Familial avascular necrosis of femoral head

Summary

Familial avascular necrosis of femoral head (MONDO:0012126) is a disease with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• Phenotypes (HPO): 9

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	5	United States	Validated

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (Orphanet curated; top 9 by frequency):

HPO ID	Term	Frequency
HP:0003366	Abnormality of the femoral neck or head region	Very frequent (80-99%)
HP:0031520	Groin pain	Very frequent (80-99%)
HP:0007311	Short stepped shuffling gait	Frequent (30-79%)
HP:0008800	Limited hip movement	Frequent (30-79%)
HP:0008812	Flattened femoral head	Frequent (30-79%)
HP:0008843	Hip osteoarthritis	Frequent (30-79%)
HP:0030838	Hip pain	Frequent (30-79%)
HP:0031058	Impairment of activities of daily living	Frequent (30-79%)
HP:0100559	Lower limb asymmetry	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial avascular necrosis of femoral head
Mondo ID	MONDO:0012126
MeSH	D005271
OMIM	608805
Orphanet	86820
ICD-11	1216860745
NCIT	C35480
SNOMED CT	715657008
UMLS	C4275066
MedGen	909851
GARD	0010914
Is cancer (heuristic)	no

Also known as: ANFH · ANFH1 · aseptic Necrosis of femoral head · aseptic Necrosis of head of femur · avascular NECROSIS of femoral head, primary · familial avascular necrosis of the femoral head · familial osteonecrosis of the femoral head · ischaemic Necrosis of femoral head · primary avascular necrosis of the femoral head

Data availability: 2 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › osteonecrosis › avascular necrosis › primary avascular necrosis › familial avascular necrosis of femoral head

Related subtypes (2): pseudohypoparathyroidism type 1C, idiopathic avascular necrosis

Subtypes (2): avascular necrosis of femoral head, primary, 1, avascular necrosis of femoral head, primary, 2

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 65 · Orphanet: 27 · 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
COL2A1	Definitive	Autosomal dominant	dysplasia of the proximal femoral epiphyses	46
TRPV4	Supportive	Autosomal dominant	familial avascular necrosis of femoral head	19

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TRPV4	Orphanet:1216	Autosomal dominant congenital benign spinal muscular atrophy
TRPV4	Orphanet:263482	Spondyloepimetaphyseal dysplasia, Maroteaux type
TRPV4	Orphanet:2635	Metatropic dysplasia
TRPV4	Orphanet:431255	Scapuloperoneal spinal muscular atrophy
TRPV4	Orphanet:85169	Familial digital arthropathy-brachydactyly
TRPV4	Orphanet:86820	Familial avascular necrosis of femoral head
TRPV4	Orphanet:93304	Autosomal dominant brachyolmia
TRPV4	Orphanet:93314	Spondylometaphyseal dysplasia, Kozlowski type
TRPV4	Orphanet:99937	Autosomal dominant Charcot-Marie-Tooth disease type 2C
COL2A1	Orphanet:137678	Spondyloepiphyseal dysplasia with metatarsal shortening
COL2A1	Orphanet:166100	Autosomal dominant otospondylomegaepiphyseal dysplasia
COL2A1	Orphanet:1856	Spondyloperipheral dysplasia-short ulna syndrome
COL2A1	Orphanet:209867	Autosomal dominant rhegmatogenous retinal detachment
COL2A1	Orphanet:2380	Legg-Calvé-Perthes disease
COL2A1	Orphanet:459051	Spondyloepiphyseal dysplasia, Stanescu type
COL2A1	Orphanet:485	Kniest dysplasia
COL2A1	Orphanet:85166	Platyspondylic dysplasia, Torrance type
COL2A1	Orphanet:85198	Dysspondyloenchondromatosis
COL2A1	Orphanet:86820	Familial avascular necrosis of femoral head
COL2A1	Orphanet:90653	Stickler syndrome type 1
COL2A1	Orphanet:93279	Mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis
COL2A1	Orphanet:93296	Achondrogenesis type 2
COL2A1	Orphanet:93297	Hypochondrogenesis
COL2A1	Orphanet:93315	Spondylometaphyseal dysplasia, ‘corner fracture’ type
COL2A1	Orphanet:93316	Spondylometaphyseal dysplasia, Schmidt type
COL2A1	Orphanet:93346	Spondyloepimetaphyseal dysplasia congenita, Strudwick type
COL2A1	Orphanet:94068	Spondyloepiphyseal dysplasia congenita

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
TRPV4	HGNC:18083	ENSG00000111199	Q9HBA0	Transient receptor potential cation channel subfamily V member 4	gencc
COL2A1	HGNC:2200	ENSG00000139219	P02458	Collagen alpha-1(II) chain	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TRPV4	Transient receptor potential cation channel subfamily V member 4	Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity.
COL2A1	Collagen alpha-1(II) chain	Type II collagen is specific for cartilaginous tissues.

