GDF5

Gene Facts

• HGNC Symbol: GDF5 (HGNC:4220)
• HGNC Name: growth differentiation factor 5
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: CDMP1, BMP14
• %HI: 5.52
• pLI: 0.03
• LOEUF: 0.71
• Cytoband: 20q11.22
• Genomic Coordinates:

  GRCh37/hg19:	chr20:34021145-34042571
  GRCh38/hg38:	chr20:35433347-35454749

• MANE Select Transcript: NM_000557.5 ENST00000374369.8
• Function: Growth factor involved in bone and cartilage formation. During cartilage development regulates differentiation of chondrogenic tissue through two pathways. Firstly, positively regulates differentiation of chondrogenic tissue through its binding of high affinity with BMPR1B and of less affinity with BMPR1A, leading to induction of SMAD1-SMAD5-SMAD8 complex phosphorylation and then SMAD protein signaling transduction (PubMed:24098149, PubMed:21976273, PubMed:15530414, PubMed:25092592). Secondly, n... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-6296
• ClinGen Curation ID: CCID:007201
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 02/24/2021

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• brachydactyly type C

HI Evidence

• PUBMED: 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.
• PUBMED: 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.
• PUBMED: 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.
• PUBMED: 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.

• HI Evidence 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 (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity