GDF5 – Brachydactyly Type A2

Heterozygous variants in GDF5 cause autosomal dominant brachydactyly type A2 (BDA2), characterized by hypoplasia or aplasia of the second middle phalanx and shortening of index finger digits. Two independent families have been reported: the Mohr–Wriedt kindred with a c.1322T>C (p.Leu441Pro) variant segregating with 9 affected individuals (8 additional relatives) and a second family carrying a c.1139G>A (p.Arg380Gln) variant in all 4 affected members. c.1322T>C (p.Leu441Pro) ([PMID:16014698]) modifies the receptor‐binding interface of GDF5, leading to near‐complete loss of BMP type I receptor activation and impaired chondrogenesis in chicken micromass and ATDC5 assays. c.1139G>A (p.Arg380Gln) ([PMID:18203755]) disrupts the prodomain cleavage site, reducing proGDF5 processing and downstream SMAD1/5 signaling in vitro.

Genetic evidence for GDF5 in BDA2 includes segregation of pathogenic missense variants in two families (n=13 affected; 8 segregating relatives) and absence of these variants in controls, fulfilling ClinGen Moderate genetic criteria. Functional studies demonstrate concordant loss-of-function through defective receptor binding, impaired dimer formation, and reduced SMAD-dependent signaling, supporting a haploinsufficiency mechanism consistent with autosomal dominant inheritance.

No conflicting reports have been published disputing the role of GDF5 in BDA2. Together, genetic segregation and robust functional assays establish a moderate to strong gene-disease association. Key take-home: GDF5 variants causing haploinsufficiency reliably predict autosomal dominant BDA2 and should inform molecular diagnosis and genetic counseling.

References

• Journal of medical genetics • 2006 • A mutation in the receptor binding site of GDF5 causes Mohr-Wriedt brachydactyly type A2 PMID:16014698
• Human molecular genetics • 2008 • Brachydactyly type A2 associated with a defect in proGDF5 processing PMID:18203755

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