TY - JOUR
T1 - Whole exome sequencing in the diagnostic workup of patients with a bleeding diathesis
AU - Saes, Joline L
AU - Simons, Annet
AU - de Munnik, Sonja A
AU - Nijziel, Marten R
AU - Blijlevens, Nicole M A
AU - Jongmans, Marjolijn C
AU - van der Reijden, Bert A
AU - Smit, Yolba
AU - Brons, Paul P
AU - van Heerde, Waander L
AU - Schols, Saskia E M
N1 - Funding Information:
LS, AS, SAdM, MCJ, MRN, NMAB, BAvdR, YS, PPB and SEMS have no conflict of interests to declare. WvH received unrestricted grants from Bayer, Shire (formerly Baxalta, Baxter), Novo Nordisk and CSL Behring. WvH is the founder and CSE of Enzyre BV, a Radboudumc spin‐off company.
Publisher Copyright:
© 2018 John Wiley & Sons Ltd
PY - 2019/1
Y1 - 2019/1
N2 - 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.
AB - 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.
KW - Journal Article
KW - bleeding disorders
KW - genetic analysis
KW - platelet disorders
KW - haemostasis diagnostics
KW - personalized treatment
KW - whole exome sequencing
KW - Genetic Predisposition to Disease
KW - Humans
KW - Middle Aged
KW - Genotype
KW - Male
KW - Factor VIII/genetics
KW - Endoribonucleases/genetics
KW - Myosin Heavy Chains/genetics
KW - Whole Exome Sequencing/methods
KW - von Willebrand Factor/genetics
KW - Adult
KW - Factor VII/genetics
KW - Female
KW - Molecular Motor Proteins/genetics
KW - Hemorrhagic Disorders/diagnosis
UR - http://www.scopus.com/inward/record.url?scp=85056735062&partnerID=8YFLogxK
U2 - 10.1111/hae.13638
DO - 10.1111/hae.13638
M3 - Article
C2 - 30431218
SN - 1351-8216
VL - 25
SP - 127
EP - 135
JO - Haemophilia
JF - Haemophilia
IS - 1
ER -