The ClinGen Syndromic Disorders Gene Curation Expert Panel: Assessing the Clinical Validity of 111 Gene-Disease...

The Clinical Genome Resource (ClinGen) Gene Curation Expert Panels (GCEPs) have historically focused on specific organ systems or phenotypes; thus, the ClinGen Syndromic Disorders GCEP (SD-GCEP) was formed to address an unmet need.

The SD-GCEP applied ClinGen's framework to evaluate the clinical validity of genes associated with rare syndromic disorders. 111 Gene-Disease Relationships (GDRs) associated with 100 genes spanning the clinical spectrum of syndromic disorders were curated.

From April 2020 through March 2024, 38 precurations were performed on genes with multiple disease relationships and were reviewed to determine if the disorders were part of a spectrum or distinct entities. 14 genes were lumped into a single disease entity and 24 were split into separate entities, of which 11 were curated by the SD-GCEP. A full review of 111 GDRs for 100 genes followed, with 78 classified as Definitive, 9 as Strong, 15 as Moderate, and 9 as Limited highlighting where further data are needed. All diseases involved two or more organ systems, while the majority (88/111 GDRs, 79.2%) had five or more organ systems affected.

The SD-GCEP addresses a critical gap in gene curation efforts, enabling inclusion of genes for syndromic disorders in clinical testing and contributing to keeping pace with the rapid discovery of new genetic syndromes.