Osteogenesis imperfecta type 15

Summary

Osteogenesis imperfecta type 15 (MONDO:0014086) is a disease caused by WNT1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: WNT1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 33

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	osteogenesis imperfecta type 15
Mondo ID	MONDO:0014086
OMIM	615220
DOID	DOID:0110347
UMLS	C3808844
MedGen	815174
GARD	0015919
Is cancer (heuristic)	no

Also known as: OI15 · osteogenesis imperfecta caused by mutation in WNT1 · osteogenesis imperfecta, type XV · WNT1 osteogenesis imperfecta

Data availability: 33 ClinVar variants · 3 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 development disease › osteochondrodysplasia › osteogenesis imperfecta › osteogenesis imperfecta and a reduction of bone mineral density. › osteogenesis imperfecta type 15

Related subtypes (32): Cole-Carpenter syndrome 1, calvarial doughnut lesions-bone fragility syndrome, osteogenesis imperfecta type 1, osteogenesis imperfecta type 2, osteogenesis imperfecta type 4, gnathodiaphyseal dysplasia, geroderma osteodysplastica, osteogenesis imperfecta type 3, osteogenesis imperfecta type 9, osteoporosis-pseudoglioma syndrome, Wiedemann-Rautenstrauch syndrome, spondylo-ocular syndrome, Bruck syndrome 2, osteogenesis imperfecta type 7, osteogenesis imperfecta type 8, osteogenesis imperfecta type 5, osteogenesis imperfecta type 11, autosomal recessive cutis laxa type 2B, osteogenesis imperfecta type 10, osteogenesis imperfecta type 12, osteogenesis imperfecta type 6, short stature-optic atrophy-Pelger-Huët anomaly syndrome, osteogenesis imperfecta type 14, osteogenesis imperfecta type 16, Cole-Carpenter syndrome 2, Singleton-Merten syndrome 2, osteogenesis imperfecta type 17, autosomal recessive cutis laxa type 2A, Ehlers-Danlos syndrome, spondylodysplastic type, 1, Singleton-Merten syndrome 1, osteogenesis imperfecta, type 18, osteogenesis imperfecta, type 19

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

33 retrieved; paginated sample, class counts are floors:

