Multiple synostoses syndrome 3

Summary

Multiple synostoses syndrome 3 (MONDO:0013064) is a disease caused by FGF9 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: FGF9 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 88

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple synostoses syndrome 3
Mondo ID	MONDO:0013064
MeSH	C567839
OMIM	612961
DOID	DOID:0081319
UMLS	C2751826
MedGen	414116
GARD	0015597
Is cancer (heuristic)	no

Also known as: FGF9 multiple synostoses syndrome · multiple synostoses syndrome 3 · multiple synostoses syndrome caused by mutation in FGF9 · multiple synostoses syndrome type 3 · SYNS3

Data availability: 88 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 › dysostosis › synostosis › multiple synostoses syndrome › multiple synostoses syndrome 3

Related subtypes (3): multiple synostoses syndrome 1, multiple synostoses syndrome 2, multiple synostoses syndrome 4

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

88 retrieved; paginated sample, class counts are floors:

50 uncertain significance, 31 benign, 2 likely pathogenic, 2 conflicting classifications of pathogenicity, 2 pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
444874	NM_002010.3(FGF9):c.184A>G (p.Arg62Gly)	FGF9	Pathogenic	no assertion criteria provided
8705	NM_002010.3(FGF9):c.296G>A (p.Ser99Asn)	FGF9	Pathogenic	no assertion criteria provided
1804963	NM_002010.3(FGF9):c.11T>C (p.Leu4Ser)	FGF9	Likely pathogenic	criteria provided, single submitter
2413189	NM_002010.3(FGF9):c.430T>C (p.Trp144Arg)	FGF9	Likely pathogenic	criteria provided, single submitter
311422	NM_002010.3(FGF9):c.283C>G (p.Leu95Val)	FGF9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
881305	NM_002010.3(FGF9):c.*274A>G	FGF9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
311402	NM_002010.3(FGF9):c.-796C>T	FGF9	Uncertain significance	criteria provided, single submitter
311403	NM_002010.3(FGF9):c.-777G>T	FGF9	Uncertain significance	criteria provided, single submitter
311406	NM_002010.3(FGF9):c.-703C>T	FGF9	Uncertain significance	criteria provided, single submitter
311408	NM_002010.3(FGF9):c.-452A>T	FGF9	Uncertain significance	criteria provided, single submitter
311412	NM_002010.3(FGF9):c.-256G>A	FGF9	Uncertain significance	criteria provided, single submitter
311414	NM_002010.3(FGF9):c.-151G>T	FGF9	Uncertain significance	criteria provided, single submitter
311419	NM_002010.3(FGF9):c.-45C>T	FGF9	Uncertain significance	criteria provided, single submitter
311427	NM_002010.3(FGF9):c.*56C>T	FGF9	Uncertain significance	criteria provided, single submitter
311428	NM_002010.3(FGF9):c.*124C>A	FGF9	Uncertain significance	criteria provided, single submitter
311438	NM_002010.3(FGF9):c.*306A>G	FGF9	Uncertain significance	criteria provided, single submitter
311442	NM_002010.3(FGF9):c.*380C>G	FGF9	Uncertain significance	criteria provided, single submitter
311448	NM_002010.3(FGF9):c.*566T>A	FGF9	Uncertain significance	criteria provided, single submitter
311449	NM_002010.3(FGF9):c.*713T>C	FGF9	Uncertain significance	criteria provided, single submitter
311450	NM_002010.3(FGF9):c.*736C>T	FGF9	Uncertain significance	criteria provided, single submitter
311451	NM_002010.3(FGF9):c.*737G>A	FGF9	Uncertain significance	criteria provided, single submitter
311452	NM_002010.3(FGF9):c.*737G>T	FGF9	Uncertain significance	criteria provided, single submitter
311456	NM_002010.3(FGF9):c.*1360C>T	FGF9	Uncertain significance	criteria provided, single submitter
311457	NM_002010.3(FGF9):c.*1471C>T	FGF9	Uncertain significance	criteria provided, single submitter
311461	NM_002010.3(FGF9):c.*1847G>T	FGF9	Uncertain significance	criteria provided, single submitter
311463	NM_002010.3(FGF9):c.*1903C>T	FGF9	Uncertain significance	criteria provided, single submitter
311464	NM_002010.3(FGF9):c.*2186T>A	FGF9	Uncertain significance	criteria provided, single submitter
311467	NM_002010.3(FGF9):c.*2363A>G	FGF9	Uncertain significance	criteria provided, single submitter
311472	NM_002010.3(FGF9):c.*2586A>G	FGF9	Uncertain significance	criteria provided, single submitter
311474	NM_002010.3(FGF9):c.*2787G>T	FGF9	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
FGF9	Definitive	Autosomal dominant	multiple synostoses syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FGF9	Orphanet:3237	Multiple synostoses syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FGF9	HGNC:3687	ENSG00000102678	P31371	Fibroblast growth factor 9	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FGF9	Fibroblast growth factor 9	Plays an important role in the regulation of embryonic development, cell proliferation, cell differentiation and cell migration.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FGF9	Other/Unknown	no		Fibroblast_GF_fam, IL1/FGF

