Dysosteosclerosis

Summary

Dysosteosclerosis (MONDO:0009138) is a disease with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 2
• Phenotypes (HPO): 22

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		23	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0000256	Macrocephaly	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0000639	Nystagmus	Very frequent (80-99%)
HP:0000648	Optic atrophy	Very frequent (80-99%)
HP:0000682	Abnormality of dental enamel	Very frequent (80-99%)
HP:0000684	Delayed eruption of teeth	Very frequent (80-99%)
HP:0000926	Platyspondyly	Very frequent (80-99%)
HP:0000944	Abnormal metaphysis morphology	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001291	Abnormal cranial nerve morphology	Very frequent (80-99%)
HP:0001629	Ventricular septal defect	Very frequent (80-99%)
HP:0002376	Developmental regression	Very frequent (80-99%)
HP:0002514	Cerebral calcification	Very frequent (80-99%)
HP:0002757	Recurrent fractures	Very frequent (80-99%)
HP:0003301	Irregular vertebral endplates	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0004493	Craniofacial hyperostosis	Very frequent (80-99%)
HP:0008479	Hypoplastic vertebral bodies	Very frequent (80-99%)
HP:0011001	Increased bone mineral density	Very frequent (80-99%)
HP:0100670	Rough bone trabeculation	Very frequent (80-99%)
HP:0008065	Aplasia/Hypoplasia of the skin	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	dysosteosclerosis
Mondo ID	MONDO:0009138
MeSH	C562973
OMIM	224300
Orphanet	1782
ICD-11	1853176074
SNOMED CT	254123002
UMLS	C0432262
MedGen	98150
GARD	0002012
Is cancer (heuristic)	no

Also known as: dysosteosclerosis

Data availability: 2 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 › skeletal dysplasia › osteopetrosis › dysosteosclerosis

Related subtypes (10): melorheostosis, osteomesopyknosis, 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, 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

2 retrieved; paginated sample, class counts are floors:

1 likely pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
3780698	NM_006019.4(TCIRG1):c.2118+1G>A	TCIRG1	Likely pathogenic	criteria provided, single submitter
934211	NM_018344.6(SLC29A3):c.303_320dup (p.Tyr102_Leu107dup)	LOC105378353	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 26 · Orphanet: 11 · 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
SLC29A3	Supportive	Autosomal recessive	dysosteosclerosis	5
TCIRG1	Supportive	Autosomal recessive	dysosteosclerosis	9
TNFRSF11A	Supportive	Autosomal recessive	dysosteosclerosis	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TCIRG1	Orphanet:1782	Dysosteosclerosis
TCIRG1	Orphanet:210110	Intermediate osteopetrosis
TCIRG1	Orphanet:486	Autosomal dominant severe congenital neutropenia
TCIRG1	Orphanet:667	Autosomal recessive malignant osteopetrosis
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
SLC29A3	Orphanet:168569	H syndrome
SLC29A3	Orphanet:1782	Dysosteosclerosis

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TCIRG1	HGNC:11647	ENSG00000110719	Q13488	V-type proton ATPase 116 kDa subunit a 3	gencc,clinvar
TNFRSF11A	HGNC:11908	ENSG00000141655	Q9Y6Q6	Tumor necrosis factor receptor superfamily member 11A	gencc
SLC29A3	HGNC:23096	ENSG00000198246	Q9BZD2	Equilibrative nucleoside transporter 3	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TCIRG1	V-type proton ATPase 116 kDa subunit a 3	Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.
TNFRSF11A	Tumor necrosis factor receptor superfamily member 11A	Receptor for TNFSF11/RANKL/TRANCE/OPGL; essential for RANKL-mediated osteoclastogenesis.
SLC29A3	Equilibrative nucleoside transporter 3	Uniporter that mediates the facilitative transport of nucleoside across lysosomal and mitochondrial membranes.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TCIRG1	Other/Unknown	no		V-ATPase_116kDa_su, V-type_ATPase_116kDa_su_euka
TNFRSF11A	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFR_11, TNFR_11A
SLC29A3	Other/Unknown	no		Eqnu_transpt

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	1
granulocyte	1
spleen	1
jejunal mucosa	1
mucosa of sigmoid colon	1
parotid gland	1
olfactory bulb	1
primordial germ cell in gonad	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TCIRG1	148	ubiquitous	marker	granulocyte, blood, spleen
TNFRSF11A	221	broad	marker	parotid gland, mucosa of sigmoid colon, jejunal mucosa
SLC29A3	219	ubiquitous	yes	olfactory bulb, type B pancreatic cell, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TCIRG1	1,931
TNFRSF11A	1,186
SLC29A3	864

