Novel FGF9 variant contributes to multiple synostoses syndrome 3

Area of Science:

• Genetics
• Molecular Biology
• Skeletal Dysplasias

Background:

• Multiple synostoses syndromes (SYNS) are a group of genetic disorders characterized by the fusion of multiple joints.
• These syndromes exhibit genetic heterogeneity, with mutations identified in genes such as NOG, GDF5, FGF9, and GDF6.
• SYNS3 is specifically associated with pathogenic variants in the FGF9 gene, presenting with joint fusions, craniosynostosis, and normal development otherwise.

Observation:

• A patient presented with elbow instability and reduced range of motion.
• Radiological imaging revealed bilateral radial head deformities, carpal-tarsal fusions, brachydactyly, and sacroiliac joint osteoarthritis.
• Whole-exome sequencing identified a novel FGF9 variant, c.569G>C p.(Arg190Thr).

Findings:

• The identified FGF9 variant, p.(Arg190Thr), was predicted by in silico modeling to destabilize ligand-receptor binding, supporting its pathogenicity.
• This discovery expands the known spectrum of FGF9 variants associated with SYNS3.
• Phenotypic manifestations appear more correlated with the functional impact of the variant on the receptor rather than its specific localization.

Implications:

• This finding contributes to a better understanding of the genotype-phenotype correlations in SYNS3.
• The results are valuable for genetic counseling, particularly with the emergence of de novo variants.
• Further research into FGF9 variant effects can refine diagnostic and prognostic capabilities for patients with multiple synostoses syndromes.