Genome medicine for bleeding, thrombotic and platelet disorders

Platelets, the 2nd most abundant cell in the blood, play an essential role in cardiovascular disease. Inherited bleeding, thrombotic and platelet disorders (BTPD) are characterized by marked genetic heterogeneity. The list of genes involved in the regulation of platelet formation and function and bleeding or thrombosis has been growing rapidly to almost 100 genes since the introduction of high-throughput sequencing (HTS) approaches in research. Thanks to the gradual adoption of HTS in diagnostic practice, these discoveries are not only improving the diagnostic yield but also the treatment for BTPD patients, who often have symptoms outside the blood system. Screening for all known aetiologies offers a diagnosis for about 50 % of index patients with an expected BTPD and 40% of the discovered variants are novel while whole genome sequencing of these negative BTPD cases allows the identification of a candidate gene in about 10% of these cases by analyzing coding regions. Further research should focus a trio sequencing instead of only index cases, novel modes of inheritance and the identification of variants outside exons. The exploration of the non-coding genome space is a huge challenge that can be tackled with the implementation of our current understanding of the regulatory landscape that is available from BLUEPRINT epigenome data delivered for all blood cell types. These data will be supplemented with RNAseq from platelets and megakaryocytes of unexplained patients. It will be important to work on the transition from targeted sequencing to whole-genome sequencing in a clinical setting. By fostering a culture of data exchange through international collaboration, expert-led teams are expected to deliver a conclusive genetic diagnosis for a larger group of currently unexplained BTPDs as novel candidate genes are still often found in single pedigrees.

Keywords:thrombosis, whole genomes, bleeding, inherited, RNAsequencing, platelets

Disciplines:Vascular diseases