| Abstract [eng] |
Rare genetic diseases encompass a wide range of health conditions marked by diverse geographical, etiological, and phenotypic features. Their complexity is heightened by each individual’s unique genetic and epigenetic traits, as well as their rarity. These factors pose significant diagnostic challenges. Nonetheless, advances in molecular genetics, particularly the development of next-generation sequencing technologies, have significantly improved the identification of genetic causes of rare disorders. Despite this, the clinical significance and impact of identified DNA variants on disease development often remain uncertain. To address this, this dissertation aimed to evaluate the pathogenicity of DNA sequence changes identified in genes associated with rare diseases, their significance at the RNA, protein, and cellular levels through bioinformatic, molecular, and functional approaches. A unique case of germline chromothripsis was analyzed and described. Using bioinformatic and molecular techniques, the influence of single nucleotide variants in the RLIM and NAA15 genes on protein function and their potential role in disease pathogenesis was assessed. Additionally, an interdisciplinary approach involving various molecular genetics and biology methods was used to characterize DNA variants in the WRN, DYNC1H1, FAS, DNMT3A, and KCNQ1 genes at the cellular level, focusing on the functions of the proteins encoded by these genes, which improved the understanding of the clinical relevance of these genetic alterations. The research presented in this dissertation contributes to the diagnosis of patients with rare hereditary disorders, offers valuable insights into the molecular mechanisms of disease development, and highlights the importance of interdisciplinary research for future progress. |
