Sclerosteosis

Summary

Sclerosteosis (MONDO:0017838) is a disease with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• Phenotypes (HPO): 14

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		80	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0000098	Tall stature	Very frequent (80-99%)
HP:0000366	Abnormality of the nose	Very frequent (80-99%)
HP:0001233	2-3 finger syndactyly	Very frequent (80-99%)
HP:0003103	Abnormal cortical bone morphology	Very frequent (80-99%)
HP:0004493	Craniofacial hyperostosis	Very frequent (80-99%)
HP:0005019	Diaphyseal thickening	Very frequent (80-99%)
HP:0006101	Finger syndactyly	Very frequent (80-99%)
HP:0009838	Curved distal phalanges of the hand	Very frequent (80-99%)
HP:0011001	Increased bone mineral density	Very frequent (80-99%)
HP:0100798	Fingernail dysplasia	Very frequent (80-99%)
HP:0000407	Sensorineural hearing impairment	Frequent (30-79%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0010628	Facial palsy	Frequent (30-79%)
HP:0000648	Optic atrophy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	sclerosteosis
Mondo ID	MONDO:0017838
MeSH	C537525
OMIM	269500
Orphanet	3152
DOID	DOID:0060251
ICD-11	371637416
NCIT	C131133
SNOMED CT	17568006
UMLS	C0265301
MedGen	120530
GARD	0004771
Is cancer (heuristic)	no

Also known as: cortical hyperostosis with syndactyly · cortical hyperostosis-syndactyly syndrome

Data availability: 2 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone remodeling disease › hyperostosis › sclerosteosis

Related subtypes (8): exostosis, bone Paget disease, diffuse idiopathic skeletal hyperostosis, Caffey disease, autosomal dominant osteosclerosis, Worth type, craniodiaphyseal dysplasia, hyperostosis corticalis generalisata, X-linked calvarial hyperostosis

Subtypes (2): sclerosteosis 1, sclerosteosis 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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 35 · 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
SOST	Strong	Autosomal recessive	sclerosteosis 1	8
CORIN	Supportive	Autosomal recessive	sclerosteosis	14
LRP4	Supportive	Autosomal recessive	sclerosteosis	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SOST	Orphanet:1513	Craniodiaphyseal dysplasia
SOST	Orphanet:3152	Sclerosteosis
SOST	Orphanet:3416	Hyperostosis corticalis generalisata
CORIN	Orphanet:275555	Preeclampsia
LRP4	Orphanet:3152	Sclerosteosis
LRP4	Orphanet:3258	Cenani-Lenz syndrome
LRP4	Orphanet:98913	Postsynaptic congenital myasthenic syndrome

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
SOST	HGNC:13771	ENSG00000167941	Q9BQB4	Sclerostin	gencc
CORIN	HGNC:19012	ENSG00000145244	Q9Y5Q5	Atrial natriuretic peptide-converting enzyme	gencc
LRP4	HGNC:6696	ENSG00000134569	O75096	Low-density lipoprotein receptor-related protein 4	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SOST	Sclerostin	Negative regulator of bone growth that acts through inhibition of Wnt signaling and bone formation.
CORIN	Atrial natriuretic peptide-converting enzyme	Serine-type endopeptidase involved in atrial natriuretic peptide (NPPA) and brain natriuretic peptide (NPPB) processing.
LRP4	Low-density lipoprotein receptor-related protein 4	Mediates SOST-dependent inhibition of bone formation.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Protease	1	12.2×	0.159
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SOST	Other/Unknown	no		Cys_knot_C, Sclerostin/SOSTDC1, Cystine-knot_cytokine
CORIN	Protease	yes		SRCR, Trypsin_dom, LDrepeatLR_classA_rpt
LRP4	Other/Unknown	no		LDLR_classB_rpt, EGF, EGF-like_Ca-bd_dom

Expression context

Cohort genes with no expression data: 0.

