Research and practice in thrombosis and haemostasis · 2024
Targeted exome analysis in patients with rare bleeding disorders: data from the Rare Bleeding Disorders in the Netherlands study.
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Willems Sterre P E, Simons Annet, Saes Joline L, Weiss Marjan, Rijpma Sanna, Schoormans Selene, Meijer Karina, Cnossen Marjon H, Schutgens Roger E G, van Es Nick, Nieuwenhuizen Laurens, den Exter Paul L, Kruis Ilmar C, Blijlevens Nicole M A, van Heerde Waander L, Schols Saskia E M
Аннотация
BACKGROUND: Rare coagulation factor deficiencies and disorders of fibrinolysis (defined as rare bleeding disorders [RBDs]) present with a heterogeneous bleeding phenotype, and bleeding severity is difficult to predict.
OBJECTIVES: Describe underlying rare genetic variants in the Dutch RBD population and investigate the relationship between genotype, laboratory phenotype, and clinical phenotype.
METHODS: The Rare Bleeding Disorders in the Netherlands is a cross-sectional, nationwide study conducted between October 1, 2017, and November 30, 2019. Bleeding scores and blood samples were collected during a single study visit. Coagulation factor levels were measured centrally, and targeted exome analysis was performed on 156 genes involved in thrombosis and hemostasis. Pathogenicity was assigned according to the Association for Clinical Genetic Science guidelines.
RESULTS: Rare genetic variants specific to the diagnosed RBD were found in 132 of 156 patients (85%). Of the 214 rare genetic variants identified, 57% (n = 123) were clearly pathogenic, 19% (n = 40) were likely pathogenic, and 24% (n = 51) were variants of unknown significance. No explanatory genetic variants were found in patients with plasminogen activator inhibitor type 1 deficiency or hyperfibrinolysis. A correlation existed between factor activity levels and the presence of a genetic variant in the corresponding gene in patients with rare coagulation factor deficiencies and alpha-2-antiplasmin deficiency. Co-occurrence of multiple genetic variants was present in a quarter of patients, but effect on phenotype remains unclear.
CONCLUSION: Targeted exome analysis may offer advantages over single-gene analysis, emphasized by a number of combined deficiencies in this study. Further studies are required to determine the role of co-occurring hemostasis gene variants on the bleeding phenotype in RBDs.
OBJECTIVES: Describe underlying rare genetic variants in the Dutch RBD population and investigate the relationship between genotype, laboratory phenotype, and clinical phenotype.
METHODS: The Rare Bleeding Disorders in the Netherlands is a cross-sectional, nationwide study conducted between October 1, 2017, and November 30, 2019. Bleeding scores and blood samples were collected during a single study visit. Coagulation factor levels were measured centrally, and targeted exome analysis was performed on 156 genes involved in thrombosis and hemostasis. Pathogenicity was assigned according to the Association for Clinical Genetic Science guidelines.
RESULTS: Rare genetic variants specific to the diagnosed RBD were found in 132 of 156 patients (85%). Of the 214 rare genetic variants identified, 57% (n = 123) were clearly pathogenic, 19% (n = 40) were likely pathogenic, and 24% (n = 51) were variants of unknown significance. No explanatory genetic variants were found in patients with plasminogen activator inhibitor type 1 deficiency or hyperfibrinolysis. A correlation existed between factor activity levels and the presence of a genetic variant in the corresponding gene in patients with rare coagulation factor deficiencies and alpha-2-antiplasmin deficiency. Co-occurrence of multiple genetic variants was present in a quarter of patients, but effect on phenotype remains unclear.
CONCLUSION: Targeted exome analysis may offer advantages over single-gene analysis, emphasized by a number of combined deficiencies in this study. Further studies are required to determine the role of co-occurring hemostasis gene variants on the bleeding phenotype in RBDs.