Infantile osteopetrosis with neuroaxonal dysplasia

Summary

Infantile osteopetrosis with neuroaxonal dysplasia (MONDO:0010866) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Europe)
• Cohort genes: 2
• ClinVar variants: 1
• Phenotypes (HPO): 15

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0001250	Seizure	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001274	Agenesis of corpus callosum	Frequent (30-79%)
HP:0001338	Partial agenesis of the corpus callosum	Frequent (30-79%)
HP:0002059	Cerebral atrophy	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0004330	Increased skull ossification	Frequent (30-79%)
HP:0006824	Cranial nerve paralysis	Frequent (30-79%)
HP:0009830	Peripheral neuropathy	Frequent (30-79%)
HP:0012444	Brain atrophy	Frequent (30-79%)
HP:0012447	Abnormal myelination	Frequent (30-79%)
HP:0025517	Hypoplastic hippocampus	Frequent (30-79%)
HP:0000405	Conductive hearing impairment	Occasional (5-29%)
HP:0002090	Pneumonia	Occasional (5-29%)
HP:0025116	Fetal distress	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	infantile osteopetrosis with neuroaxonal dysplasia
Mondo ID	MONDO:0010866
MeSH	C536055
OMIM	600329
Orphanet	85179
DOID	DOID:0070343
ICD-11	1434293148
SNOMED CT	724226009
UMLS	C1838258
MedGen	373924
GARD	0010082
Is cancer (heuristic)	no

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

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › osteopetrosis › infantile osteopetrosis with neuroaxonal dysplasia

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

Subtypes (1): autosomal recessive osteopetrosis 5

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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
159748	NM_003560.4(PLA2G6):c.1799G>A (p.Arg600Gln)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 3 · 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
OSTM1	Definitive	Autosomal recessive	autosomal recessive osteopetrosis 5	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
OSTM1	Orphanet:85179	Infantile osteopetrosis with neuroaxonal dysplasia
PLA2G6	Orphanet:199351	Adult-onset dystonia-parkinsonism
PLA2G6	Orphanet:35069	Infantile neuroaxonal dystrophy

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
OSTM1	HGNC:21652	ENSG00000081087	Q86WC4	Osteopetrosis-associated transmembrane protein 1	gencc
PLA2G6	HGNC:9039	ENSG00000184381	O60733	85/88 kDa calcium-independent phospholipase A2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
OSTM1	Osteopetrosis-associated transmembrane protein 1	Required for osteoclast and melanocyte maturation and function.
PLA2G6	85/88 kDa calcium-independent phospholipase A2	Calcium-independent phospholipase involved in phospholipid remodeling with implications in cellular membrane homeostasis, mitochondrial integrity and signal transduction.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
OSTM1	Other/Unknown	no		Osteopetrosis-assoc_TM_1
PLA2G6	Scaffold/PPI	no	3.1.1.4	Ankyrin_rpt, PNPLA_dom, Acyl_Trfase/lysoPLipase

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
adrenal tissue	1
choroid plexus epithelium	1
popliteal artery	1
left lobe of thyroid gland	1
right lobe of thyroid gland	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
OSTM1	287	ubiquitous	marker	choroid plexus epithelium, adrenal tissue, popliteal artery
PLA2G6	232	ubiquitous	marker	right uterine tube, right lobe of thyroid gland, left lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PLA2G6	1,769
OSTM1	1,108

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
OSTM1	Q86WC4	9

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PLA2G6	O60733	86.16

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Acyl chain remodeling of CL	1	951.7×	0.006	PLA2G6
Role of phospholipids in phagocytosis	1	228.4×	0.008	PLA2G6
Acyl chain remodelling of PC	1	211.5×	0.008	PLA2G6
Acyl chain remodelling of PE	1	196.9×	0.008	PLA2G6
COPI-independent Golgi-to-ER retrograde traffic	1	103.8×	0.012	PLA2G6
Stimuli-sensing channels	1	68.0×	0.015	OSTM1

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
platelet activating factor metabolic process	1	2808.7×	0.002	PLA2G6
cardiolipin acyl-chain remodeling	1	2106.5×	0.002	PLA2G6
phosphatidylethanolamine catabolic process	1	2106.5×	0.002	PLA2G6
phosphatidic acid metabolic process	1	1404.3×	0.002	PLA2G6
positive regulation of ceramide biosynthetic process	1	1203.7×	0.002	PLA2G6
transepithelial chloride transport	1	936.2×	0.002	OSTM1
phosphatidylcholine catabolic process	1	648.1×	0.003	PLA2G6
Fc-gamma receptor signaling pathway involved in phagocytosis	1	351.1×	0.004	PLA2G6
positive regulation of insulin secretion involved in cellular response to glucose stimulus	1	187.2×	0.007	PLA2G6
osteoclast differentiation	1	172.0×	0.007	OSTM1
antibacterial humoral response	1	165.2×	0.007	PLA2G6
chemotaxis	1	68.0×	0.015	PLA2G6

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · 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).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PLA2G6	1	2
OSTM1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VARESPLADIB	2	PLA2G6

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PLA2G6	47	Binding:47

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PLA2G6	3.1.1.4	phospholipase A2

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)
VARESPLADIB	2	PLA2G6

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	PLA2G6
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	OSTM1

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)
OSTM1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.