12 likely pathogenic, 7 uncertain significance, 6 pathogenic, 4 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic, 1 benign/likely benign, 1 pathogenic; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
1332774	NM_005430.4(WNT1):c.506dup (p.Cys170fs)	WNT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1372966	NM_005430.4(WNT1):c.681C>A (p.Cys227Ter)	WNT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
180210	NM_005430.4(WNT1):c.1026del (p.Glu343fs)	WNT1	Pathogenic	criteria provided, single submitter
2438690	NM_005430.4(WNT1):c.255del (p.Leu86fs)	WNT1	Pathogenic	criteria provided, single submitter
50257	NM_005430.4(WNT1):c.859dup (p.His287fs)	WNT1	Pathogenic; risk factor	no assertion criteria provided
50258	NM_005430.4(WNT1):c.624+4A>G	WNT1	Pathogenic	no assertion criteria provided
50259	NM_005430.4(WNT1):c.565G>T (p.Glu189Ter)	WNT1	Pathogenic	no assertion criteria provided
50260	NM_005430.4(WNT1):c.884C>A (p.Ser295Ter)	WNT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
50261	NM_005430.4(WNT1):c.946_949dup (p.Ser317fs)	WNT1	Pathogenic	no assertion criteria provided
1332751	NM_000158.4(GBE1):c.1843G>C (p.Ala615Pro)	GBE1	Likely pathogenic	criteria provided, single submitter
1299523	NM_005430.4(WNT1):c.617G>A (p.Gly206Asp)	WNT1	Likely pathogenic	criteria provided, single submitter
1683629	NM_005430.4(WNT1):c.860dup (p.His287fs)	WNT1	Likely pathogenic	criteria provided, single submitter
1687618	NM_005430.4(WNT1):c.893T>G (p.Phe298Cys)	WNT1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2434662	NM_005430.4(WNT1):c.331dup (p.His111fs)	WNT1	Likely pathogenic	criteria provided, single submitter
3336151	NM_005430.4(WNT1):c.397G>A (p.Ala133Thr)	WNT1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3362448	NM_005430.4(WNT1):c.437G>A (p.Gly146Asp)	WNT1	Likely pathogenic	criteria provided, single submitter
3574644	NM_005430.4(WNT1):c.393del (p.Ser132fs)	WNT1	Likely pathogenic	criteria provided, single submitter
4076159	NM_005430.4(WNT1):c.502G>A (p.Gly168Arg)	WNT1	Likely pathogenic	no assertion criteria provided
4819328	NM_005430.4(WNT1):c.887C>T (p.Pro296Leu)	WNT1	Likely pathogenic	criteria provided, single submitter
488347	NM_005430.4(WNT1):c.104+4_104+44del	WNT1	Likely pathogenic	criteria provided, single submitter
50262	NM_005430.4(WNT1):c.1063G>T (p.Val355Phe)	WNT1	Likely pathogenic	criteria provided, single submitter
1212910	NM_005430.4(WNT1):c.506G>A (p.Gly169Asp)	WNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2735848	NM_005430.4(WNT1):c.505G>T (p.Gly169Cys)	WNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2795475	NM_005430.4(WNT1):c.287A>G (p.Gln96Arg)	WNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2806973	NM_005430.4(WNT1):c.437G>T (p.Gly146Val)	WNT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3064878	NM_005430.4(WNT1):c.216dup (p.Arg73fs)	WNT1	Uncertain significance	criteria provided, single submitter
3362746	NM_005430.4(WNT1):c.750C>G (p.Phe250Leu)	WNT1	Uncertain significance	criteria provided, single submitter
3376447	NM_005430.4(WNT1):c.589C>A (p.Leu197Ile)	WNT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
388128	NM_005430.4(WNT1):c.521T>C (p.Ile174Thr)	WNT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
4294048	NM_005430.4(WNT1):c.508T>G (p.Cys170Gly)	WNT1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
WNT1	Definitive	Autosomal recessive	osteogenesis imperfecta type 15	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WNT1	Orphanet:216812	Osteogenesis imperfecta type 3
WNT1	Orphanet:216820	Osteogenesis imperfecta type 4
WNT1	Orphanet:85193	Idiopathic juvenile osteoporosis
GBE1	Orphanet:206583	Adult polyglucosan body disease
GBE1	Orphanet:308621	Glycogen storage disease due to glycogen branching enzyme deficiency, progressive hepatic form
GBE1	Orphanet:308638	Glycogen storage disease due to glycogen branching enzyme deficiency, non progressive hepatic form
GBE1	Orphanet:308655	Glycogen storage disease due to glycogen branching enzyme deficiency, fatal perinatal neuromuscular form
GBE1	Orphanet:308670	Glycogen storage disease due to glycogen branching enzyme deficiency, congenital neuromuscular form
GBE1	Orphanet:308684	Glycogen storage disease due to glycogen branching enzyme deficiency, childhood combined hepatic and myopathic form
GBE1	Orphanet:308698	Glycogen storage disease due to glycogen branching enzyme deficiency, childhood neuromuscular form
GBE1	Orphanet:308712	Glycogen storage disease due to glycogen branching enzyme deficiency, adult neuromuscular form

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
WNT1	HGNC:12774	ENSG00000125084	P04628	Proto-oncogene Wnt-1	gencc,clinvar
GBE1	HGNC:4180	ENSG00000114480	Q04446	1,4-alpha-glucan-branching enzyme	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WNT1	Proto-oncogene Wnt-1	Ligand for members of the frizzled family of seven transmembrane receptors.
GBE1	1,4-alpha-glucan-branching enzyme	Glycogen-branching enzyme participates in the glycogen biosynthetic process along with glycogenin and glycogen synthase.

