Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1

Summary

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1 (MONDO:0020749) is a disease caused by TYROBP (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: TYROBP (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 40

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1
Mondo ID	MONDO:0020749
OMIM	221770
UMLS	C4721893
MedGen	1648386
GARD	0025236
Is cancer (heuristic)	no

Also known as: polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1

Data availability: 40 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly › polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1

Related subtypes (1): polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 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

ClinVar germline variants

40 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 6 pathogenic, 5 pathogenic/likely pathogenic, 5 conflicting classifications of pathogenicity, 5 benign/likely benign, 5 likely pathogenic, 3 benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
5795	NC_000019.10:g.35905861_35911126del	LOC130064269	Pathogenic	no assertion criteria provided
192241	NM_018965.4(TREM2):c.113A>G (p.Tyr38Cys)	TREM2	Pathogenic	criteria provided, single submitter
192242	NM_018965.4(TREM2):c.197C>T (p.Thr66Met)	TREM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5218	NM_018965.4(TREM2):c.377T>G (p.Val126Gly)	TREM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5219	NM_018965.4(TREM2):c.97C>T (p.Gln33Ter)	TREM2	Pathogenic	criteria provided, multiple submitters, no conflicts
56722	NM_018965.4(TREM2):c.313del (p.Ala105fs)	TREM2	Pathogenic	criteria provided, single submitter
56723	NM_018965.4(TREM2):c.40+4_40+6del	TREM2	Pathogenic/Likely pathogenic	no assertion criteria provided
56724	NM_018965.4(TREM2):c.40G>T (p.Glu14Ter)	TREM2	Pathogenic	criteria provided, single submitter
56725	NM_018965.4(TREM2):c.482+2T>C	TREM2	Pathogenic/Likely pathogenic	no assertion criteria provided
56395	NM_003332.4(TYROBP):c.141del (p.Met48fs)	TYROBP	Pathogenic/Likely pathogenic	no assertion criteria provided
5797	NM_003332.4(TYROBP):c.2T>C (p.Met1Thr)	TYROBP	Pathogenic	no assertion criteria provided
5213	NM_018965.4(TREM2):c.233G>A (p.Trp78Ter)	TREM2	Likely pathogenic	criteria provided, single submitter
56721	NM_018965.4(TREM2):c.269del (p.Gly90fs)	TREM2	Likely pathogenic	no assertion criteria provided
4849333	NM_003332.4(TYROBP):c.178del (p.Ala60fs)	TYROBP	Likely pathogenic	criteria provided, single submitter
56394	NM_003332.4(TYROBP):c.116G>A (p.Ser39Asn)	TYROBP	Likely pathogenic	no assertion criteria provided
56397	NM_003332.4(TYROBP):c.262G>T (p.Glu88Ter)	TYROBP	Likely pathogenic	criteria provided, single submitter
290058	NM_018965.4(TREM2):c.399G>T (p.Leu133=)	TREM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
522336	NM_018965.4(TREM2):c.514C>T (p.Pro172Ser)	TREM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
732760	NM_003332.4(TYROBP):c.46C>T (p.Leu16=)	TYROBP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
737347	NM_003332.4(TYROBP):c.111G>A (p.Thr37=)	TYROBP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
892113	NM_003332.4(TYROBP):c.180C>G (p.Ala60=)	TYROBP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
328889	NM_003332.4(TYROBP):c.*103T>A	TYROBP	Uncertain significance	criteria provided, single submitter
328890	NM_003332.4(TYROBP):c.*85C>T	TYROBP	Uncertain significance	criteria provided, single submitter
328893	NM_003332.4(TYROBP):c.*5G>A	TYROBP	Uncertain significance	criteria provided, single submitter
328897	NM_003332.4(TYROBP):c.-34C>T	TYROBP	Uncertain significance	criteria provided, single submitter
328898	NM_003332.4(TYROBP):c.-50G>A	TYROBP	Uncertain significance	criteria provided, single submitter
56396	NM_003332.4(TYROBP):c.145G>C (p.Gly49Arg)	TYROBP	Uncertain significance	criteria provided, single submitter
890876	NM_003332.4(TYROBP):c.*154T>C	TYROBP	Uncertain significance	criteria provided, single submitter
892112	NM_003332.4(TYROBP):c.230-3C>T	TYROBP	Uncertain significance	criteria provided, single submitter
892114	NM_003332.4(TYROBP):c.140T>C (p.Val47Ala)	TYROBP	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 7 · 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
TYROBP	Strong	Autosomal recessive	polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TYROBP	Orphanet:2770	Nasu-Hakola disease
TREM2	Orphanet:100069	Semantic dementia
TREM2	Orphanet:100070	Progressive non-fluent aphasia
TREM2	Orphanet:1020	Early-onset autosomal dominant Alzheimer disease
TREM2	Orphanet:275864	Behavioral variant of frontotemporal dementia
TREM2	Orphanet:2770	Nasu-Hakola disease
TREM2	Orphanet:803	Amyotrophic lateral sclerosis

