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GDF5
growth differentiation factor 5
The GDF5 gene, or growth differentiation factor 5, is crucial for proper skeletal development, particularly influencing joint formation and bone growth. The GDF5 gene provides instructions for a protein involved in the signalling pathways that guide cartilage and bone development.
GDF5 is located on the long (q) arm of chromosome 20, at band 20q11.22. Arm ratio per GRCh38 - banding schematic.
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Clinical tests that include this
Overview
The GDF5 gene encodes Growth Differentiation Factor 5, a protein recognised for its vital role in the formation and maintenance of joints, bones, and cartilage throughout the body. It belongs to the transforming growth factor-beta (TGF-β) superfamily, a group of proteins involved in many cellular processes, including cell growth, differentiation, and tissue development. Defects in GDF5 can disrupt normal skeletal morphogenesis, leading to various inherited disorders affecting the limbs and joints.
What the gene does
Growth Differentiation Factor 5 (GDF5) primarily functions as a signalling molecule that regulates cell proliferation and differentiation during embryonic development, particularly within the musculoskeletal system. It is integral to chondrogenesis, the process of cartilage formation, and osteogenesis, the formation of bone. GDF5 acts by binding to specific receptor proteins on cell surfaces, initiating a cascade of intracellular events that influence the expression of genes critical for skeletal tissue development. This signalling is essential for proper joint articulation and the patterning of limbs, with its activity being particularly important in the development of synovial joints.
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Chromosome location
The GDF5 gene is situated on the long arm of chromosome 20 at position 11.22, a region designated as 20q11.22. This chromosomal location indicates where the gene can be found within human DNA, contributing to its role in genetic studies and diagnostics.
Protein structure
The Growth Differentiation Factor 5 protein is composed of 501 amino acids. It features a precursor region that undergoes cleavage to yield the mature, active protein. Key structural elements include two disordered regions: one spanning amino acids 29-169 and another from amino acids 246-265. These disordered regions often play roles in protein-protein interactions and flexibility.
Key variants
Variations within the GDF5 gene can encompass a range of changes, including single nucleotide polymorphisms (SNPs), insertions, and deletions. These genetic alterations can impact the protein's ability to function correctly in skeletal development. The clinical consequences of such variants depend on their specific nature and location, potentially leading to diverse phenotypic expressions.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.157del | p.Leu53fs | Pathogenic | ★★☆☆ | Type A2 brachydactyly |
c.157dup | p.Leu53fs | Pathogenic | ★★☆☆ | not provided |
c.158del | p.Leu53fs | Pathogenic/Likely pathogenic | ★★☆☆ | Brachydactyly type C |
c.205dup | p.Ala69fs | Pathogenic | ★★☆☆ | not provided |
c.466C>T | p.Arg156Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.498del | p.Ile167fs | Pathogenic | ★★☆☆ | Brachydactyly type C |
c.498dup | p.Ile167fs | Pathogenic | ★★☆☆ | not provided |
c.628C>T | p.Gln210Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.234_235del | p.Gly79fs | Pathogenic | ★☆☆☆ | not provided |
c.298dup | p.Arg100fs | Pathogenic | ★☆☆☆ | not provided |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Changes in the GDF5 gene are associated with several inherited skeletal conditions. These include Brachydactyly type C, which is characterised by shortened fingers and toes, and Symphalangism (proximal), a condition involving the fusion of finger or toe joints. The inheritance patterns for these conditions can be either autosomal dominant or autosomal recessive, depending on the specific variant and disorder.
- Brachydactyly type C
- Symphalangism (proximal) Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic GDF5 variants typically follow ad/ar inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The GDF5 gene is recognised within the NHS Genomic Medicine Service, indicating its relevance for diagnostic testing in the UK. It is listed on several Green panels, including DDG2P, Foetal anomalies (R21), Limb disorders, and Skeletal dysplasia (R104), signifying that there is strong evidence for a gene-disease association in these contexts.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the function of the GDF5 gene?
The GDF5 gene provides instructions for making Growth Differentiation Factor 5, a protein crucial for the normal development of cartilage, bone, and joints. It acts as a signalling molecule, guiding cell growth and differentiation in the musculoskeletal system.
What conditions are associated with GDF5 gene variants?
Variations in the GDF5 gene are linked to several inherited skeletal disorders, such as Brachydactyly type C, which causes shortened digits, and Symphalangism (proximal), characterised by fused finger or toe joints.
How is GDF5 relevant to UK clinical practice?
The GDF5 gene is featured on several NHS Genomic Medicine Service panels, including those for Foetal anomalies and Skeletal dysplasia. This indicates that it is a gene of clinical significance for diagnosing certain inherited conditions in the UK.