3 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
descending thoracic aorta	1
male germ line stem cell (sensu Vertebrata) in testis	1
trabecular bone tissue	1
cardiac muscle of right atrium	1
heart right ventricle	1
myocardium	1
dorsal motor nucleus of vagus nerve	1
medial globus pallidus	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SOST	73	broad	marker	trabecular bone tissue, descending thoracic aorta, male germ line stem cell (sensu Vertebrata) in testis
CORIN	176	tissue_specific	marker	cardiac muscle of right atrium, heart right ventricle, myocardium
LRP4	242	ubiquitous	marker	ventricular zone, dorsal motor nucleus of vagus nerve, medial globus pallidus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SOST	2,417
CORIN	1,291
LRP4	1,250

Intra-cohort edges

A	B	Sources
LRP4	SOST	biogrid_interaction, intact

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SOST	Q9BQB4	3
LRP4	O75096	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CORIN	Q9Y5Q5	70.20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Negative regulation of TCF-dependent signaling by WNT ligand antagonists	1	237.9×	0.016	SOST
Physiological factors	1	223.9×	0.016	CORIN
ECM proteoglycans	1	50.1×	0.037	LRP4
TCF dependent signaling in response to WNT	1	39.2×	0.037	SOST
Signaling by WNT	1	37.3×	0.037	SOST
Extracellular matrix organization	1	21.0×	0.055	LRP4
Signal Transduction	1	3.4×	0.267	SOST

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
negative regulation of ossification	2	416.1×	3e-04	SOST, LRP4
positive regulation of presynaptic membrane organization	1	5617.3×	0.003	LRP4
negative regulation of canonical Wnt signaling pathway	2	78.6×	0.003	SOST, LRP4
regulation of systemic arterial blood pressure by atrial natriuretic peptide	1	1872.4×	0.004	CORIN
synaptic assembly at neuromuscular junction	1	1872.4×	0.004	LRP4
regulation of renal sodium excretion	1	1404.3×	0.005	CORIN
postsynaptic membrane assembly	1	802.5×	0.006	LRP4
amyloid-beta clearance by cellular catabolic process	1	702.2×	0.006	LRP4
skeletal muscle acetylcholine-gated channel clustering	1	624.1×	0.006	LRP4
positive regulation of skeletal muscle acetylcholine-gated channel clustering	1	624.1×	0.006	LRP4
presynaptic membrane assembly	1	561.7×	0.006	LRP4
generation of neurons	1	510.7×	0.006	LRP4
cellular response to parathyroid hormone stimulus	1	468.1×	0.006	SOST
enzyme-linked receptor protein signaling pathway	1	432.1×	0.006	LRP4
negative regulation of axonogenesis	1	432.1×	0.006	LRP4
peptide hormone processing	1	312.1×	0.008	CORIN
regulation of cardiac conduction	1	280.9×	0.009	CORIN
proximal/distal pattern formation	1	216.1×	0.010	LRP4
positive regulation of Rac protein signal transduction	1	216.1×	0.010	LRP4
Rac protein signal transduction	1	187.2×	0.011	LRP4
negative regulation of protein-containing complex assembly	1	151.8×	0.012	SOST
dendrite morphogenesis	1	144.0×	0.012	LRP4
dorsal/ventral pattern formation	1	140.4×	0.012	LRP4
limb development	1	137.0×	0.012	LRP4
hair follicle development	1	127.7×	0.013	LRP4
negative regulation of Wnt signaling pathway	1	114.6×	0.013	SOST
regulation of postsynapse assembly	1	114.6×	0.013	LRP4
response to mechanical stimulus	1	100.3×	0.014	SOST
odontogenesis of dentin-containing tooth	1	100.3×	0.014	LRP4
embryonic digit morphogenesis	1	100.3×	0.014	LRP4

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
SOST	CIANIDANOL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SOST	2	4
CORIN	0	0
LRP4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CIANIDANOL	4	SOST
COUMARIN	4	SOST

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SOST	9	Binding:9

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

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)
CIANIDANOL	4	SOST
COUMARIN	4	SOST

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SOST
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	CORIN
E	Difficult family or no structure, no drug	1	LRP4

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)
CORIN	0	—
LRP4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.