Whole exome sequencing in the diagnostic workup of patients with a bleeding diathesis

Haemophilia. 2019 Jan;25(1):127-135. doi: 10.1111/hae.13638. Epub 2018 Nov 15.


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.

Keywords: bleeding disorders; genetic analysis; haemostasis diagnostics; personalized treatment; platelet disorders; whole exome sequencing.

MeSH terms

  • Adult
  • Endoribonucleases / genetics
  • Exome Sequencing / methods*
  • Factor VII / genetics
  • Factor VIII / genetics
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Hemorrhagic Disorders / diagnosis*
  • Hemorrhagic Disorders / genetics
  • Humans
  • Male
  • Middle Aged
  • Molecular Motor Proteins / genetics
  • Myosin Heavy Chains / genetics
  • von Willebrand Factor / genetics


  • MYH9 protein, human
  • Molecular Motor Proteins
  • Von Willebrand antigen
  • von Willebrand Factor
  • Factor VII
  • Factor VIII
  • Endoribonucleases
  • SLFN14 protein, human
  • Myosin Heavy Chains