder

Summary

Skeletal system disorder (MONDO:0005172) is a disease (an umbrella term covering 48 Mondo subtypes) with 2 cohort genes (2 GWAS associations across 20 studies).

At a glance

• Umbrella term: 48 Mondo subtypes
• Cohort genes: 2
• GWAS associations: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	skeletal system disorder
Mondo ID	MONDO:0005172
EFO	EFO:0002461
SNOMED CT	88230002
UMLS	C0263661
MedGen	538042
Anatomy (UBERON)	UBERON:0001434
Is cancer (heuristic)	no

Also known as: disease of skeletal system · disease or disorder of skeletal system · disorder of skeletal system · skeletal system disease · skeletal system disease or disorder

Data availability: 2 GWAS associations (20 studies) · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 48 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder

Related subtypes (21): autoimmune disorder of musculoskeletal system, musculoskeletal system benign neoplasm, musculoskeletal system cancer, Klippel-Feil syndrome, enthesopathy, muscle tissue disorder, fasciitis, synovial chondromatosis, auriculoosteodysplasia, hypertrophic osteoarthropathy, primary, autosomal dominant, Upington disease, Ramon syndrome, osteoporosis-oculocutaneous hypopigmentation syndrome, short stature, Brussels type, wormian bone-multiple fractures-dentinogenesis imperfecta-skeletal dysplasia, CINCA syndrome, chondrodysplasia with joint dislocations, gPAPP type, ligament disorder, synovium disorder, disease of the tendon, Short stature, Dauber-Argente type

Subtypes (48): symphalangism, cartilage cancer, vertebral column disorder, patellar tendinitis, necrosis of ear ossicle, laryngeal cartilage cancer, ochronosis disorder, chondroma, periodontal disorder, posterior cranial fossa meningioma, anterior cranial fossa meningioma, middle cranial fossa meningioma, bone marrow disorder, cranial nodular fasciitis, flatfoot, bone disorder, skeletal tuberculosis, arthropathy, tooth disorder, primary basilar invagination, Brachymorphism-onychodysplasia-dysphalangism syndrome, cherubism, fibrodysplasia ossificans progressiva, Marfan syndrome, Buschke-Ollendorff syndrome, scalp defects-postaxial polydactyly syndrome, cartilage-hair hypoplasia, Teebi-Shaltout syndrome, short stature-auditory canal atresia-mandibular hypoplasia-skeletal anomalies syndrome, ossification of the posterior longitudinal ligament of the spine, temtamy preaxial brachydactyly syndrome, metaphyseal undermodeling, spondylar dysplasia, and overgrowth, Al-Gazali syndrome, brachydactyly-syndactyly syndrome, endocrine-cerebro-osteodysplasia syndrome, metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria, multiple congenital anomalies-hypotonia-seizures syndrome 3, Rienhoff syndrome, Coffin-Siris syndrome, microcephaly-brachydactyly-kyphoscoliosis syndrome, cartilage development disorder, syndactyly, polydactyly, brachydactyly, sternal neoplasm, short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis, skeletal ligament disorder, brachydactyly-syndactyly-oligodactyly syndrome

Genetics & variants

GWAS landscape

2 GWAS associations across 20 studies. Top hits map to 0 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs2647062	3e-14	HLA-DRB1 - HLA-DQA1	A	0.11
chr6:32560026	4e-13		T	0.11

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90479420	Verma A	2024	64,597	251,071	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90479430	Verma A	2024	29,860	285,808	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90476261	Verma A	2024	18,113	417,909	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90479419	Verma A	2024	10,139	45,366	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90481205	Verma A	2024	10,139	45,366	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90478971	Verma A	2024	10,130	421,570	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90479417	Verma A	2024	6,242	23,072	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90479429	Verma A	2024	6,044	49,461	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90481227	Verma A	2024	6,044	49,461	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90436700	Zhou W	2018	3,773	391,041	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	2

MAF distribution

Bucket	Variants
common (>=0.05)	2
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intergenic_variant	1
unknown	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs2647062	6	32602640	A>C,T	0.143	intergenic_variant	HLA-DRB1 - HLA-DQA1	3e-14	Tier 4: intronic/intergenic
chr6:32560026				0.188			4e-13	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 13 · 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
KIAA1217	Moderate	Autosomal dominant	skeletal system disorder
SHH	Moderate	Autosomal dominant	skeletal system disorder	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SHH	Orphanet:220386	Semilobar holoprosencephaly
SHH	Orphanet:280195	Septopreoptic holoprosencephaly
SHH	Orphanet:280200	Microform holoprosencephaly
SHH	Orphanet:476119	Autosomal dominant preaxial polydactyly-upperback hypertrichosis syndrome
SHH	Orphanet:485275	Acquired schizencephaly
SHH	Orphanet:93321	Isolated radial hemimelia
SHH	Orphanet:93336	Polydactyly of a triphalangeal thumb
SHH	Orphanet:93405	Syndactyly type 4
SHH	Orphanet:93924	Lobar holoprosencephaly
SHH	Orphanet:93925	Alobar holoprosencephaly
SHH	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
SHH	Orphanet:988	Tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome
SHH	Orphanet:98938	Colobomatous microphthalmia

