Osteosclerotic metaphyseal dysplasia

Summary

Osteosclerotic metaphyseal dysplasia (MONDO:0014080) is a disease caused by LRRK1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LRRK1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 13

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	osteosclerotic metaphyseal dysplasia
Mondo ID	MONDO:0014080
OMIM	615198
Orphanet	500548
DOID	DOID:0081111
UMLS	C3554665
MedGen	767579
GARD	0017931
Is cancer (heuristic)	no

Also known as: OSMD · osteosclerotic metaphyseal dysplasia

Data availability: 13 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › osteopetrosis › osteosclerotic metaphyseal dysplasia

Related subtypes (10): melorheostosis, osteomesopyknosis, dysosteosclerosis, pycnodysostosis, anhidrotic ectodermal dysplasia-immunodeficiency-osteopetrosis-lymphedema syndrome, osteopathia striata with cranial sclerosis, infantile osteopetrosis with neuroaxonal dysplasia, autosomal recessive osteopetrosis, autosomal dominant osteopetrosis, early-onset calcifying leukoencephalopathy-skeletal 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

13 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 5 pathogenic, 1 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1327992	NM_024652.6(LRRK1):c.5971dup (p.Ala1991fs)	LRRK1	Pathogenic	criteria provided, multiple submitters, no conflicts
1327994	NM_024652.6(LRRK1):c.261G>A (p.Lys87=)	LRRK1	Pathogenic	no assertion criteria provided
1679875	NM_024652.6(LRRK1):c.4480C>T (p.Arg1494Ter)	LRRK1	Pathogenic	criteria provided, single submitter
254688	NM_024652.6(LRRK1):c.5939_5945del (p.Glu1980fs)	LRRK1	Pathogenic	no assertion criteria provided
522616	NM_024652.6(LRRK1):c.2785G>T (p.Glu929Ter)	LRRK1	Pathogenic	criteria provided, multiple submitters, no conflicts
3383996	NM_024652.6(LRRK1):c.2404_2405+1del	LRRK1	Likely pathogenic	criteria provided, single submitter
1443819	NM_024652.6(LRRK1):c.4312C>T (p.Arg1438Cys)	LRRK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2433533	NM_024652.6(LRRK1):c.185A>G (p.Tyr62Cys)	LRRK1	Uncertain significance	criteria provided, single submitter
2689383	NM_024652.6(LRRK1):c.1397C>T (p.Pro466Leu)	LRRK1	Uncertain significance	criteria provided, single submitter
3065491	NM_024652.6(LRRK1):c.3086A>G (p.Gln1029Arg)	LRRK1	Uncertain significance	criteria provided, single submitter
3068060	NM_024652.6(LRRK1):c.4849C>T (p.Pro1617Ser)	LRRK1	Uncertain significance	criteria provided, single submitter
4846840	NM_024652.6(LRRK1):c.4532C>T (p.Pro1511Leu)	LRRK1	Uncertain significance	criteria provided, single submitter
779276	NM_024652.6(LRRK1):c.5387C>A (p.Pro1796His)	LRRK1	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · 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
LRRK1	Strong	Autosomal recessive	osteosclerotic metaphyseal dysplasia

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LRRK1	Orphanet:500548	Osteosclerotic metaphyseal dysplasia

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
LRRK1	HGNC:18608	ENSG00000154237	Q38SD2	Leucine-rich repeat serine/threonine-protein kinase 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LRRK1	Leucine-rich repeat serine/threonine-protein kinase 1	Serine/threonine-protein kinase which phosphorylates RAB proteins involved in intracellular trafficking.

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LRRK1	Kinase	yes		Prot_kinase_dom, Leu-rich_rpt, Ankyrin_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
lymph node	1
transverse colon	1
vermiform appendix	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LRRK1	210	ubiquitous	marker	lymph node, vermiform appendix, transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LRRK1	1,366

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LRRK1	Q38SD2	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
osteoclast development	1	2106.5×	0.002	LRRK1
positive regulation of intracellular signal transduction	1	648.1×	0.003	LRRK1
bone resorption	1	581.1×	0.003	LRRK1
positive regulation of canonical Wnt signaling pathway	1	154.6×	0.008	LRRK1
intracellular signal transduction	1	38.1×	0.026	LRRK1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LRRK1	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	1	LRRK1
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)
LRRK1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.