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

Research output: Contribution to journalArticlepeer-review


  • Rachel Stapley
  • Ibrahim Abdullah F Almazni
  • Kellie Machlus

Colleges, School and Institutes


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.

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.

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.

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.

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
JournalJournal of Thrombosis and Haemostasis
Early online date6 Oct 2020
Publication statusE-pub ahead of print - 6 Oct 2020


  • bleeding, platelets, megakaryocytes, genetics, RNAseq