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
SHH	HGNC:10848	ENSG00000164690	Q15465	Sonic hedgehog protein	gencc
KIAA1217	HGNC:25428	ENSG00000120549	Q5T5P2	Sickle tail protein homolog	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SHH	Sonic hedgehog protein	The C-terminal part of the sonic hedgehog protein precursor displays an autoproteolysis and a cholesterol transferase activity.
KIAA1217	Sickle tail protein homolog	Required for normal development of intervertebral disks.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SHH	Other/Unknown	no		Hedgehog_signalling_dom, Hedgehog, Hedgehog_Hint
KIAA1217	Other/Unknown	no		AIP3-like_C, SRCIN1

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
epithelial cell of pancreas	2
buccal mucosa cell	1
right lobe of liver	1
oviduct epithelium	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SHH	131	broad	marker	buccal mucosa cell, right lobe of liver, epithelial cell of pancreas
KIAA1217	256	ubiquitous	marker	epithelial cell of pancreas, oviduct epithelium, tibialis anterior

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SHH	4,953
KIAA1217	1,074

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SHH	Q15465	20

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KIAA1217	Q5T5P2	46.88

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. Enrichment computed across 2 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
HHAT G278V doesn’t palmitoylate Hh-Np	1	2284.0×	0.003	SHH
Formation of lateral plate mesoderm	1	2284.0×	0.003	SHH
Release of Hh-Np from the secreting cell	1	1427.5×	0.003	SHH
Hh mutants abrogate ligand secretion	1	1427.5×	0.003	SHH
Ligand-receptor interactions	1	1427.5×	0.003	SHH
Formation of axial mesoderm	1	815.7×	0.004	SHH
Activation of SMO	1	634.4×	0.005	SHH
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	1	601.0×	0.005	SHH
Developmental Lineage of Pancreatic Acinar Cells	1	300.5×	0.008	SHH
Gastrulation	1	259.6×	0.008	SHH
Hh mutants are degraded by ERAD	1	243.0×	0.008	SHH
Developmental Cell Lineages	1	223.9×	0.008	SHH
Hedgehog ligand biogenesis	1	211.5×	0.008	SHH
Class B/2 (Secretin family receptors)	1	190.3×	0.008	SHH
Signaling by Hedgehog	1	184.2×	0.008	SHH
Hedgehog ‘on’ state	1	158.6×	0.009	SHH
GPCR ligand binding	1	64.2×	0.020	SHH
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.022	SHH
Signaling by GPCR	1	40.1×	0.029	SHH
Developmental Biology	1	14.5×	0.076	SHH
Disease	1	13.1×	0.080	SHH
Signal Transduction	1	10.2×	0.098	SHH

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
embryonic skeletal system development	2	391.9×	1e-03	SHH, KIAA1217
polarity specification of anterior/posterior axis	1	8426.0×	0.001	SHH
trachea morphogenesis	1	8426.0×	0.001	SHH
right lung development	1	8426.0×	0.001	SHH
left lung development	1	8426.0×	0.001	SHH
primary prostatic bud elongation	1	8426.0×	0.001	SHH
regulation of prostatic bud formation	1	8426.0×	0.001	SHH
obsolete regulation of mesenchymal cell proliferation involved in prostate gland development	1	8426.0×	0.001	SHH
mesenchymal smoothened signaling pathway involved in prostate gland development	1	8426.0×	0.001	SHH
positive regulation of sclerotome development	1	8426.0×	0.001	SHH
tracheoesophageal septum formation	1	8426.0×	0.001	SHH
negative regulation of ureter smooth muscle cell differentiation	1	8426.0×	0.001	SHH
positive regulation of ureter smooth muscle cell differentiation	1	8426.0×	0.001	SHH
negative regulation of kidney smooth muscle cell differentiation	1	8426.0×	0.001	SHH
positive regulation of kidney smooth muscle cell differentiation	1	8426.0×	0.001	SHH
positive regulation of skeletal muscle cell proliferation	1	4213.0×	0.002	SHH
intein-mediated protein splicing	1	4213.0×	0.002	SHH
trunk neural crest cell migration	1	4213.0×	0.002	SHH
regulation of nodal signaling pathway	1	4213.0×	0.002	SHH
positive regulation of mesenchymal cell proliferation involved in ureter development	1	4213.0×	0.002	SHH
ventral midline development	1	2808.7×	0.002	SHH
CD4-positive or CD8-positive, alpha-beta T cell lineage commitment	1	2808.7×	0.002	SHH
negative regulation of alpha-beta T cell differentiation	1	2808.7×	0.002	SHH
regulation of glial cell proliferation	1	2808.7×	0.002	SHH
bud outgrowth involved in lung branching	1	2808.7×	0.002	SHH
prostate epithelial cord elongation	1	2808.7×	0.002	SHH
positive regulation of epithelial cell proliferation involved in prostate gland development	1	2808.7×	0.002	SHH
metanephric mesenchymal cell proliferation involved in metanephros development	1	2808.7×	0.002	SHH
hindgut morphogenesis	1	2106.5×	0.002	SHH
formation of anatomical boundary	1	2106.5×	0.002	SHH

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
SHH	VISMODEGIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SHH	1	4
KIAA1217	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VISMODEGIB	4	SHH

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SHH	27	Binding:23, Functional:4

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

1 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)
VISMODEGIB	4	SHH

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SHH
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	KIAA1217

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)
KIAA1217	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.