Novel Frameshift Deletion Pathogenic Variant Characterization in Tuberous Sclerosis-2 Using Exome Sequencing and...

Tuberous sclerosis complex (TSC) is a rare genetic disorder with an autosomal dominant inheritance pattern, affecting roughly 1 in 6,000 to 1 in 10,000 live births. The genetic mutations in the TSC1 or TSC2 genes lead to this condition, while TSC2 mutations tend to produce more severe symptoms at an earlier age. The research uses exome sequencing (ES) and molecular dynamics (MD) simulations to detect and study a novel pathogenic TSC2 frameshift deletion variant and its structural and functional consequences. The causative variant was identified by ES and then confirmed by Sanger sequencing and cosegregation analysis. MD simulations with GROMACS software were used to investigate the structural and functional impacts of the variant on the tuberin protein. The American College of Medical Genetics and Genomics (ACMG) guidelines were followed for the variant interpretation. We identified a novel de novo frameshift deletion variant, c.3647_3651del (p.Leu1216Profs*16), in the TSC2 gene in a 12-year-old boy with skin lesions, seizures, and autistic behaviors. A frameshift deletion variant was detected in the 31st exon of TSC2. It fulfills the pathogenic criteria established by ACMG guidelines. The structural modeling and molecular dynamics simulations show that the mutation causes three main effects: it eliminates the GAP domain while breaking intramolecular hydrogen bonds. It decreases solvent exposure, which results in decreased stability and modified conformational movements of tuberin. This study highlights the effective use of ES for TSC diagnosis and genetic counseling. Our computational analysis provides predictive molecular insights into the potential mechanisms driving TSC pathology. The combined approach could aid in developing new therapeutic and management strategies for TSC. These findings suggest that such variants could be amenable to therapeutic modulation of the mTOR pathway, for example, through mTOR inhibitors.