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)
WNT1	Other/Unknown	no		Wnt, Wnt1, Wnt_CS
GBE1	Antibody/Immunoglobulin	yes		Glyco_hydro_13_N, GH13_cat_dom, A-amylase/branching_C

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
nucleus accumbens	1
superior frontal gyrus	1
biceps brachii	1
gluteal muscle	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WNT1	73	tissue_specific	yes	granulocyte, nucleus accumbens, superior frontal gyrus
GBE1	293	ubiquitous	marker	gluteal muscle, tibialis anterior, biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GBE1	3,402
WNT1	2,506

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GBE1	Q04446	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
WNT1	P04628	86.53

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
Glycogen storage disease type IV (GBE1)	1	1903.3×	0.004	GBE1
Glycogen synthesis	1	407.9×	0.010	GBE1
WNT ligand biogenesis and trafficking	1	211.5×	0.011	WNT1
Disassembly of the destruction complex and recruitment of AXIN to the membrane	1	178.4×	0.011	WNT1
PCP/CE pathway	1	150.3×	0.011	WNT1
Class B/2 (Secretin family receptors)	1	95.2×	0.014	WNT1
Transcriptional regulation of white adipocyte differentiation	1	64.9×	0.017	WNT1
TCF dependent signaling in response to WNT	1	58.9×	0.017	WNT1

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
cerebellum formation	1	8426.0×	0.003	WNT1
midbrain-hindbrain boundary maturation during brain development	1	8426.0×	0.003	WNT1
diencephalon development	1	4213.0×	0.003	WNT1
central nervous system morphogenesis	1	4213.0×	0.003	WNT1
astrocyte-dopaminergic neuron signaling	1	2808.7×	0.003	WNT1
Spemann organizer formation	1	2808.7×	0.003	WNT1
positive regulation of dermatome development	1	2808.7×	0.003	WNT1
forebrain anterior/posterior pattern specification	1	2106.5×	0.003	WNT1
cell proliferation in midbrain	1	1685.2×	0.003	WNT1
embryonic axis specification	1	1203.7×	0.004	WNT1
neuron fate determination	1	1053.2×	0.005	WNT1
positive regulation of hematopoietic stem cell proliferation	1	936.2×	0.005	WNT1
spinal cord association neuron differentiation	1	648.1×	0.005	WNT1
negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway	1	648.1×	0.005	WNT1
positive regulation of insulin-like growth factor receptor signaling pathway	1	601.9×	0.005	WNT1
hepatocyte differentiation	1	601.9×	0.005	WNT1
midbrain dopaminergic neuron differentiation	1	601.9×	0.005	WNT1
negative regulation of cell-substrate adhesion	1	526.6×	0.006	WNT1
negative regulation of cell-cell adhesion	1	495.6×	0.006	WNT1
glycogen biosynthetic process	1	468.1×	0.006	GBE1
cellular response to peptide hormone stimulus	1	421.3×	0.006	WNT1
negative regulation of ubiquitin-dependent protein catabolic process	1	421.3×	0.006	WNT1
signal transduction in response to DNA damage	1	401.2×	0.006	WNT1
embryonic brain development	1	401.2×	0.006	WNT1
hematopoietic stem cell proliferation	1	324.1×	0.006	WNT1
negative regulation of cellular senescence	1	324.1×	0.006	WNT1
myoblast fusion	1	300.9×	0.006	WNT1
positive regulation of lamellipodium assembly	1	300.9×	0.006	WNT1
midbrain development	1	300.9×	0.006	WNT1
animal organ regeneration	1	300.9×	0.006	WNT1

Therapeutics

Drug target analysis

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

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
WNT1	1	1
GBE1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CIRTUVIVINT	1	WNT1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
WNT1	10	Binding:10

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

1 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)
CIRTUVIVINT	1	WNT1

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	WNT1
C	Druggable family + PDB, no drug	1	GBE1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GBE1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.