Novel TSC2 Variant Uncovered, Offers Insights for Tuberous Sclerosis Treatment

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. While mutations in either the TSC1 or TSC2 genes can lead to this condition, TSC2 mutations tend to produce more severe symptoms at an earlier age. This 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.

A novel de novo frameshift deletion variant, c.3647_3651del (p.Leu1216Profs*16), was identified in the TSC2 gene in a 12-year-old boy with skin lesions, seizures, and autistic behaviors. This frameshift deletion variant was detected in the 31st exon of TSC2. The causative variant was initially identified by exome sequencing (ES) and subsequently confirmed by Sanger sequencing and cosegregation analysis. Its pathogenicity fulfills the criteria established by the American College of Medical Genetics and Genomics (ACMG) guidelines.

Structural modeling and molecular dynamics (MD) simulations, performed with GROMACS software, were used to investigate the variant's structural and functional impacts on the tuberin protein. These simulations showed that the mutation causes three main effects: it eliminates the GAP domain, breaks intramolecular hydrogen bonds, and decreases solvent exposure. These changes collectively result in decreased stability and modified conformational movements of tuberin, providing molecular insights into the potential mechanisms driving TSC pathology.

This study highlights the effective use of exome sequencing (ES) for TSC diagnosis and genetic counseling. The computational analysis provided predictive molecular insights into the potential mechanisms driving TSC pathology. The combined approach could aid in developing new therapeutic and management strategies for TSC. As lead author Fadaie notes in the paper, "These findings suggest that such variants could be amenable to therapeutic modulation of the mTOR pathway, for example, through mTOR inhibitors."