FGF9 – Multiple Synostoses Syndrome

Multiple synostoses syndrome type 3 (SYNS3; MONDO:0017923) is an autosomal dominant skeletal dysplasia characterized by progressive fusion of joints in the hands, feet, elbows, and spine. Heterozygous missense variants in FGF9 (HGNC:3687) disrupt FGF9 homodimerization or receptor binding, leading to aberrant FGF signaling during joint development.

Clinical Validity

FGF9–SYNS3 association is classified as Strong based on segregation in multiple families and concordant functional data. A missense variant, c.296G>A (p.Ser99Asn), segregated with disease in 12 affected individuals in a large Chinese pedigree ([PMID:19589401]). Subsequently, five independent FGF9 missense variants were identified in 18 additional affected individuals across distinct pedigrees ([PMID:36980996]), totaling 30 symptomatic relatives. Experimental studies in transgenic mice and cell assays confirm the pathogenic mechanism.

Genetic Evidence

Inheritance is Autosomal dominant with complete penetrance. Segregation has been documented in six families, involving 30 affected relatives with co-segregating FGF9 variants (c.296G>A (p.Ser99Asn); c.430T>C (p.Trp144Arg); c.427A>T (p.Asn143Tyr); c.566C>G (p.Pro189Arg); c.569G>C (p.Arg190Thr)) ([PMID:19589401]; [PMID:36980996]; [PMID:33140402]; [PMID:33174625]; [PMID:35316564]). The recurrent S99N variant accounts for a substantial fraction of cases.

Functional Evidence

FGF9(S99N) exhibits normal secretion but fails to activate FGFR signaling, as shown by reduced ERK1/2 phosphorylation, β-catenin and c-Myc expression, and impaired chondrocyte proliferation and differentiation in vitro ([PMID:19589401]). Molecular dynamics and biochemical assays demonstrate that S99N and other SYNS3 variants disrupt FGF9 homodimerization and receptor/heparin binding, increasing ligand diffusion and ectopic signaling ([PMID:22920789]; [PMID:19219044]). A knock-in mouse model harboring the S99N mutation phenocopies human joint fusions and defective interzone formation ([PMID:28169396]).

Conflicting Evidence

No studies to date have refuted the FGF9–SYNS3 link or described alternative etiologies in variant carriers.

Conclusion

Robust genetic and mechanistic data establish FGF9 missense variants as a strong determinant of SYNS3. Genetic testing for FGF9 variants informs diagnosis, guides counseling, and may identify candidates for targeted modulation of FGF signaling.

References

• American Journal of Human Genetics • 2009 • Multiple synostoses syndrome is due to a missense mutation in exon 2 of FGF9 gene. PMID:19589401
• Genes • 2023 • FGF9-Associated Multiple Synostoses Syndrome Type 3 in a Multigenerational Family. PMID:36980996
• Human Molecular Genetics • 2017 • A point mutation in Fgf9 impedes joint interzone formation leading to multiple synostoses syndrome. PMID:28169396
• Nature Genetics • 2009 • FGF9 monomer-dimer equilibrium regulates extracellular matrix affinity and tissue diffusion. PMID:19219044
• Journal of Chemical Information and Modeling • 2012 • Autoinhibitory mechanism for the mutation-induced impaired FGF9 signaling. PMID:22920789

Evidence Based Scoring (AI generated)