Paget disease of bone 2, early-onset

Summary

Paget disease of bone 2, early-onset (MONDO:0011183) is a disease caused by TNFRSF11A (GenCC Strong), with 5 cohort genes.

At a glance

• Causal gene: TNFRSF11A (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 831

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Paget disease of bone 2, early-onset
Mondo ID	MONDO:0011183
OMIM	602080
DOID	DOID:0081365
UMLS	C4085251
MedGen	899166
GARD	0024779
Is cancer (heuristic)	no

Also known as: Paget disease of bone 2, early-onset · PDB2

Data availability: 831 ClinVar variants · 2 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 › bone Paget disease › Paget disease of bone 2, early-onset

Related subtypes (4): Paget disease of bone 3, juvenile Paget disease, paget disease of bone 4, Paget disease of bone 6

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

600 retrieved; paginated sample, class counts are floors:

304 uncertain significance, 207 likely benign, 29 conflicting classifications of pathogenicity, 21 pathogenic, 14 benign, 14 benign/likely benign, 8 likely pathogenic, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
208143	NM_003839.4(TNFRSF11A):c.45_62dup (p.Leu16_Leu21dup)	LOC130062628	Pathogenic	criteria provided, multiple submitters, no conflicts
208144	NM_003839.4(TNFRSF11A):c.49_63dup (p.Leu17_Leu21dup)	LOC130062628	Pathogenic	no assertion criteria provided
1069495	NM_003900.5(SQSTM1):c.1170del (p.Asp391fs)	SQSTM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071292	NM_003900.5(SQSTM1):c.1210A>G (p.Met404Val)	SQSTM1	Pathogenic	criteria provided, multiple submitters, no conflicts
1076912	NM_003900.5(SQSTM1):c.244G>T (p.Glu82Ter)	SQSTM1	Pathogenic	criteria provided, single submitter
1323651	NM_003900.5(SQSTM1):c.415del (p.Arg139fs)	SQSTM1	Pathogenic	criteria provided, multiple submitters, no conflicts
1387627	NM_003900.5(SQSTM1):c.301+1G>T	SQSTM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458052	NM_003900.5(SQSTM1):c.1231G>A (p.Gly411Ser)	SQSTM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459183	NM_003900.5(SQSTM1):c.1165G>C (p.Glu389Gln)	SQSTM1	Pathogenic	criteria provided, multiple submitters, no conflicts
1912117	NM_003900.5(SQSTM1):c.815_818del (p.Val271_Ser272insTer)	SQSTM1	Pathogenic	criteria provided, single submitter
1948518	NM_003900.5(SQSTM1):c.259_260insATGCCTTTTCCAGTGACGAGGAATTGACGAGGAAT (p.Met87fs)	SQSTM1	Pathogenic	criteria provided, single submitter
1962648	NM_003900.5(SQSTM1):c.979dup (p.Glu327fs)	SQSTM1	Pathogenic	criteria provided, single submitter
2083476	NM_003900.5(SQSTM1):c.820G>T (p.Glu274Ter)	SQSTM1	Pathogenic	criteria provided, single submitter
2136359	NM_003900.5(SQSTM1):c.1175del (p.Pro392fs)	SQSTM1	Pathogenic	criteria provided, single submitter
2166073	NM_003900.5(SQSTM1):c.901G>T (p.Glu301Ter)	SQSTM1	Pathogenic	criteria provided, single submitter
265782	NM_003900.5(SQSTM1):c.286C>T (p.Arg96Ter)	SQSTM1	Pathogenic	criteria provided, multiple submitters, no conflicts
2943392	NM_003900.5(SQSTM1):c.1111C>T (p.Gln371Ter)	SQSTM1	Pathogenic	criteria provided, single submitter
2948186	NM_003900.5(SQSTM1):c.763dup (p.Val255fs)	SQSTM1	Pathogenic	criteria provided, single submitter
2949509	NM_003900.5(SQSTM1):c.973C>T (p.Gln325Ter)	SQSTM1	Pathogenic	criteria provided, single submitter
2952106	NM_003900.5(SQSTM1):c.309dup (p.Glu104fs)	SQSTM1	Pathogenic	criteria provided, single submitter
3750300	NM_003900.5(SQSTM1):c.571G>T (p.Gly191Ter)	SQSTM1	Pathogenic	criteria provided, single submitter
3753178	NM_003900.5(SQSTM1):c.616_617del (p.Trp206fs)	SQSTM1	Pathogenic	criteria provided, single submitter
3757914	NM_003900.5(SQSTM1):c.686C>A (p.Ser229Ter)	SQSTM1	Pathogenic	criteria provided, single submitter
451357	NM_003900.5(SQSTM1):c.823_824del (p.Ser275fs)	SQSTM1	Pathogenic	criteria provided, multiple submitters, no conflicts
2942752	NM_003900.5(SQSTM1):c.185_205+48delinsCACTACAGAGGTCCTGGTCTGTGCGGGGGCCTCCAGGCCTTCTGCGCTGCAGCCACTGCGCTGTGTCCCCTGTGATTGTCAATCTCCCTAAAGATGGCCCAGAGCAGTGCGGCCTGAATC	LOC129995449	Likely pathogenic	criteria provided, single submitter
1473565	NM_003900.5(SQSTM1):c.970-2A>G	SQSTM1	Likely pathogenic	criteria provided, single submitter
1985646	NM_003900.5(SQSTM1):c.205+2T>C	SQSTM1	Likely pathogenic	criteria provided, single submitter
2940935	NM_003900.5(SQSTM1):c.206-2A>G	SQSTM1	Likely pathogenic	criteria provided, single submitter
2951682	NM_003900.5(SQSTM1):c.1181_*644del (p.Leu394fs)	SQSTM1	Likely pathogenic	criteria provided, single submitter
3749705	NM_003900.5(SQSTM1):c.1145dup (p.Leu382fs)	SQSTM1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · 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
TNFRSF11A	Strong	Autosomal dominant	Paget disease of bone 2, early-onset	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TNFRSF11A	Orphanet:1782	Dysosteosclerosis
TNFRSF11A	Orphanet:178389	Osteopetrosis-hypogammaglobulinemia syndrome
TNFRSF11A	Orphanet:2801	Juvenile Paget disease
TNFRSF11A	Orphanet:391490	Adult-onset myasthenia gravis
TNFRSF11A	Orphanet:85195	Familial expansile osteolysis
SQSTM1	Orphanet:275864	Behavioral variant of frontotemporal dementia
SQSTM1	Orphanet:275872	Frontotemporal dementia with motor neuron disease
SQSTM1	Orphanet:603	Distal myopathy, Welander type
SQSTM1	Orphanet:803	Amyotrophic lateral sclerosis