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	1
renal medulla	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FGF9	237	broad	marker	secondary oocyte, renal medulla, oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FGF9	4,036

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FGF9	P31371	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 38. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
FGFR3b ligand binding and activation	1	1631.4×	0.003	FGF9
Signaling by activated point mutants of FGFR1	1	951.7×	0.003	FGF9
Signaling by activated point mutants of FGFR3	1	951.7×	0.003	FGF9
FGFR3c ligand binding and activation	1	878.5×	0.003	FGF9
FGFR2c ligand binding and activation	1	878.5×	0.003	FGF9
Phospholipase C-mediated cascade; FGFR3	1	878.5×	0.003	FGF9
FGFR4 ligand binding and activation	1	815.7×	0.003	FGF9
FGFR1c ligand binding and activation	1	761.3×	0.003	FGF9
Phospholipase C-mediated cascade; FGFR4	1	761.3×	0.003	FGF9
Transcriptional regulation of testis differentiation	1	713.8×	0.003	FGF9
Activated point mutants of FGFR2	1	671.8×	0.003	FGF9
Phospholipase C-mediated cascade: FGFR1	1	671.8×	0.003	FGF9
Phospholipase C-mediated cascade; FGFR2	1	634.4×	0.003	FGF9
PI-3K cascade:FGFR3	1	634.4×	0.003	FGF9
SHC-mediated cascade:FGFR3	1	601.0×	0.003	FGF9
PI-3K cascade:FGFR4	1	571.0×	0.003	FGF9
Downstream signaling of activated FGFR1	1	543.8×	0.003	FGF9
FRS-mediated FGFR3 signaling	1	543.8×	0.003	FGF9
SHC-mediated cascade:FGFR4	1	543.8×	0.003	FGF9
PI-3K cascade:FGFR1	1	519.1×	0.003	FGF9
SHC-mediated cascade:FGFR1	1	496.5×	0.003	FGF9
PI-3K cascade:FGFR2	1	496.5×	0.003	FGF9
FRS-mediated FGFR4 signaling	1	496.5×	0.003	FGF9
Signaling by FGFR3 in disease	1	496.5×	0.003	FGF9
SHC-mediated cascade:FGFR2	1	475.8×	0.003	FGF9
FRS-mediated FGFR1 signaling	1	456.8×	0.003	FGF9
FRS-mediated FGFR2 signaling	1	439.2×	0.003	FGF9
Negative regulation of FGFR3 signaling	1	439.2×	0.003	FGF9
Negative regulation of FGFR4 signaling	1	407.9×	0.003	FGF9
Negative regulation of FGFR1 signaling	1	368.4×	0.003	FGF9

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete negative regulation of vascular associated smooth muscle cell differentiation involved in phenotypic switching	1	8426.0×	0.004	FGF9
regulation of timing of cell differentiation	1	4213.0×	0.004	FGF9
positive regulation of activin receptor signaling pathway	1	2808.7×	0.004	FGF9
Sertoli cell proliferation	1	2808.7×	0.004	FGF9
lung-associated mesenchyme development	1	1685.2×	0.004	FGF9
male sex determination	1	1404.3×	0.004	FGF9
mesenchymal cell proliferation	1	1123.5×	0.004	FGF9
positive regulation of vascular endothelial growth factor receptor signaling pathway	1	1053.2×	0.004	FGF9
embryonic digestive tract development	1	991.3×	0.004	FGF9
positive regulation of vascular associated smooth muscle cell migration	1	991.3×	0.004	FGF9
activin receptor signaling pathway	1	887.0×	0.005	FGF9
positive regulation of cardiac muscle cell proliferation	1	624.1×	0.005	FGF9
positive regulation of mesenchymal cell proliferation	1	601.9×	0.005	FGF9
cardiac muscle cell proliferation	1	581.1×	0.005	FGF9
positive regulation of stem cell proliferation	1	526.6×	0.005	FGF9
vascular endothelial growth factor receptor signaling pathway	1	481.5×	0.005	FGF9
positive regulation of vascular associated smooth muscle cell proliferation	1	432.1×	0.005	FGF9
positive regulation of smoothened signaling pathway	1	421.3×	0.005	FGF9
embryonic limb morphogenesis	1	401.2×	0.005	FGF9
embryonic skeletal system development	1	391.9×	0.005	FGF9
substantia nigra development	1	366.4×	0.005	FGF9
eye development	1	351.1×	0.005	FGF9
negative regulation of Wnt signaling pathway	1	343.9×	0.005	FGF9
positive regulation of cell division	1	337.0×	0.005	FGF9
stem cell proliferation	1	312.1×	0.005	FGF9
chondrocyte differentiation	1	300.9×	0.005	FGF9
inner ear morphogenesis	1	300.9×	0.005	FGF9
fibroblast growth factor receptor signaling pathway	1	285.6×	0.006	FGF9
positive regulation of epithelial cell proliferation	1	244.2×	0.006	FGF9
neurogenesis	1	208.1×	0.007	FGF9

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FGF9	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	FGF9

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)
FGF9	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.