Combining next generation sequencing with clinical studies to unravel novel inherited thrombocytopenias affecting half of the patients

Marco Seri from Medical and Surgical Sciences Department – DIMEC, coordinates this research. Other partners are the University of Trieste and the “Policlinico San Matteo” hospital from Pavia.

Summary

A reduced blood platelet count since birth characterizes a number of genetic disorders named inherited thrombocytopenias (ITHCs). In severe forms patients present recurrent spontaneous bleedings, while in mild cases haemorrhages occur on the occasion of surgery, delivery or trauma. Making a definite diagnosis of these disorders is often difficult because complex laboratory tests are required. Despite recent progress, almost half of the patients remains without a diagnosis because affected with forms that do not fit criteria for any known disorder. This project aims at identifying new forms of ITHCs to reduce the number of subjects who remain without a diagnosis. To achieve this aim, we will take advantage of a large cohort of patients including sporadic as well as familial cases. It is reasonable, in patients that have no defects in the genes already identified as responsible for ITHCs, to search for a genetic defect elsewhere in the genome, a task that has become feasible in the past few years with the introduction of new technologies such as next generation sequencing (NGS). In this study we aim at applying the sequencing of all the genes contained in our genome through Whole Exome Sequencing (WES) in 163 patients to overcome genetic heterogeneity and limitations of this new technology. In familial cases, a linkage analysis will help to define the genomic regions in order to increase the possibility of identification of an ITHC gene among those included within the interval. Finding new genes causative of ITHCs would also benefit research on the molecular mechanisms that are assigned to platelet formation. This knowledge is a crucial step for the future development of therapies. In fact, based on the positive results we are obtaining with a new drug in another form of ITHC, a relevant problem of patients with new forms of ITHC is that the lack of a specific diagnosis excludes them from ongoing and future clinical trials evaluating the effects of new promising drugs.