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TNFRSF11A	HGNC:11908	ENSG00000141655	Q9Y6Q6	Tumor necrosis factor receptor superfamily member 11A	gencc,clinvar
SQSTM1	HGNC:11280	ENSG00000161011	Q13501	Sequestosome-1	clinvar
CANX	HGNC:1473	ENSG00000127022	P27824	Calnexin	clinvar
ZNF354C	HGNC:16736	ENSG00000177932	Q86Y25	Zinc finger protein 354C	clinvar
LTC4S	HGNC:6719	ENSG00000213316	Q16873	Leukotriene C4 synthase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNFRSF11A	Tumor necrosis factor receptor superfamily member 11A	Receptor for TNFSF11/RANKL/TRANCE/OPGL; essential for RANKL-mediated osteoclastogenesis.
SQSTM1	Sequestosome-1	Molecular adapter required for selective macroautophagy (aggrephagy) by acting as a bridge between polyubiquitinated proteins and autophagosomes.
CANX	Calnexin	Calcium-binding protein that interacts with newly synthesized monoglucosylated glycoproteins in the endoplasmic reticulum.
ZNF354C	Zinc finger protein 354C	Transcriptional repressor that inhibits endothelial angiogenic sprouting.
LTC4S	Leukotriene C4 synthase	Catalyzes the conjugation of leukotriene A4 with reduced glutathione (GSH) to form leukotriene C4 with high specificity.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 2 · Druggable fraction: 0.2