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
TYROBP	HGNC:12449	ENSG00000011600	O43914	TYRO protein tyrosine kinase-binding protein	gencc,clinvar
TREM2	HGNC:17761	ENSG00000095970	Q9NZC2	Triggering receptor expressed on myeloid cells 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TYROBP	TYRO protein tyrosine kinase-binding protein	Adapter protein which non-covalently associates with activating receptors found on the surface of a variety of immune cells to mediate signaling and cell activation following ligand binding by the receptors.
TREM2	Triggering receptor expressed on myeloid cells 2	Forms a receptor signaling complex with TYROBP which mediates signaling and cell activation following ligand binding.

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
Antibody/Immunoglobulin	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TYROBP	Other/Unknown	no		Tyrobp
TREM2	Antibody/Immunoglobulin	yes		Ig_V-set, Ig-like_fold, Ig-like_dom_sf

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
leukocyte	1
monocyte	1
mononuclear cell	1
C1 segment of cervical spinal cord	1
amniotic fluid	1
spinal cord	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TYROBP	271	broad	marker	monocyte, mononuclear cell, leukocyte
TREM2	186	broad	marker	C1 segment of cervical spinal cord, spinal cord, amniotic fluid

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TYROBP	2,723
TREM2	2,354

Intra-cohort edges

A	B	Sources
TREM2	TYROBP	intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TREM2	Q9NZC2	15
TYROBP	O43914	5

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
Other semaphorin interactions	2	601.0×	1e-05	TYROBP, TREM2
DAP12 interactions	2	475.8×	1e-05	TYROBP, TREM2
DAP12 signaling	2	368.4×	1e-05	TYROBP, TREM2
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	2	87.2×	2e-04	TYROBP, TREM2
Signal regulatory protein family interactions	1	335.9×	0.004	TYROBP
Neutrophil degranulation	1	11.5×	0.085	TYROBP

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
microglial cell activation involved in immune response	2	3370.4×	5e-06	TYROBP, TREM2
positive regulation of macrophage fusion	2	3370.4×	5e-06	TYROBP, TREM2
T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell	2	2106.5×	8e-06	TYROBP, TREM2
amyloid-beta clearance	2	936.2×	3e-05	TYROBP, TREM2
apoptotic cell clearance	2	887.0×	3e-05	TYROBP, TREM2
response to axon injury	2	510.7×	8e-05	TYROBP, TREM2
cellular response to amyloid-beta	2	391.9×	1e-04	TYROBP, TREM2
osteoclast differentiation	2	343.9×	1e-04	TYROBP, TREM2
myeloid leukocyte activation	1	8426.0×	7e-04	TYROBP
detection of peptidoglycan	1	8426.0×	7e-04	TREM2
regulation of toll-like receptor 6 signaling pathway	1	8426.0×	7e-04	TREM2
positive regulation of complement activation, classical pathway	1	8426.0×	7e-04	TREM2
detection of lipoteichoic acid	1	8426.0×	7e-04	TREM2
regulation of macrophage inflammatory protein 1 alpha production	1	8426.0×	7e-04	TREM2
import into cell	1	8426.0×	7e-04	TREM2
regulation of hippocampal neuron apoptotic process	1	8426.0×	7e-04	TREM2
regulation of plasma membrane bounded cell projection organization	1	8426.0×	7e-04	TREM2
positive regulation of C-C chemokine receptor CCR7 signaling pathway	1	8426.0×	7e-04	TREM2
excitatory synapse pruning	1	8426.0×	7e-04	TREM2
positive regulation of synapse pruning	1	8426.0×	7e-04	TREM2
positive regulation of CD40 signaling pathway	1	8426.0×	7e-04	TREM2
stimulatory killer cell immunoglobulin-like receptor signaling pathway	1	4213.0×	0.001	TYROBP
positive regulation of antigen processing and presentation of peptide antigen via MHC class II	1	4213.0×	0.001	TREM2
negative regulation of cell activation	1	4213.0×	0.001	TREM2
positive regulation of engulfment of apoptotic cell	1	4213.0×	0.001	TREM2
natural killer cell mediated immunity	1	2808.7×	0.001	TYROBP
negative regulation of triglyceride storage	1	2808.7×	0.001	TREM2
positive regulation of high-density lipoprotein particle clearance	1	2808.7×	0.001	TREM2
negative regulation of astrocyte activation	1	2808.7×	0.001	TREM2
negative regulation of macrophage colony-stimulating factor signaling pathway	1	2808.7×	0.001	TREM2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

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
TYROBP	0	0
TREM2	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
TREM2	1	Binding:1

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

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	TREM2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TYROBP

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TYROBP	0	—
TREM2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.