Novel gene variants in patients with platelet-based bleeding using combined exome sequencing and RNAseq murine expression data

UK GAPP Study Group

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)
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Essentials Identifying genetic variants in platelet disorders is challenging due to its heterogenous nature. We combine WES, RNAseq, and python-based bioinformatics to identify novel gene variants. We find novel candidates in patient data by cross-referencing against a murine RNAseq model of thrombopoiesis. This innovative combined bioinformatic approach provides novel data for future research in the field. Abstract: Background The UK Genotyping and Phenotyping of Platelets study has recruited and analyzed 129 patients with suspected heritable bleeding. Previously, 55 individuals had a definitive genetic diagnosis based on whole exome sequencing (WES) and platelet morphological and functional testing. A significant challenge in this field is defining filtering criteria to identify the most likely candidate mutations for diagnosis and further study. Objective Identify candidate gene mutations for the remaining 74 patients with platelet-based bleeding with unknown genetic cause, forming the basis of future re-recruitment and further functional testing and assessment. Methods Using python-based data frame indexing, we first identify and filter all novel and rare variants using a panel of 116 genes known to cause bleeding across the full cohort of WES data. This identified new variants not previously reported in this cohort. We then index the remaining patients, with rare or novel variants in known bleeding genes against a murine RNA sequencing dataset that models proplatelet-forming megakaryocytes. Results Filtering against known genes identified candidate variants in 59 individuals, including novel variants in several known genes. In the remaining cohort of “unknown” patients, indexing against differentially expressed genes revealed candidate gene variants in several novel unreported genes, focusing on 14 patients with a severe clinical presentation. Conclusions We identified candidate mutations in a cohort of patients with no previous genetic diagnosis. This work involves innovative coupling of RNA sequencing and WES to identify candidate variants forming the basis of future study in a significant number of undiagnosed patients.

Original languageEnglish
Pages (from-to)262-268
Number of pages7
JournalJournal of Thrombosis and Haemostasis
Issue number1
Early online date6 Oct 2020
Publication statusPublished - Jan 2021

Bibliographical note

Funding Information:
The work in the authors' laboratories is supported by the British Heart Foundation (PG/13/36/30275; FS/15/18/31317; PG/16/103/32650; FS/18/11/33443) (N.V.M.) and the Saudi Arabia Cultural Bureau in London (I.A.). A.O.K. is a Wellcome‐funded Sir Henry Wellcome Fellow (218649/Z/19/Z). K.R.M. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (K01DK111515) at the National Institutes of Health, and is an American Society of Hematology Scholar.

Publisher Copyright:
© 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis


  • RNAseq
  • bleeding
  • genetics
  • megakaryocytes
  • platelets

ASJC Scopus subject areas

  • Hematology


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