Evidence-based classification of genes implicated in skeletal disorders using the ClinGen curation framework
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.
Authors
- Valérie Cormier‐Daire (ORCID: https://orcid.org/0000-0002-2839-9856)
- Deepika Burkardt (ORCID: https://orcid.org/0000-0002-1743-7503)
- Deborah Krakow (ORCID: https://orcid.org/0000-0001-9906-4968)
- Madeline Hughes
- Marina T. DiStefano (ORCID: https://orcid.org/0000-0002-8218-5111)
- Hannah McCurry
- Andrea Superti‐Furga (ORCID: https://orcid.org/0000-0002-3543-7531)
- Eleanor C Broeren
- Lindsay C. Burrage (ORCID: https://orcid.org/0000-0002-5108-8861)
- Geert R. Mortier (ORCID: https://orcid.org/0000-0001-9871-4578)
- Pedro A. Sanchez‐Lara (ORCID: https://orcid.org/0000-0003-1181-7828)
- Danita Velasco (ORCID: https://orcid.org/0000-0002-8076-3969)
- Emma H. Wilcox (ORCID: https://orcid.org/0000-0003-4972-2947)
- Lorenzo D. Botto (ORCID: https://orcid.org/0000-0002-5322-7116)
- Anne Girod
- Carlos R. Ferreira (ORCID: https://orcid.org/0000-0002-2697-1046)
- Sandesh C. Sreenath Nagamani
- Shahida Moosa (ORCID: https://orcid.org/0000-0002-4463-3067)
- Matthew L. Warman (ORCID: https://orcid.org/0000-0003-2020-3449)
- Nadja Ehmke (ORCID: https://orcid.org/0000-0003-1449-9909)
- Juan Dong (ORCID: https://orcid.org/0000-0002-3089-3167)
- Sheila Unger (ORCID: https://orcid.org/0000-0002-9539-8941)
- Kezang Tshering (ORCID: https://orcid.org/0000-0001-9619-3625)
- Loren D.M. Peña (ORCID: https://orcid.org/0000-0001-8044-512X)
- Ryan Webb (ORCID: https://orcid.org/0009-0003-2127-3550)
- Mayher Patel
- Kerry K. Brown
Institutions
- Broad Institute (US)
- Cedars-Sinai Medical Center (US)
- Cincinnati Children's Hospital Medical Center (US)
- Boston Children's Hospital (US)
- Nebraska Medical Center (US)
- Children's National (US)
- University of California, Los Angeles (US)
- Université Paris Cité (FR)
- University of Utah (US)
- Stellenbosch University (ZA)
- Tygerberg Hospital (ZA)
- Institut Necker Enfants Malades (FR)
- Centro de Genética Clínica (PT)
- Center for Human Genetics (US)
- Exact Sciences (United States) (US)
- Tissue Gene (United States) (US)
- Institute of Human Genetics (PL)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (US)
- Texas Children's Hospital (US)
- University of Nebraska Medical Center (US)
- Charité - Universitätsmedizin Berlin (DE)
- University of Lausanne (CH)
Publication Details
- Journal
- Journal of Bone and Mineral Research
- Published
- 2025-11-26
- DOI
- https://doi.org/10.1093/jbmr/zjaf183
- Primary Topic
- Genomics and Rare Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00