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Project

Improved disease modelling and genetics for inherited platelet disorders

Inherited platelet disorders (IPD) are highly heterogeneous with genetic defects in 63 genes and characterized by a high susceptibility to bleeding and often associated with syndromic features. Many genes have been discovered by whole exome/genome sequencing (WES/WGS) but their exact role in platelet formation and function remains unknown due to the lack of animal or efficient cell-based models. Today, high throughput-sequencing multi-gene panel tests comprising these genes can diagnose 48 to 26% of patients with platelet formation and function disorders, respectively. Many patients still remain undiagnosed and even with WGS data available, it remains extremely difficult to pinpoint the causative genetic defect because of the hundreds of rare coding variants present. This project therefore aims to deliver a rapid stem cell-based model to study known (but functionally undefined) and novel genes using CRISPR/Cas technology, quantitative in vivo imaging and genetic studies. Novel genes will be obtained from WGS data obtained for undiagnosed patients with very well-known platelet disorders, supplemented with platelet transcriptomes. This will allow WGS data analysis of differentially expressed genes. Validated novel candidate genes will be used to expand our existing diagnostic multi-gene panel test to increase detection of patients with the same IPD. This project will provide novel insights in platelet biology that is of use for therapeutic discoveries.

Date:1 Jan 2021 →  Today
Keywords:Megakaryopoiesis, in vivo imaging, RNAsequencing
Disciplines:Analysis of next-generation sequence data, Cell growth and development, Genetics, Stem cell biology, Hematology