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
Transcription factor	2	3.3×	0.343
Enzyme (other)	1	2.4×	0.530
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNFRSF11A	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFR_11, TNFR_11A
SQSTM1	Transcription factor	no		PB1_dom, Znf_ZZ, UBA-like_sf
CANX	Other/Unknown	no		Calret/calnex, Calreticulin/calnexin_P_dom_sf, ConA-like_dom_sf
ZNF354C	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf
LTC4S	Enzyme (other)	yes	4.4.1.20	Membr-assoc_MAPEG, 5_LipOase_AP, FLAP/GST2/LTC4S_CS

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
jejunal mucosa	1
mucosa of sigmoid colon	1
parotid gland	1
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1
calcaneal tendon	1
islet of Langerhans	1
stromal cell of endometrium	1
cardiac muscle of right atrium	1
cortical plate	1
left ventricle myocardium	1
apex of heart	1
male germ line stem cell (sensu Vertebrata) in testis	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNFRSF11A	221	broad	marker	parotid gland, mucosa of sigmoid colon, jejunal mucosa
SQSTM1	241	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland
CANX	148	ubiquitous	marker	stromal cell of endometrium, islet of Langerhans, calcaneal tendon
ZNF354C	195	ubiquitous	marker	cardiac muscle of right atrium, left ventricle myocardium, cortical plate
LTC4S	133	ubiquitous	marker	right uterine tube, male germ line stem cell (sensu Vertebrata) in testis, apex of heart

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CANX	8,019
SQSTM1	7,269
TNFRSF11A	1,186
LTC4S	758
ZNF354C	458

