Evidence-based classification of genes implicated in skeletal disorders using the ClinGen curation framework

Abstract More than 770 genetic skeletal disorders have been described, most with disease-causing variants reported in one of over 550 different genes. The ClinGen Skeletal Disorders Gene Curation Expert Panel was established to determine the strength of evidence that supports specific gene-disease relationships. Such information can assist clinical testing laboratories in choosing genes that should be included on diagnostic panels. Nine genes accounting for the most frequently encountered skeletal dysplasias (COL1A1, COL1A2, COL2A1, FGFR3, SLC26A2, TRPV4, COMP, ALPL, and SOX9) associated in the medical literature with 26 different skeletal disorders were reviewed using a semi-quantitative scoring framework. This framework is utilized by ClinGen to assess the clinical validity of gene-disease relationships. All nine genes were “Definitively” associated with at least one skeletal disorder and several were associated with multiple clinically or radiographically distinct skeletal conditions. Among these 26 gene-disease relationships, the ClinGen Skeletal Disorders Gene Curation Expert Panel determined that 22 (84.6%) had Definitive relationships, 2 (7.7%) had Moderate relationships, and 2 (7.7%) had Limited relationships. None of the 26 gene-disease relationships were Disputed or Refuted. For Moderate and Limited gene-disease relationships, clinical and genetic reports from additional probands and their families are needed to upgrade these gene-disease relationships to Definitive. Up-to-date assessments about the strength of the relationship between genes and phenotypes should improve the sensitivity and specificity of genetic testing in individuals with skeletal disease. The expert curations for the nine aforementioned genes are published on the ClinGen website.