autosomal dominant osteosclerosis, Worth type

Summary

autosomal dominant osteosclerosis, Worth type (MONDO:0007764) is a disease caused by LRP5 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LRP5 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 480
• Phenotypes (HPO): 13

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0000772	Abnormal rib morphology	Very frequent (80-99%)
HP:0003103	Abnormal cortical bone morphology	Very frequent (80-99%)
HP:0004493	Craniofacial hyperostosis	Very frequent (80-99%)
HP:0005019	Diaphyseal thickening	Very frequent (80-99%)
HP:0005789	Generalized osteosclerosis	Very frequent (80-99%)
HP:0100789	Torus palatinus	Very frequent (80-99%)
HP:0100923	Clavicular sclerosis	Very frequent (80-99%)
HP:0003312	Abnormal form of the vertebral bodies	Frequent (30-79%)
HP:0100861	Sclerotic vertebral body	Frequent (30-79%)
HP:0000303	Mandibular prognathia	Occasional (5-29%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0010628	Facial palsy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant osteosclerosis, Worth type
Mondo ID	MONDO:0007764
OMIM	144750, 607636
Orphanet	2790
DOID	DOID:0080037
ICD-11	1038854228
SNOMED CT	254131007
UMLS	C0432273
MedGen	140932
GARD	0000390
Is cancer (heuristic)	no

Also known as: endosteal hyperostosis, Worth type · hyperostosis corticalis generalisata, benign form of Worth with torus palatinus · hyperostosis, endosteal · osteosclerosis of the skull and enlarged mandible · osteosclerosis, autosomal dominant, Worth type · Ostéosclérose autosomique dominante type Worth · Van Buchem disease type 2 · VBCH2 · Worth syndrome · Worth’s syndrome

Data availability: 480 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 remodeling disease › hyperostosis › autosomal dominant osteosclerosis, Worth type

Related subtypes (8): exostosis, bone Paget disease, diffuse idiopathic skeletal hyperostosis, Caffey disease, craniodiaphyseal dysplasia, hyperostosis corticalis generalisata, X-linked calvarial hyperostosis, sclerosteosis

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

480 retrieved; paginated sample, class counts are floors:

305 uncertain significance, 69 likely benign, 61 conflicting classifications of pathogenicity, 21 benign/likely benign, 9 pathogenic/likely pathogenic, 8 likely pathogenic, 4 pathogenic, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1179140	NM_002335.4(LRP5):c.2555C>T (p.Thr852Met)	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1450334	NM_002335.4(LRP5):c.3122C>T (p.Thr1041Met)	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1512510	NM_002335.4(LRP5):c.3236+2T>G	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
191023	NM_002335.4(LRP5):c.685C>T (p.Arg229Trp)	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1943870	NM_002335.4(LRP5):c.4263del (p.Phe1422fs)	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225406	NM_002335.4(LRP5):c.593A>G (p.Asn198Ser)	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
287187	NM_002335.4(LRP5):c.2737dup (p.Cys913fs)	LRP5	Pathogenic	criteria provided, multiple submitters, no conflicts
6269	NM_002335.4(LRP5):c.1282C>T (p.Arg428Ter)	LRP5	Pathogenic	criteria provided, multiple submitters, no conflicts
6274	NM_002335.4(LRP5):c.1481G>A (p.Arg494Gln)	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6282	NM_002335.4(LRP5):c.724G>A (p.Ala242Thr)	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6283	NM_002335.4(LRP5):c.640G>A (p.Ala214Thr)	LRP5	Pathogenic	criteria provided, multiple submitters, no conflicts
6284	NM_002335.4(LRP5):c.641C>T (p.Ala214Val)	LRP5	Pathogenic	no assertion criteria provided
865885	NM_002335.4(LRP5):c.209_210delinsAA (p.Phe70Ter)	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1520877	NM_002335.4(LRP5):c.1210G>A (p.Gly404Arg)	LRP5	Likely pathogenic	criteria provided, multiple submitters, no conflicts
162391	NM_002335.4(LRP5):c.3562C>T (p.Arg1188Trp)	LRP5	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2085657	NM_002335.4(LRP5):c.1378G>A (p.Glu460Lys)	LRP5	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2152119	NM_002335.4(LRP5):c.3863A>G (p.Asp1288Gly)	LRP5	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3573936	NM_002335.4(LRP5):c.4191_4192dup (p.Phe1398fs)	LRP5	Likely pathogenic	criteria provided, single submitter
3600191	NM_002335.4(LRP5):c.1264G>A (p.Ala422Thr)	LRP5	Likely pathogenic	criteria provided, single submitter
3600192	NM_002335.4(LRP5):c.1293C>G (p.Tyr431Ter)	LRP5	Likely pathogenic	criteria provided, single submitter
3600212	NM_002335.4(LRP5):c.2626G>A (p.Gly876Ser)	LRP5	Likely pathogenic	criteria provided, single submitter
1008864	NM_002335.4(LRP5):c.1096G>A (p.Val366Met)	LRP5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1009413	NM_002335.4(LRP5):c.1331G>A (p.Arg444His)	LRP5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1025837	NM_002335.4(LRP5):c.1183C>T (p.Arg395Trp)	LRP5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1042717	NM_002335.4(LRP5):c.4566G>A (p.Pro1522=)	LRP5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1043257	NM_002335.4(LRP5):c.533G>A (p.Arg178Gln)	LRP5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1060132	NM_002335.4(LRP5):c.4466C>T (p.Thr1489Met)	LRP5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1060268	NM_002335.4(LRP5):c.1412+11C>T	LRP5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1062021	NM_002335.4(LRP5):c.2414G>A (p.Arg805Gln)	LRP5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1088678	NM_002335.4(LRP5):c.2504-11T>G	LRP5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 26 · Orphanet: 9 · 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
LRP5	Strong	Autosomal dominant	autosomal dominant osteosclerosis, Worth type	26

