High-throughput sequencing for diagnosing platelet disorders: lessons learned from exploring the causes of bleeding...

Inherited platelet disorders (IPDs) are a heterogeneous group of disorders caused by multiple genetic defects. Obtaining a molecular diagnosis for IPD patients using a phenotype- and laboratory-based approach is complex, expensive, time-consuming, and not always successful. High-throughput sequencing (HTS) methods offer a genotype-based approach to facilitate molecular diagnostics. Such approaches are expected to decrease time to diagnosis, increase the diagnostic rate, and they have provided novel insights into the genotype-phenotype correlation of IPDs. Some of these approaches have also focused on the discovery of novel genes and unexpected molecular pathways which modulate megakaryocyte and platelet biology were discovered. A growing number of genetic defects underlying IPDs have been identified and we will here provide an overview of the diverse molecular players. Screening of these genes will deliver a genetic diagnosis for about 40%-50% of the IPDs patients and we will compare different HTS applications that have been developed. A brief focus on gene variant interpretation and classification in a diagnostic setting will be given. Although it is true that successes in diagnostics and gene discovery have been reached, a large fraction of patients still remains without a conclusive diagnosis. In these patients, the sum of non-diagnostic variants in known genes or in potential novel genes might only be proven informative in future studies with larger patient cohorts and by data sharing among the diverse genome medicine initiatives. Finally, we still do not understand the role of the non-coding genome space for IPDs.