Genetic Screening of Tuberous Sclerosis Complex in Sicily with a Focus on Neurological Manifestations

Tuberous Sclerosis Complex (TSC) is an autosomal dominant disorder characterized by widespread hamartomas in multiple organs and significant neurological involvement. TSC is caused by pathogenic variants in TSC1 or TSC2 genes, leading to hyperactivation of the mTOR pathway and consequent dysregulation of cell growth. These tumor suppressor genes encode hamartin and tuberin, proteins critical for regulating cell proliferation, neuronal excitability and synaptogenesis. In this retrospective study, we analyzed clinical, genetic and radiological features of 81 TSC patients from Sicily, focusing on genotype-phenotype correlations and intergroup comparisons. TSC2 mutations were more common than TSC1 mutations (61.7% vs. 38.3%). Patients with TSC2 mutations Patients with TSC2 mutations tended to exhibit a higher frequency of weekly seizures, a higher prevalence of infantile spasms and hypsarrhythmia compared to those with TSC1 mutations, consistent with a more severe phenotype. Interestingly, TSC1 patients exhibited a higher incidence of radial bands, while TSC2 patients harbored a larger average size of tubers and subependymal nodules. Cognitive and behavioral disorders were similarly distributed, although TSC1 patients had higher rates of normal or borderline cognitive function, while TSC2 patients had more severe neuropsychiatric profiles compared to TSC1. Additionally, we present four novel potential genotype-phenotype correlations. To our knowledge, these is the first comprehensive TSC1 and TSC2 mutational analysis and genotype-phenotype correlation study carried out in in a large cohort of Sicilian patients affected by TSC. Our findings contribute to regional and global data on TSC, emphasizing the utility of genotype-informed management strategies.