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LRP5	Orphanet:178377	Osteosclerosis-developmental delay-craniosynostosis syndrome
LRP5	Orphanet:2783	Autosomal dominant osteopetrosis type 1
LRP5	Orphanet:2788	Osteoporosis-pseudoglioma syndrome
LRP5	Orphanet:2790	Endosteal hyperostosis, Worth type
LRP5	Orphanet:2924	Isolated polycystic liver disease
LRP5	Orphanet:3416	Hyperostosis corticalis generalisata
LRP5	Orphanet:498481	LRP5-related primary osteoporosis
LRP5	Orphanet:891	Familial exudative vitreoretinopathy
LRP5	Orphanet:90050	Retinopathy of prematurity

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
LRP5	HGNC:6697	ENSG00000162337	O75197	Low-density lipoprotein receptor-related protein 5	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LRP5	Low-density lipoprotein receptor-related protein 5	Acts as a coreceptor with members of the frizzled family of seven-transmembrane spanning receptors to transduce signal by Wnt proteins.

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)
LRP5	Other/Unknown	no		LDLR_classB_rpt, EGF, LDrepeatLR_classA_rpt

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
ascending aorta	1
mucosa of transverse colon	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LRP5	224	ubiquitous	marker	right lobe of liver, mucosa of transverse colon, ascending aorta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LRP5	2,619

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LRP5	O75197	78.65

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Signaling by LRP5 mutants	1	1631.4×	0.004	LRP5
Signaling by RNF43 mutants	1	1268.9×	0.004	LRP5
Negative regulation of TCF-dependent signaling by WNT ligand antagonists	1	713.8×	0.004	LRP5
Signaling by WNT in cancer	1	601.0×	0.004	LRP5
Regulation of FZD by ubiquitination	1	519.1×	0.004	LRP5
Disassembly of the destruction complex and recruitment of AXIN to the membrane	1	356.9×	0.005	LRP5
TCF dependent signaling in response to WNT	1	117.7×	0.012	LRP5
Signaling by WNT	1	112.0×	0.012	LRP5
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.022	LRP5
Disease	1	13.1×	0.084	LRP5
Signal Transduction	1	10.2×	0.098	LRP5

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
cell-cell signaling involved in mammary gland development	1	5617.3×	0.002	LRP5
mesodermal cell migration	1	3370.4×	0.002	LRP5
extracellular matrix-cell signaling	1	3370.4×	0.002	LRP5
anatomical structure regression	1	3370.4×	0.002	LRP5
Norrin signaling pathway	1	3370.4×	0.002	LRP5
apoptotic process involved in blood vessel morphogenesis	1	2808.7×	0.002	LRP5
establishment of blood-retinal barrier	1	2808.7×	0.002	LRP5
glucose catabolic process	1	2407.4×	0.002	LRP5
retinal blood vessel morphogenesis	1	2407.4×	0.002	LRP5
retina morphogenesis in camera-type eye	1	1872.4×	0.002	LRP5
cell migration involved in gastrulation	1	1532.0×	0.002	LRP5
bone marrow development	1	1532.0×	0.002	LRP5
osteoblast proliferation	1	1404.3×	0.002	LRP5
branching involved in mammary gland duct morphogenesis	1	1404.3×	0.002	LRP5
establishment of blood-brain barrier	1	1404.3×	0.002	LRP5
positive regulation of osteoblast proliferation	1	1203.7×	0.002	LRP5
osteoblast development	1	991.3×	0.002	LRP5
gastrulation with mouth forming second	1	936.2×	0.002	LRP5
bone remodeling	1	936.2×	0.002	LRP5
regulation of insulin secretion involved in cellular response to glucose stimulus	1	936.2×	0.002	LRP5
positive regulation of mesenchymal cell proliferation	1	601.9×	0.003	LRP5
bone morphogenesis	1	601.9×	0.003	LRP5
positive regulation of mitotic nuclear division	1	543.6×	0.004	LRP5
adipose tissue development	1	401.2×	0.004	LRP5
response to peptide hormone	1	391.9×	0.004	LRP5
amino acid transport	1	312.1×	0.005	LRP5
embryonic digit morphogenesis	1	300.9×	0.005	LRP5
positive regulation of fat cell differentiation	1	300.9×	0.005	LRP5
negative regulation of osteoblast differentiation	1	295.6×	0.005	LRP5
somatic stem cell population maintenance	1	247.8×	0.006	LRP5

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
LRP5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
LRP5	1	Binding:1

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	LRP5

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)
LRP5	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.