GDF5 – Proximal Symphalangism

Proximal symphalangism (SYM1B) is an autosomal dominant skeletal dysplasia characterized by fusion of the proximal interphalangeal joints of the hands—most often the ring and little fingers—with sparing of the thumb—and coalition of tarsal bones often associated with conductive hearing loss ([MONDO:0008511]). The disorder results from heterozygous mutations in GDF5, encoding a BMP family ligand critical for joint morphogenesis ([HGNC:4220]).

Genetic evidence for GDF5 involvement in SYM1B includes a British family in which a heterozygous missense variant c.1313G>T (p.Arg438Leu) segregated with disease in a mother and her three children (4 probands) ([PMID:28032038]). Independently, two five-generation Chinese families with autosomal dominant proximal symphalangism were mapped to GDF5, revealing the novel heterozygous variant c.1471G>A (p.Glu491Lys) that co-segregated with affected status and was absent in >200 controls ([PMID:16892395]).

Inheritance is autosomal dominant. Segregation analysis demonstrated co-segregation across multiple generations (British family: 3 additional affected relatives; Chinese families: numerous meioses) and linkage (LOD 4.32) supporting pathogenicity. The spectrum of variants comprises recurrent pro-symphyseal alleles R438L and E491K, both in the mature TGF-β domain. c.1313G>T (p.Arg438Leu) represents a founder or recurrent variant observed in multiple European SYM1B pedigrees.

Functional studies of the R438L mutant indicate a gain-of-function mechanism: limb-bud micromass cultures expressing R438L GDF5 display enhanced chondrogenesis, increased SMAD1/5 activation, and altered receptor specificity with increased BMPR1A binding, consistent with joint fusion in SYM1 ([PMID:16127465]). Animal models bearing the orthologous Gdf5^L367R^ knock-in allele recapitulate proximal phalanx fusions and joint development defects, corroborating pathogenicity.

No reported conflicting studies dispute the association of GDF5 with proximal symphalangism. Both genetic and experimental data are concordant with a dosage-sensitive gain-of-function mechanism.

Integration of multi-family segregation, linkage data, and mechanistic assays provides strong evidence for a definitive gene-disease relationship. Genetic testing for GDF5 variants—particularly c.1313G>T (p.Arg438Leu) and c.1471G>A (p.Glu491Lys)—should be considered in patients with familial symphalangism. Key Take-home: Heterozygous gain-of-function variants in GDF5 cause autosomal dominant proximal symphalangism and can be reliably diagnosed through targeted molecular testing.

References

• World journal of orthopedics • 2016 • Recurrent missense mutation of GDF5 (p.R438L) causes proximal symphalangism in a British family. PMID:28032038
• American journal of medical genetics. Part A • 2006 • A novel mutation in GDF5 causes autosomal dominant symphalangism in two Chinese families. PMID:16892395
• The Journal of clinical investigation • 2005 • Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2. PMID:16127465

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