GDF5 – Brachydactyly Type A1

Growth differentiation factor 5 (GDF5) is a secreted bone morphogenetic protein essential for cartilage and joint formation. Heterozygous mutations in GDF5 have been linked to a spectrum of skeletal malformations, including isolated brachydactyly type A1 (BDA1; MONDO:0007215). The tight coupling of GDF5 ligand–receptor interfaces underpins its pivotal role in phalangeal development and justifies its evaluation in patients presenting with shortened middle phalanges (HP:0009371).

Autosomal dominant inheritance of BDA1 has been demonstrated in two unrelated pedigrees harboring distinct GDF5 missense variants. In a European family, the c.1240T>C (p.Trp414Arg) variant segregated with BDA1 and multiple synostoses syndrome 2, confirming co-inheritance of brachydactyly and joint fusion ([PMID:24098149]). More recently, a Chinese kindred carrying c.1424G>A (p.Ser475Asn) presented with combined BDA1 and SYNS2 features and complete cosegregation across affected members ([PMID:38222807]).

Functional studies of p.Trp414Arg revealed a dual pathomechanism: chondrogenesis assays in primary mesenchymal cells, luciferase reporter assays, and Surface Plasmon Resonance analyses showed both a gain of function due to insensitivity to the antagonist NOGGIN and a loss of signaling via the BMP receptor type IA (BMPR1A) consistent with the BDA1 phenotype ([PMID:24098149]). In silico structural modeling of p.Ser475Asn supports disruption of a conserved salt-bridge network critical for antagonist and receptor binding, predicting deleterious effects on protein stability and function ([PMID:38222807]).

These data demonstrate that single amino acid substitutions at the overlapping antagonist–receptor interface of GDF5 can concurrently diminish BMPR1A signaling and abrogate NOGGIN inhibition, yielding the isolated brachydactyly phenotype alongside joint synostosis. The reproducible segregation in two independent families and the concordant functional assays solidify the gene–disease relationship.

No studies to date have refuted the association between these GDF5 variants and BDA1. Population data indicate these variants are absent or extremely rare in control databases, arguing against benign polymorphism. The mechanistic insights from W414R and S475N reinforce pathogenicity assignments and support targeted genetic testing.

In conclusion, GDF5 variants c.1240T>C (p.Trp414Arg) and c.1424G>A (p.Ser475Asn) are established causes of autosomal dominant brachydactyly type A1. Clinical sequencing of GDF5 should be considered in individuals with characteristic middle phalange shortening, enabling precision diagnosis and genetic counseling.

Key Take-home: GDF5 variant analysis is clinically actionable for diagnosing brachydactyly type A1 and informs management and familial risk assessment.

References

• PLoS genetics • 2013 • A GDF5 point mutation strikes twice--causing BDA1 and SYNS2. PMID:24098149
• JOR Spine • 2024 • A missense GDF5 variant causes brachydactyly type A1 and multiple-synostoses syndrome 2. PMID:38222807

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