Intra-cohort edges

A	B	Sources
SQSTM1	TNFRSF11A	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SQSTM1	Q13501	26
LTC4S	Q16873	20
TNFRSF11A	Q9Y6Q6	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CANX	P27824	77.15
ZNF354C	Q86Y25	66.18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 71. Enrichment computed across 5 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Biosynthesis of DHA-derived sulfido conjugates	1	2284.0×	0.012	LTC4S
Biosynthesis of protectin and resolvin conjugates in tissue regeneration (PCTR and RCTR)	1	2284.0×	0.012	LTC4S
Virus Assembly and Release	1	1142.0×	0.012	CANX
Assembly of Viral Components at the Budding Site	1	1142.0×	0.012	CANX
Biosynthesis of maresin conjugates in tissue regeneration (MCTR)	1	1142.0×	0.012	LTC4S
p75NTR signals via NF-kB	1	380.7×	0.017	SQSTM1
Biosynthesis of Lipoxins (LX)	1	380.7×	0.017	LTC4S
Biosynthesis of DHA-derived SPMs	1	380.7×	0.017	LTC4S
Biosynthesis of specialized proresolving mediators (SPMs)	1	380.7×	0.017	LTC4S
Maturation of spike protein	1	380.7×	0.017	CANX
Signaling by Interleukins	2	25.7×	0.017	SQSTM1, CANX
Synthesis of 5-eicosatetraenoic acids	1	253.8×	0.020	LTC4S
Mitophagy	1	207.6×	0.020	SQSTM1
Interleukin-27 signaling	1	207.6×	0.020	CANX
Interleukin-35 Signalling	1	190.3×	0.020	CANX
Pexophagy	1	190.3×	0.020	SQSTM1
p75NTR recruits signalling complexes	1	175.7×	0.020	SQSTM1
NF-kB is activated and signals survival	1	175.7×	0.020	SQSTM1
Translation of Structural Proteins	1	175.7×	0.020	CANX
Cytokine Signaling in Immune system	2	16.3×	0.020	SQSTM1, CANX
NRIF signals cell death from the nucleus	1	142.8×	0.023	SQSTM1
Calnexin/calreticulin cycle	1	142.8×	0.023	CANX
TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway	1	134.3×	0.023	TNFRSF11A
Synthesis of Leukotrienes (LT) and Eoxins (EX)	1	114.2×	0.025	LTC4S
Arachidonate metabolism	1	114.2×	0.025	LTC4S
Interleukin-12 family signaling	1	95.2×	0.029	CANX
N-glycan trimming in the ER and Calnexin/Calreticulin cycle	1	84.6×	0.031	CANX
Translation of Structural Proteins	1	81.6×	0.031	CANX
Antigen Presentation: Folding, assembly and peptide loading of class I MHC	1	78.8×	0.031	CANX
PINK1-PRKN Mediated Mitophagy	1	71.4×	0.033	SQSTM1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of fever generation by positive regulation of prostaglandin secretion	1	1685.2×	0.014	TNFRSF11A
circadian temperature homeostasis	1	1123.5×	0.014	TNFRSF11A
brown fat cell proliferation	1	1123.5×	0.014	SQSTM1
protein targeting to vacuole involved in autophagy	1	1123.5×	0.014	SQSTM1
multinuclear osteoclast differentiation	1	1123.5×	0.014	TNFRSF11A
response to mitochondrial depolarisation	1	561.7×	0.020	SQSTM1
cellular response to zinc ion starvation	1	481.5×	0.020	TNFRSF11A
regulation of Ras protein signal transduction	1	374.5×	0.020	SQSTM1
aggrephagy	1	337.0×	0.020	SQSTM1
protein folding in endoplasmic reticulum	1	280.9×	0.020	CANX
protein localization to perinuclear region of cytoplasm	1	280.9×	0.020	SQSTM1
leukotriene metabolic process	1	259.3×	0.020	LTC4S
leukotriene biosynthetic process	1	259.3×	0.020	LTC4S
negative regulation of sprouting angiogenesis	1	259.3×	0.020	ZNF354C
negative regulation of toll-like receptor 4 signaling pathway	1	224.7×	0.020	SQSTM1
membraneless organelle assembly	1	224.7×	0.020	SQSTM1
pexophagy	1	210.7×	0.020	SQSTM1
regulation of protein complex stability	1	210.7×	0.020	SQSTM1
positive regulation of bone resorption	1	198.3×	0.020	TNFRSF11A
mammary gland alveolus development	1	198.3×	0.020	TNFRSF11A
regulation of mitochondrion organization	1	168.5×	0.020	SQSTM1
cellular response to stress	1	168.5×	0.020	SQSTM1
lymph node development	1	160.5×	0.020	TNFRSF11A
negative regulation of ferroptosis	1	160.5×	0.020	SQSTM1
autophagy of mitochondrion	1	146.5×	0.021	SQSTM1
positive regulation of long-term synaptic potentiation	1	134.8×	0.022	SQSTM1
temperature homeostasis	1	129.6×	0.022	SQSTM1
response to tumor necrosis factor	1	124.8×	0.022	TNFRSF11A
monocyte chemotaxis	1	116.2×	0.022	TNFRSF11A
positive regulation of osteoclast differentiation	1	116.2×	0.022	TNFRSF11A

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 5 evidence-associated genes (60%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LTC4S	2	3
TNFRSF11A	0	0
SQSTM1	0	0
CANX	0	0
ZNF354C	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FIBOFLAPON	3	LTC4S
AZD-9898	1	LTC4S

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
LTC4S	37	Binding:36, ADMET:1
SQSTM1	20	Binding:20
CANX	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
LTC4S	4.4.1.20	leukotriene-C4 synthase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 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)
FIBOFLAPON	3	LTC4S
AZD-9898	1	LTC4S

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	LTC4S
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	TNFRSF11A, SQSTM1, CANX, ZNF354C

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TNFRSF11A	0	—
SQSTM1	20	—
CANX	2	—
ZNF354C	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.