<abstract xmlns="http://www.w3.org/1999/xhtml">

<sec><h3>Objective</h3><p>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.</p></sec>
<sec><h3>Material and Methods</h3><p>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.</p></sec>
<sec><h3>Results</h3><p>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.</p></sec>
<sec><h3>Conclusion</h3><p>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.</p></sec>
</abstract>

ObjectiveThe 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 MethodsIn 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.
ResultsIn 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.
ConclusionAlthough 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

Department of Medical Chemistry and Biochemistry, Medical Faculty

Clinic of Child Neurology, Multiprofile Hospital for Active Treatment in Neurology and Psychiatry “Sv. Naum”

Genetic Medico-Diagnostic Laboratory “Genica”

Clinic of Child Neurology, Multiprofile Hospital for Active Treatment in Neurology and Psychiatry “Sv. Naum”, Department of Neurology, Medical Faculty

Department of Law and Ethics in Medicine, Faculty of Public Health

Acta Medica Bulgarica

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

ObjectiveThe aim of the study was to determine the molecular-genetic characteristics of the autosomal dominant systematic disorder Tuberous Sclerosis Complex...

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

Article Category: Original Articles

Published Online: Aug 11, 2021

Page range: 29 - 36

Received: May 01, 2020

Accepted: Jun 26, 2020

DOI: https://doi.org/10.2478/amb-2021-0020

Keywords
tuberous sclerosis complex, TSC1 gene, TSC2 gene

© 2021 B. Georgieva et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

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

Article Category: Original Articles

Published Online: Aug 11, 2021

Page range: 29 - 36

Received: May 01, 2020

Accepted: Jun 26, 2020

DOI: https://doi.org/10.2478/amb-2021-0020

Keywordstuberous sclerosis complex, TSC1 gene, TSC2 gene

© 2021 B. Georgieva et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Keywords
tuberous sclerosis complex, TSC1 gene, TSC2 gene