Clinical Domain Working Groups

The Skeletal Disorders Variant Curation Expert Panel (VCEP) will initially focus on the Collagenopathies, a group of disorders caused by dysfunction of collagen genes, resulting in abnormal protein and affecting connective tissue. Many Collagenopathies affect long bones and cartilage, and result in congenital- or childhood-onset skeletal phenotypes such as Osteogenesis Imperfecta, Achondrogenesis, Hypochondrogenesis, and other skeletal dysplasias that can significantly impact quality of life.

The Skeletal Disorders VCEP will initiate work with the following collagen genes involved in Skeletal Disorders: COL1A1, COL2A1, and COL1A2. These genes share a specific mechanism of pathogenicity involving Glycine substitutions in the Gly-X-Y structure of the triple helix region. These variants are highly causative and specific to the disease group, but are difficult to interpret with the generalized ACMG/AMP guidelines for sequence variant interpretation. Specifying the ACMG/AMP guidelines will allow these variants to be classified in a way that reflects their highly causative nature. Skeletal disorders associated with COL1A1 and COL2A1 have been curated as ‘definitive’ by the Skeletal Disorders GCEP, and efforts to curate COL1A2 will be prioritized in the GCEP, with the goal of completing curation for this gene within the next 6 months. The skeletal disorders associated with COL1A1, COL2A1, and COL1A2 are similar enough that rules will be specified across the disease assertions associated with each gene (ie. COL1A1-related Collagenopathies, etc...).

Future plans for the Skeletal Disorders VCEP include expanding the gene list to include other genes associated with Osteogenesis Imperfecta, the FGFR genes (especially FGFR3 associated with Achondroplasia, Hypochondroplasia, and other syndromic skeletal disorders), and other genes curated as ‘definitive’ by the Skeletal Disorders GCEP.