Molecular Characterization of TSC1 and TSC2 Variants in a Greek Cohort of Tuberous Sclerosis Complex Patients

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem genetic disorder caused by pathogenic variants in the TSC1 or TSC2 genes, resulting in dysregulation of the mTOR signaling pathway and subsequent hamartoma formation. Although the genetic basis of TSC is well established, population-specific data on TSC1 and TSC2 variants are still emerging. The aim of this study was to characterize the variant spectrum of the TSC1 and TSC2 genes in a cohort of 34 unrelated probands from Greece, 26 of whom had a definite TSC diagnosis, whereas eight had a possible TSC diagnosis. Targeted next-generation sequencing (NGS) was performed to analyze all coding exons and flanking exon-intron boundaries of TSC1 and TSC2. Identified variants were subsequently validated by Sanger sequencing. Pathogenic or likely pathogenic variants were identified in 22 of 34 probands, corresponding to an overall diagnostic yield of 65% using the testing strategy applied in this study. Of these variants, 32% (7/22) occurred in TSC1 and 68% (15/22) in TSC2; seven variants (7/22; 32%) were previously unreported. The molecular detection rate was 77% (20/26) for patients meeting the criteria for definite clinical TSC diagnosis and 25% (2/8) for those with a possible TSC diagnosis. Exploratory genotype-phenotype analysis revealed a trend toward a more severe clinical presentation among patients harboring TSC2 variants. These findings expand the known molecular landscape of TSC and support the clinical utility of genetic testing for diagnosis, genetic counseling, and patient management.