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
Ion channel	1	55.8×	0.036
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TRPV4	Ion channel	yes		Ankyrin_rpt, Ion_trans_dom, TrpV1-4
COL2A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen

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
cartilage tissue	2
lower esophagus mucosa	1
olfactory segment of nasal mucosa	1
corpus epididymis	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TRPV4	171	ubiquitous	marker	cartilage tissue, lower esophagus mucosa, olfactory segment of nasal mucosa
COL2A1	145	broad	marker	tibia, cartilage tissue, corpus epididymis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL2A1	2,491
TRPV4	1,948

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TRPV4	Q9HBA0	19
COL2A1	P02458	11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. 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
Fibronectin matrix formation	1	285.5×	0.015	COL2A1
TRP channels	1	203.9×	0.015	TRPV4
MET activates PTK2 signaling	1	190.3×	0.015	COL2A1
Collagen chain trimerization	1	129.8×	0.015	COL2A1
Signaling by PDGF	1	126.9×	0.015	COL2A1
NCAM1 interactions	1	124.1×	0.015	COL2A1
Developmental Lineage of Pancreatic Ductal Cells	1	114.2×	0.015	COL2A1
Assembly of collagen fibrils and other multimeric structures	1	100.2×	0.015	COL2A1
Collagen degradation	1	87.8×	0.015	COL2A1
Collagen biosynthesis and modifying enzymes	1	85.2×	0.015	COL2A1
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	80.4×	0.015	TRPV4
Non-integrin membrane-ECM interactions	1	77.2×	0.015	COL2A1
ECM proteoglycans	1	75.1×	0.015	COL2A1
Integrin cell surface interactions	1	67.2×	0.016	COL2A1
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	43.6×	0.023	COL2A1

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
cartilage development involved in endochondral bone morphogenesis	2	2407.4×	1e-05	TRPV4, COL2A1
hyperosmotic salinity response	1	8426.0×	0.002	TRPV4
blood vessel endothelial cell delamination	1	8426.0×	0.002	TRPV4
vasopressin secretion	1	4213.0×	0.002	TRPV4
positive regulation of striated muscle contraction	1	4213.0×	0.002	TRPV4
regulation of response to osmotic stress	1	4213.0×	0.002	TRPV4
calcium ion import into cytosol	1	4213.0×	0.002	TRPV4
cellular hypotonic salinity response	1	2808.7×	0.003	TRPV4
positive regulation of macrophage inflammatory protein 1 alpha production	1	2808.7×	0.003	TRPV4
positive regulation of microtubule depolymerization	1	1685.2×	0.003	TRPV4
otic vesicle development	1	1404.3×	0.003	COL2A1
positive regulation of chemokine (C-C motif) ligand 5 production	1	1404.3×	0.003	TRPV4
anterior head development	1	1404.3×	0.003	COL2A1
negative regulation of brown fat cell differentiation	1	1404.3×	0.003	TRPV4
positive regulation of chemokine (C-X-C motif) ligand 1 production	1	1404.3×	0.003	TRPV4
regulation of aerobic respiration	1	1053.2×	0.004	TRPV4
proteoglycan metabolic process	1	936.2×	0.004	COL2A1
cortical microtubule organization	1	936.2×	0.004	TRPV4
notochord development	1	842.6×	0.004	COL2A1
multicellular organismal-level water homeostasis	1	842.6×	0.004	TRPV4
osmosensory signaling pathway	1	766.0×	0.004	TRPV4
limb bud formation	1	766.0×	0.004	COL2A1
embryonic skeletal joint morphogenesis	1	766.0×	0.004	COL2A1
diet induced thermogenesis	1	702.2×	0.004	TRPV4
cellular hypotonic response	1	702.2×	0.004	TRPV4
positive regulation of vascular permeability	1	648.1×	0.004	TRPV4
cellular response to osmotic stress	1	601.9×	0.004	TRPV4
positive regulation of monocyte chemotactic protein-1 production	1	601.9×	0.004	TRPV4
microtubule polymerization	1	443.5×	0.005	TRPV4
positive regulation of macrophage chemotaxis	1	401.2×	0.005	TRPV4

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
TRPV4	6	3
COL2A1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CANNABINOL	3	TRPV4
TETRAHYDROCANNABIVARIN	2	TRPV4
CANNABIDIVARIN	2	TRPV4
GSK2798745	2	TRPV4
CANNABIGEROL	2	TRPV4
ABT-102	1	TRPV4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TRPV4	99	Binding:94, Functional:5
COL2A1	2	Binding:2

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

6 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)
CANNABINOL	3	TRPV4
TETRAHYDROCANNABIVARIN	2	TRPV4
CANNABIDIVARIN	2	TRPV4
GSK2798745	2	TRPV4
CANNABIGEROL	2	TRPV4
ABT-102	1	TRPV4

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	1	TRPV4
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	COL2A1

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)
COL2A1	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.