GDF6 – Multiple Synostoses Syndrome 4

Growth differentiation factor 6 (GDF6) is a BMP family ligand critically involved in joint morphogenesis. Heterozygous gain-of-function variants in GDF6 cause Multiple Synostoses Syndrome 4 (SYNS4), an autosomal dominant disorder characterized by congenital synostoses of the carpal and tarsal bones and progressive conductive hearing loss. SYNS4 follows an autosomal dominant inheritance pattern with full penetrance and variable expressivity.

The association between GDF6 and SYNS4 is supported by a multigenerational Chinese pedigree in which the missense variant c.1330T>A (p.Tyr444Asn) fully cosegregates with disease across six generations (>10 affected individuals) (PMID:26643732). No other pathogenic GDF6 variants have been reported in unrelated SYNS4 cases to date.

Segregation analysis in the pedigree demonstrated complete concordance of the c.1330T>A (p.Tyr444Asn) variant with bilateral carpal and tarsal fusions and late-onset conductive hearing impairment, yielding strong segregation evidence in a single family (PMID:26643732).

Functional assays in patient-derived cells and in vitro reporter systems showed that the p.Tyr444Asn mutant exhibits resistance to NOG-mediated antagonism and induces a significantly higher SMAD1/5/8 signaling response compared with wild-type GDF6 (PMID:26643732).

A knock-in mouse model harboring the orthologous Gdf6 p.Tyr443Asn mutation recapitulates the human SYNS4 phenotype, including fusion of wrists, ankles, phalanges, and auditory ossicles, and transcriptome profiling of limb buds confirmed upregulated BMP pathway activity in mutant embryos (PMID:36744814).

Collectively, the genetic and experimental data indicate that SYNS4 is caused by a gain-of-function mechanism in GDF6 leading to excessive BMP signaling and joint fusion. Clinical genetic testing for GDF6 c.1330T>A (p.Tyr444Asn) should be considered in patients presenting with congenital carpal/tarsal synostoses and conductive hearing loss. Key Take-home: GDF6 p.Tyr444Asn is a definitive molecular marker for SYNS4 and informs diagnosis and family counseling.

References

• Journal of bone and mineral research • 2016 • A New Subtype of Multiple Synostoses Syndrome Is Caused by a Mutation in GDF6 That Decreases Its Sensitivity to Noggin and Enhances Its Potency as a BMP Signal. PMID:26643732
• Journal of bone and mineral research • 2023 • Defective Joint Development and Maintenance in GDF6-Related Multiple Synostoses Syndrome. PMID:36744814

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