Clinical and molecular spectrum of TSC1 and TSC2 mutations in pediatric tuberous sclerosis complex: Report of five novel variants

Abstract

Background: Tuberous sclerosis complex (TSC) affects multiple systems. We evaluate the patients with TSC clinically in detail and, if possible, make genotype–phenotype correlations in patients with pathogenic variants in the TSC1 and TSC2 genes.

Methods: In this retrospective study, pathogenic germline variants in the TSC1 and TSC2 genes were identified using a combination of direct sequencing and multiplex ligation-dependent probe amplification (MLPA). There were 15 males (53.6%) and 13 females (46.4%).

Results: Twelve patients (42.8%) carried genetic mutations. All detected variants were classified as pathogenic or likely pathogenic, and five variants (41.6%)—four in the TSC1 gene and one in the TSC2 gene—had not been previously reported. Patients were divided into two groups according to the current diagnostic criteria: definite TSC (17 patients) and possible TSC (11 patients). The frequency of cortical tubers, renal cysts, adenoma sebaceum, and definite diagnosis increased with age (p = 0.023, 0.002, 0.02, and 0.013, respectively). Cortical tubers, renal cysts, and angiomyolipomas were observed more frequently in patients with genetic mutations (p = 0.001, 0.002, and <0.001, respectively). Epilepsy was common in patients with intellectual disability (p = 0.03).

Conclusion: Patients with genetic mutations frequently exhibit cortical tubers, renal cysts, and angiomyolipomas. Radiological examinations should be performed repeatedly over time, as cortical tubers, adenoma sebaceum, renal cysts, and definite diagnoses tend to increase with age. In addition, patients with epilepsy should be evaluated for intellectual disability.