Genomics of erythrocytosis

Within the project Genomics of erythrocytosis (Gen2Ery) we aim to addresses current unmet diagnostic needs for the rare inherited haematological condition, Congenital Erythrocytosis. Currently only 30% of patients in EU are diagnosed, including Slovenia, while in the rest the condition remains labelled as idiopathic. Erythrocytosis is a haematological condition with increased mass of erythrocytes and consequently increased haematocrit and haemoglobin. It is caused by inherited or acquired mutations or as a compensatory mechanism in some chronic diseases (heart, lung, kidney, etc). Clinical signs are often overlooked until complications; e.g. thrombosis that could result in morbidity and mortality. Therefore, rapid and accurate diagnosis is of high importance. The genetic cause of erythrocytosis may be Polycythaemia Vera or Congenital Erythrocytosis. Polycythaemia Vera is the most common acquired erythrocytosis and variants in JAK2 are routinely diagnosed, also in Slovenia. Congenital Erythrocytosis has heterogeneous genetic background, with variants in genes involved in oxygen sensing (VHL, EGLN1, EPAS1, EPO), erythropoietin signal transduction (EPOR, JAK2) or regulation of haemoglobin affinity to oxygen (HBA1, HBA2, HBB, BPGM). Within the previous GenEry research, targeted NGS analysis covering 39 erythrocytosis-associated genes was performed, However, among 30 patients only one patient had the pathogenic, disease driven variant in EPAS1. Due to poor diagnosis, also treatment is not well defined and medical doctors do not share a common opinion regarding best treatment selection (low dose aspirin, venesection, JAK2 inhibitors, etc.). Within the proposed Gen2Ery project we will extend current NGS diagnostic solutions and use bioinformatics predictions in aim to discover new disease mechanism on multi-omics level. Project consists of 5 working packages focusing on diagnostic as well as clinical aspect of disease. Within WP1 we will evaluate etiological data of disease in Slovenian population and enrol patients with idiopathic erythrocytosis. The specific focus of WP2 is extended NGS analysis (WGS, RNA-Seq, methylation) of families with several members, where no pathogenic variants were yet identified. Furthermore, we will plan to develop additional simple and quick genetic tests for verification of most commonly discovered genetic variants. WP3 is designed to understand functional impact and molecular mechanism of newly discovered genetic variants, including theoretical prediction of additional disease mechanisms. Within the WP4 we will transfer of extended NGS approach for diagnosis of idiopathic erythrocytosis to clinical use. The focus of WP5 is management and dissemination. Multi-omics based NGS diagnosis developed within our project will unable to better understand disease mechanism and consequently patient stratification. Thereafter the best treatment practice to each patient subgroup will be possible (personalized medicine).