Joline L Saes1,2, Annet Simons3, Sonja A de Munnik3, Marten R Nijziel4, Nicole M A Blijlevens1, Marjolijn C Jongmans3,5,6, Bert A van der Reijden7, Yolba Smit1, Paul P Brons2,8, Waander L van Heerde2, Saskia E M Schols1,2. 1. Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands. 2. Hemophilia Treatment Center, Nijmegen-Eindhoven-Maastricht, Nijmegen, The Netherlands. 3. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. 4. Department of Hematology, Catharina Hospital, Eindhoven, The Netherlands. 5. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. 6. Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands. 7. Department of Laboratory Medicine, Laboratory of Haematology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands. 8. Department of Pediatric Hemato-Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
Abstract
INTRODUCTION: Bleeding assessment tools and laboratory phenotyping often remain inconclusive in patients with a haemorrhagic diathesis. AIM: To describe the phenotype and genetic profile of patients with a bleeding tendency. METHODS: Whole exome sequencing (WES) was incorporated in the routine diagnostic pathway of patients with thrombocytopenia (n = 17), platelet function disorders (n = 19) and an unexplained bleeding tendency (n = 51). The analysis of a panel of 126 OMIM (Online Mendelian Inheritance in Man) genes involved in thrombosis and haemostasis was conducted, and if negative, further exome-wide analysis was performed if informed consent given. RESULTS: Eighteen variants were detected in 15 patients from a total of 87 patients (17%). Causative variants were observed in MYH9 (two cases), SLFN14, P2RY12 and GP9. In addition, one case was considered solved due to combined carriership of F7 and F13A1 variants and one with combined carriership of F2, F8 and VWF, all variants related to secondary haemostasis protein aberrations. Two variants of uncertain significance (VUS) were found in two primary haemostasis genes: GFI1B and VWF. Eight patients were carriers of autosomal recessive disorders. Exome-wide analysis was performed in 54 cases and identified three variants in candidate genes. CONCLUSION: Based on our findings, we conclude that performing WES at the end of the diagnostic trajectory can be of additive value to explain the complete bleeding phenotype in patients without a definite diagnosis after conventional laboratory tests. Discovery of combinations of (novel) genes that predispose to bleeding will increase the diagnostic yield in patients with an unexplained bleeding diathesis.
INTRODUCTION:Bleeding assessment tools and laboratory phenotyping often remain inconclusive in patients with a haemorrhagic diathesis. AIM: To describe the phenotype and genetic profile of patients with a bleeding tendency. METHODS: Whole exome sequencing (WES) was incorporated in the routine diagnostic pathway of patients with thrombocytopenia (n = 17), platelet function disorders (n = 19) and an unexplained bleeding tendency (n = 51). The analysis of a panel of 126 OMIM (Online Mendelian Inheritance in Man) genes involved in thrombosis and haemostasis was conducted, and if negative, further exome-wide analysis was performed if informed consent given. RESULTS: Eighteen variants were detected in 15 patients from a total of 87 patients (17%). Causative variants were observed in MYH9 (two cases), SLFN14, P2RY12 and GP9. In addition, one case was considered solved due to combined carriership of F7 and F13A1 variants and one with combined carriership of F2, F8 and VWF, all variants related to secondary haemostasis protein aberrations. Two variants of uncertain significance (VUS) were found in two primary haemostasis genes: GFI1B and VWF. Eight patients were carriers of autosomal recessive disorders. Exome-wide analysis was performed in 54 cases and identified three variants in candidate genes. CONCLUSION: Based on our findings, we conclude that performing WES at the end of the diagnostic trajectory can be of additive value to explain the complete bleeding phenotype in patients without a definite diagnosis after conventional laboratory tests. Discovery of combinations of (novel) genes that predispose to bleeding will increase the diagnostic yield in patients with an unexplained bleeding diathesis.
Authors: Rachel J Stapley; Christopher W Smith; Elizabeth J Haining; Andrea Bacon; Sian Lax; Vera P Pisareva; Andrey V Pisarev; Steve P Watson; Abdullah O Khan; Neil V Morgan Journal: Blood Adv Date: 2021-01-26
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Authors: Suzanne A M Zegers; Yolba Smit; Joline L Saes; Clint van Duren; Tim J Schuijt; Waander L van Heerde; Saskia E M Schols Journal: Haemophilia Date: 2019-12-30 Impact factor: 4.287