Molecular Diagnosis of Tuberous Sclerosis Complex

This technical report presents a detailed analysis of two adult female patients diagnosed with Tuberous Sclerosis Complex (TSC) who initially received negative results from conventional next-generation sequencing (NGS) tests. The report outlines the diagnostic challenges associated with TSC, where 10-25% of clinically diagnosed patients may not have identifiable genetic variants due to deep intronic or low-frequency mosaic variants. Through the utilization of multiplex ligation-dependent probe amplification (MLPA), Sanger sequencing, and RNA studies, both patients were found to have novel low-frequency mosaic variants in the TSC2 gene. The report details the diagnostic workup for each patient, including their clinical presentations and the genetic findings that confirmed their diagnoses. It discusses the implications of these findings on reproductive decision-making and emphasizes the need for additional testing modalities beyond conventional NGS for accurate molecular diagnosis in TSC patients. The report concludes that incorporating various testing methodologies can improve the likelihood of identifying causative variants, thereby enhancing patient care and informed decision-making.