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
Department of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands.
Hemophilia Treatment Center, Nijmegen - Eindhoven - Maastricht, the Netherlands.
Res Pract Thromb Haemost. 2024 Jun 17;8(4):102477. doi: 10.1016/j.rpth.2024.102477. eCollection 2024 May.
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.
Describe underlying rare genetic variants in the Dutch RBD population and investigate the relationship between genotype, laboratory phenotype, and clinical phenotype.
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.
Rare genetic variants specific to the diagnosed RBD were found in 132 of 156 patients (85%). Of the 214 rare genetic variants identified, 57% ( = 123) were clearly pathogenic, 19% ( = 40) were likely pathogenic, and 24% ( = 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.
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.
罕见的凝血因子缺乏症和纤维蛋白溶解障碍（定义为罕见出血性疾病[RBDs]）表现出异质性出血表型，且出血严重程度难以预测。
描述荷兰RBD人群中潜在的罕见基因变异，并研究基因型、实验室表型和临床表型之间的关系。
荷兰罕见出血性疾病研究是一项于2017年10月1日至2019年11月30日进行的全国性横断面研究。在单次研究访视期间收集出血评分和血样。凝血因子水平在中心实验室进行检测，并对156个参与血栓形成和止血的基因进行靶向外显子组分析。根据临床遗传科学协会的指南确定致病性。
156例患者中有132例（85%）发现了特定于诊断出的RBD的罕见基因变异。在鉴定出的214个罕见基因变异中，57%（n = 123）为明确致病性，19%（n = 40）为可能致病性，24%（n = 51）为意义未明的变异。在纤溶酶原激活物抑制剂1缺乏症或高纤维蛋白溶解症患者中未发现解释性基因变异。在罕见凝血因子缺乏症和α-2-抗纤溶酶缺乏症患者中，因子活性水平与相应基因中基因变异的存在之间存在相关性。四分之一的患者存在多个基因变异的共现，但对表型的影响仍不清楚。
靶向外显子组分析可能比单基因分析具有优势，本研究中多种联合缺乏症突出了这一点。需要进一步研究以确定共现的止血基因变异在RBD出血表型中的作用。
