The team's goals are based on their previous research devoted to the problems of congenital predispositions to leukemias and other blood diseases. The main members of the team have been dealing with this issue systematically since 2014.

The true incidence of most inherited blood disorders is unknown; most are rare or ultra-rare, indicating low prevalence defined as less than 1 per 2,000 people. Inherited genetic predispositions or germinal origin have been described, for example, in bone marrow failure syndromes, inherited cytopenia or hematologic malignancies. The most common inherited blood cancers arise from variants of the DDX41 (AML, MDS, CML), RUNX1 (myeloid malignancies), GATA2 (AML, MDS), and CEBPA (AML) genes and telomere length biology syndromes or other inherited bone marrow failure conditions. Several rare IBDs such as RUNX1, ETV6, and ANKRD26 thrombocytopenias, as well as GATA2, SBDS, and ELANE (HAX1, WASP, G6PC3, and SLC37A4) neutropenias are associated with increased risk of hematologic malignancy. Pathogenic germline variants in SLC3A4, GATA2, and CXCR4 genes also come with a risk of developing solid tumours.

The ability to diagnose rare inherited blood disorders has improved due to massive parallel sequencing (MPS). MPS generates such a big volume of genetic information, that new challenges are created for accurate assessment and reporting of identified variants. Thus, our ability to acquire genetic information has vastly outpaced our ability to understand the relationship between genetic variation and disease. This gap in understanding has led to an explosion in the number of variants of uncertain significance (VUS) in variant aggregation databases. To fill this gap, information on genetic variants along with patient’s phenotype will need to be shared through international initiatives. Integration of these results into routine clinical practice for patients and optimizing the management and surveillance of patients and carriers who have not developed malignancy is a part of precision medicine.

In the context of precision medicine, patients with suspected rare hereditary hematological disorders are examined using MPS. Unfortunately, the gene variants that cause the hematological disorder are often unique to a single family or very rare. Therefore, they are often classified as VUS. Their significance cannot be always clarified by the frequency of the variant in the general population, together with information on clinical data from a "healthy" population. This is because most rare VUSs present with mild clinical symptoms and a higher frequency of the variant in the population may not necessarily mean that it is harmless. Data on the frequency of variants in the Czech population are available from the databases of the Czech National Interpreted Genomic Map (ENIGMA) and Analysis of Czech Genomes for Theranostics: 1000 Czech Genomes (A-C-G-T) projects (https://www.acgt.cz/en/). This database is a suitable tool to determine the prevalence of detected VUSs as well as variants that are now considered pathogenic.