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Objective The aim of the study was to determine the molecular-genetic characteristics of the autosomal dominant systematic disorder Tuberous Sclerosis Complex (TSC1 and TSC2) in Bulgarian patients and to derive some genotype-phenotype correlations. Material and Methods In total 42 patients/families with suspected clinical diagnosis of TSC were analyzed. We used direct sequencing and MLPA for the TSC1 and TSC2 gene analysis. Results In 38 families (90.5%) we confirmed the suspected clinical diagnosis – 15 with TSC1 (35.7%) and 23 (54.8%) with TSC2. In 4 families (9.5%) pathogenic variants were not found. In all 38 patients with proven diagnosis of TSC, we found 38 different mutations, 15 of which (39%) were detected for the first time by our research group. The mutation “hotspots“ in TSC1 gene are exons 9, 15, 17 and 18, where 73% of the TSC1 mutations are localized, while the TSC2 gene mutation “hotspots“ are exons 13 and 34, with 22% of the mutations situated there. In the TSC2 patients the common clinical findings include subcortical tubers, epilepsy with generalized tonic-clonic seizures, subependymal giant cell astrocytoma, facial angiofibromas, ungual fibromas, cardiac rhabdomyomas and renal angiomyolipomas, while in the TSC1 patients typically cortical tubers, cortical dysplasia and subependymal nodules were registered. In patients with aggressive frameshift and nonsense TSC1 and TSC2 mutations commonly hypomelanotic macules, cortical and subcortical tubers, cortical dysplasia, epilepsy with different types of seizures were found. Renal angiomyolipomas and cysts were detected mainly in patients with large deletions. Shagreen patches and intellectual disability were typically registered in equal degree in patients with frameshift, nonsense and missense mutations. Conclusion Although some genotype-phenotype correlations were derived, there is a great inter- and intrafamilial clinical variability in TSC, so it is impossible to predict the course of the disease on the basis of the detected molecular defect. The obtained results helped us to develop a diagnostic algorithm for proper molecular-genetic diagnostics which permits adequate genetic counseling, prophylaxis and treatment in the affected TSC families.

Molecular-Genetic Characteristics and Genotype-Phenotype Correlations in Bulgarian Patients with Tuberous Sclerosis Complex