Klin Onkol 2023; 36(Suppl 1): 131-136. DOI: 10.48095/ccko2023S131.
Background: Familial hematopoietic disorders (FHD) are a rare and heterogeneous group of disorders that include hereditary anemias, hereditary thrombocytopenias (inherited thrombocytopenias – IT), congenital neutropenias and congenital bone marrow failure syndromes. FHD is characterized by variable clinical expressivity and incomplete penetrance of the phenotype even within a single family, making it difficult to determine a correct history. The molecular genetic defects of FHD are found in > 300 genes mainly responsible for cellular processes whose functional disorders lead to symptomatic cytopenia, organ dysfunction, tissue damage and syndromes. Some gene variants predispose to the development of severe hematological malignancies or, more rarely, solid tumours. At our institution, we have introduced genetic analysis in families with suspected hereditary hematological diseases. Our focus is unique in the Czech Republic. Patients and methods: In total, we analyzed 92 families with suspected FHD using modern genomic approaches such as whole-exome sequencing (WES), in silico predictive analysis, multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing. Results: In 70 families, we detected an already known pathogenic/probably pathogenic variant or a novel variant of unclear clinical significance (VUS), the detection of which led to confirmation or refinement of the diagnosis. Positive findings indicated the occurrence of hereditary thrombocytopenias (TUBB1, ETV6 and ANKRD26 genes – risk of the development of hematological malignancies), Glanzmann thrombasthenia (ITGA2B), anemias, thalassemias, but also the occurrence of rare syndromic diseases in the Czech Republic, e. g. Bernard-Soulier (GP1BA); Heřmanský-Pudlák (HPS1); Wiskott-Aldrich (WAS – increased risk of malignancies); Shwachman-Diamond syndrome (SBDS – a 30% risk of myeloid malignancies) and Sebastian syndrome (MYH9), etc. Conclusion: Genetic diagnosis has become part of the standard examination of patients with hereditary hematological diseases. It has also helped to clarify many unsolved cases and highlighted the occurrence of rare variants classified as VUS, for which it is necessary to determine their functional impact. Confirming a patient’s diagnosis also has a positive impact on their individualized care and on determining their risk of malignancies or other additional diseases.
