Molecular Characterization of TSC1 and TSC2 Variants in a Greek Cohort of Tuberous Sclerosis Complex Patients.
Summary
This study characterized the spectrum of TSC1 and TSC2 gene variants in a cohort of 34 Greek patients with Tuberous Sclerosis Complex (TSC). Using targeted next-generation sequencing, pathogenic or likely pathogenic variants were identified in 65% of probands. The majority of variants were found in TSC2, and seven variants were previously unreported. Exploratory genotype-phenotype analysis suggested a trend towards a more severe clinical presentation in patients with TSC2 variants. These findings underscore the utility of genetic testing for diagnosis, genetic counseling, and patient management in TSC.
Analysis
Clinique: This study demonstrates the clinical utility of genetic screening for Tuberous Sclerosis Complex (TSC), achieving an overall diagnostic yield of 65% and 77% for definite TSC cases. The exploratory correlation between TSC2 variants and a more severe clinical presentation is a significant observation that, upon validation in larger cohorts, could influence genetic counseling and clinical surveillance. These findings strengthen the rationale for integrating genetic testing into TSC diagnostic and management protocols, with potential clinical impact in the medium term (3-5 years) by improving risk stratification and personalized care. Biomol: Molecular characterization was performed using targeted next-generation sequencing (NGS) of coding exons and exon-intron boundaries of TSC1 and TSC2 genes, validated by Sanger sequencing. This approach led to the identification of novel variants (32% of pathogenic/likely pathogenic variants) and expanded the molecular landscape of TSC, particularly in the Greek population. Targeted NGS is a robust method for detecting point variants and small indels, offering good sensitivity and specificity for this type of diagnosis. The discovery of previously unreported variants highlights the importance of genetic analysis for a comprehensive understanding of the disease and could justify the development of specific NGS panels for TSC. Bioinfo: The study employed a targeted next-generation sequencing strategy, which is a standard and efficient application for analyzing specific genes. While not a novel algorithmic architecture, the application of this method to a specific cohort contributes to enriching genetic variant databases. The generated data, especially the novel variants, are valuable for clinical variant databases and can be used to improve variant annotation and classification tools, which could ultimately optimize variant interpretation workflows in a clinical setting.