Evaluating the clinical validity of genes related to hemostasis and thrombosis using the ClinGen gene curation framework.

BACKGROUND: Inherited bleeding, thrombotic, and platelet disorders (BTPDs) are a heterogeneous set of diseases, many of which are globally very rare. Over the past five decades, the genetic basis of some of these disorders has been identified, and recently, high-throughput sequencing has become the primary means of identifying disease-causing genetic variants.

OBJECTIVES: Knowledge of the clinical validity of a gene-disease relationship is essential to both providing an accurate diagnosis based on results of diagnostic gene panel tests and informing the construction of such panels. The Scientific and Standardization Committee for Genetics in Thrombosis and Haemostasis undertook a curation process for selecting 96 TIER1 genes for BTPDs. The purpose was to evaluate the evidence supporting each gene-disease relationship and provide an expert-reviewed classification for the clinical validity of genes associated with BTPDs.

METHODS: The ClinGen Hemostasis/Thrombosis Gene Curation Expert Panel (HT GCEP) assessed the strength of evidence for TIER1 genes using the semi-quantitative ClinGen gene disease clinical validity framework. ClinGen lumping and splitting guidelines were used to determine the appropriate disease entity, or entities, for each gene and 101 gene-disease relationships were identified for curation.

RESULTS: The final outcome included 68 Definitive (67%), 26 Moderate (26%), and seven Limited (7%) classifications. The summary of each curation is available on the ClinGen website.

CONCLUSIONS: Expert-reviewed assignment of gene-disease relationships by the HT GCEP facilitates accurate molecular diagnoses for BTPDs by clinicians and diagnostic laboratories. These curation efforts can allow genetic testing to focus on genes with a validated role in disease.