Early-onset calcifying leukoencephalopathy-skeletal dysplasia

Summary

Early-onset calcifying leukoencephalopathy-skeletal dysplasia (MONDO:0034143) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		13	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	early-onset calcifying leukoencephalopathy-skeletal dysplasia
Mondo ID	MONDO:0034143
Orphanet	556985
GARD	0022246
Is cancer (heuristic)	no

Data availability: 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 › early-onset calcifying leukoencephalopathy-skeletal 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, osteosclerotic metaphyseal dysplasia, autosomal recessive osteopetrosis, autosomal dominant osteopetrosis

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: 7 · Orphanet: 2 · 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
CSF1R	Definitive	Autosomal dominant	hereditary diffuse leukoencephalopathy with axonal spheroids and pigmented glia	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CSF1R	Orphanet:313808	Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia
CSF1R	Orphanet:556985	Early-onset calcifying leukoencephalopathy-skeletal 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
CSF1R	HGNC:2433	ENSG00000182578	P07333	Macrophage colony-stimulating factor 1 receptor	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CSF1R	Macrophage colony-stimulating factor 1 receptor	Tyrosine-protein kinase that acts as a cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes…

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)
CSF1R	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Tyr_kinase_rcpt_3_CS

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
granulocyte	1
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CSF1R	245	broad	marker	granulocyte, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CSF1R	4,392

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CSF1R	P07333	26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Other interleukin signaling	1	475.8×	0.004	CSF1R
Signaling by CSF1 (M-CSF) in myeloid cells	1	346.1×	0.004	CSF1R
Transcriptional Regulation by VENTX	1	265.6×	0.004	CSF1R

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
forebrain neuron differentiation	1	5617.3×	0.003	CSF1R
macrophage colony-stimulating factor signaling pathway	1	5617.3×	0.003	CSF1R
regulation of macrophage migration	1	4213.0×	0.003	CSF1R
cellular response to macrophage colony-stimulating factor stimulus	1	3370.4×	0.003	CSF1R
positive regulation of macrophage proliferation	1	3370.4×	0.003	CSF1R
mammary gland duct morphogenesis	1	2407.4×	0.003	CSF1R
positive regulation of protein tyrosine kinase activity	1	2106.5×	0.003	CSF1R
cell-cell junction maintenance	1	1872.4×	0.003	CSF1R
microglial cell proliferation	1	1872.4×	0.003	CSF1R
regulation of bone resorption	1	1532.0×	0.003	CSF1R
host-mediated activation of viral process	1	1404.3×	0.003	CSF1R
ruffle organization	1	1296.3×	0.003	CSF1R
positive regulation of macrophage chemotaxis	1	802.5×	0.003	CSF1R
monocyte differentiation	1	802.5×	0.003	CSF1R
olfactory bulb development	1	766.0×	0.003	CSF1R
positive regulation of cell motility	1	766.0×	0.003	CSF1R
positive regulation of tyrosine phosphorylation of STAT protein	1	732.7×	0.003	CSF1R
cellular response to cytokine stimulus	1	543.6×	0.004	CSF1R
macrophage differentiation	1	468.1×	0.005	CSF1R
regulation of MAPK cascade	1	455.5×	0.005	CSF1R
peptidyl-tyrosine phosphorylation	1	421.3×	0.005	CSF1R
positive regulation of chemokine production	1	374.5×	0.005	CSF1R
osteoclast differentiation	1	343.9×	0.005	CSF1R
positive regulation of protein phosphorylation	1	276.3×	0.006	CSF1R
hemopoiesis	1	267.5×	0.006	CSF1R
response to ischemia	1	251.5×	0.007	CSF1R
cell surface receptor protein tyrosine kinase signaling pathway	1	173.7×	0.009	CSF1R
regulation of actin cytoskeleton organization	1	157.5×	0.010	CSF1R
protein autophosphorylation	1	145.3×	0.010	CSF1R
cytokine-mediated signaling pathway	1	130.6×	0.011	CSF1R

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
CSF1R	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CSF1R	79	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	CSF1R
FEDRATINIB	4	CSF1R
AXITINIB	4	CSF1R
SORAFENIB	4	CSF1R
DASATINIB ANHYDROUS	4	CSF1R
SUNITINIB MALATE	4	CSF1R
NERATINIB	4	CSF1R
IBRUTINIB	4	CSF1R
ENTRECTINIB	4	CSF1R
PACRITINIB	4	CSF1R
VANDETANIB	4	CSF1R
NILOTINIB	4	CSF1R
BOSUTINIB	4	CSF1R
FILGOTINIB	4	CSF1R
BRIGATINIB	4	CSF1R
PEXIDARTINIB	4	CSF1R
PAZOPANIB	4	CSF1R
NINTEDANIB	4	CSF1R
SUNITINIB	4	CSF1R
DASATINIB	4	CSF1R
QUIZARTINIB	4	CSF1R
CRIZOTINIB	4	CSF1R
MIDOSTAURIN	4	CSF1R
IMATINIB	4	CSF1R
VATALANIB	3	CSF1R
DACTOLISIB	3	CSF1R
MASITINIB	3	CSF1R
LINIFANIB	3	CSF1R
SEMAXANIB	3	CSF1R
BRIVANIB	3	CSF1R

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CSF1R	897	Binding:879, Functional:17, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CSF1R	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CSF1R	897

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

30 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)
PONATINIB	4	CSF1R
FEDRATINIB	4	CSF1R
AXITINIB	4	CSF1R
SORAFENIB	4	CSF1R
DASATINIB ANHYDROUS	4	CSF1R
SUNITINIB MALATE	4	CSF1R
NERATINIB	4	CSF1R
IBRUTINIB	4	CSF1R
ENTRECTINIB	4	CSF1R
PACRITINIB	4	CSF1R
VANDETANIB	4	CSF1R
NILOTINIB	4	CSF1R
BOSUTINIB	4	CSF1R
FILGOTINIB	4	CSF1R
BRIGATINIB	4	CSF1R
PEXIDARTINIB	4	CSF1R
PAZOPANIB	4	CSF1R
NINTEDANIB	4	CSF1R
SUNITINIB	4	CSF1R
DASATINIB	4	CSF1R
QUIZARTINIB	4	CSF1R
CRIZOTINIB	4	CSF1R
MIDOSTAURIN	4	CSF1R
IMATINIB	4	CSF1R
VATALANIB	3	CSF1R
DACTOLISIB	3	CSF1R
MASITINIB	3	CSF1R
LINIFANIB	3	CSF1R
SEMAXANIB	3	CSF1R
BRIVANIB	3	CSF1R

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CSF1R
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	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.