Intra-cohort edges

A	B	Sources
SLC29A3	TCIRG1	string_interaction
TCIRG1	TNFRSF11A	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNFRSF11A	Q9Y6Q6	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TCIRG1	Q13488	83.52
SLC29A3	Q9BZD2	82.40

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC29A3 causes histiocytosis-lymphadenopathy plus syndrome (HLAS)	1	3806.7×	0.005	SLC29A3
Ribavirin ADME	1	346.1×	0.019	SLC29A3
Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane	1	317.2×	0.019	SLC29A3
TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway	1	223.9×	0.020	TNFRSF11A
Insulin receptor recycling	1	126.9×	0.023	TCIRG1
Transferrin endocytosis and recycling	1	122.8×	0.023	TCIRG1
ROS and RNS production in phagocytes	1	112.0×	0.023	TCIRG1
Transport of vitamins, nucleosides, and related molecules	1	90.6×	0.024	SLC29A3
Drug ADME	1	76.1×	0.024	SLC29A3
SLC transporter disorders	1	68.0×	0.024	SLC29A3
Amino acids regulate mTORC1	1	66.8×	0.024	TCIRG1
TNFR2 non-canonical NF-kB pathway	1	60.4×	0.025	TNFRSF11A
Disorders of transmembrane transporters	1	46.4×	0.030	SLC29A3
Ion channel transport	1	32.0×	0.040	TCIRG1
SLC-mediated transmembrane transport	1	19.7×	0.060	SLC29A3
Transport of small molecules	1	8.4×	0.129	SLC29A3
Neutrophil degranulation	1	7.7×	0.132	TCIRG1
Disease	1	4.4×	0.212	SLC29A3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
osteoclast differentiation	2	229.3×	0.002	TCIRG1, TNFRSF11A
ossification	2	151.8×	0.002	TCIRG1, TNFRSF11A
response to silver ion	1	5617.3×	0.003	TCIRG1
dentin mineralization	1	5617.3×	0.003	TCIRG1
protein catabolic process in the vacuole	1	2808.7×	0.003	TCIRG1
memory T cell activation	1	2808.7×	0.003	TCIRG1
positive regulation of fever generation by positive regulation of prostaglandin secretion	1	2808.7×	0.003	TNFRSF11A
pyrimidine nucleobase transmembrane transport	1	2808.7×	0.003	SLC29A3
regulation of proton transport	1	1872.4×	0.003	TCIRG1
nucleoside transport	1	1872.4×	0.003	SLC29A3
T-helper 1 cell activation	1	1872.4×	0.003	TCIRG1
circadian temperature homeostasis	1	1872.4×	0.003	TNFRSF11A
multinuclear osteoclast differentiation	1	1872.4×	0.003	TNFRSF11A
guanine transmembrane transport	1	1872.4×	0.003	SLC29A3
uracil transmembrane transport	1	1872.4×	0.003	SLC29A3
cytidine transport	1	1404.3×	0.003	SLC29A3
inosine transport	1	1404.3×	0.003	SLC29A3
osteoclast proliferation	1	1123.5×	0.003	TCIRG1
obsolete serotonin transport	1	1123.5×	0.003	SLC29A3
nucleobase transport	1	1123.5×	0.003	SLC29A3
adenosine transport	1	1123.5×	0.003	SLC29A3
tooth eruption	1	1123.5×	0.003	TCIRG1
uridine transmembrane transport	1	936.2×	0.003	SLC29A3
nucleoside transmembrane transport	1	936.2×	0.003	SLC29A3
purine nucleobase transmembrane transport	1	936.2×	0.003	SLC29A3
cellular response to zinc ion starvation	1	802.5×	0.003	TNFRSF11A
pH reduction	1	802.5×	0.003	TCIRG1
establishment of vesicle localization	1	802.5×	0.003	TCIRG1
phagosome acidification	1	802.5×	0.003	TCIRG1
obsolete norepinephrine transport	1	624.1×	0.004	SLC29A3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TCIRG1	0	0
TNFRSF11A	0	0
SLC29A3	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
SLC29A3	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	TCIRG1, TNFRSF11A, SLC29A3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TCIRG1	0	—
TNFRSF11A	0	—
SLC29A3	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.