GDF5

• Haploinsufficiency score: 3
• Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
• Haploinsufficiency Phenotype: BRACHYDACTYLY, TYPE C; BDC

Evidence for haploinsufficiency phenotype

PubMed ID	Description
33333243	Genovesi et al. (2021) reviewed several GDF5 mutations, clinical association and functional data. They reviewed 15 different loss of function variants (nonsense and frameshift) associated with brachydactyly type C. The authors also reviewed GDF5 missense variants associated with brachydactyly type C including four with functional data described by four articles. These four missense variants cause GDF5 loss of function due to different mechanisms such as intracellular and extracellular protein reduction, protein dimerization impairment, and SMAD signaling reduction.
9288091	Polinkovsky et al. (1997) identified a heterozygous C-to-T transition at nucleotide 901 of the GDF5 mRNA coding sequence in affected members of a family with brachydactyly type C. The variant results in a R301X substitution.
18283415	Yang et al (2008) identified a T-to-G transversion in GDF5 in a 4 generation family with brachydactyly type C. The variant was not detected in unaffected family members or 50 controls. The variant results in a Y487X substitution that is predicted to truncate the precursor polypeptide by 15 amino acids.
12567410	Savarirayan et al. (2003) identified a heterozygous 1-bp insertion in the GDF5 gene, 206insG, in 8 members of 3 unrelated families with type C brachydactyly. This variant results in a frameshift and premature termination 25 amino acids downstream. According to the authors, the 206insG frameshift variant was not detected in 100 control alleles, but, four carriers have normal hands and feet. In addition, several carriers have other skeletal abnormalities.

Haploinsufficiency phenotype comments:

The loss evidence listed above and the haploinsufficiency score is based only on the phenotype of brachydactyly type C; however, please note that variants in GDF5 gene have been observed in individuals with other phenotypes due to different genetic mechanisms as gain of function. Other GDF5 associated clinical pentoypes are other types of brachydactyly, multiple synostoses, symphalangism, Du Pan syndrome, Hunter-Thompson type acromesomelyc dysplasia and Grebe chondrodysplasia (see PMID:33333243 and OMIM IDs 201250, 112600, 200700, 228900, 610017, 185800, 612400).

• Triplosensitivity score: 0
• Strength of Evidence (disclaimer): No evidence for dosage pathogenicity