Genotype and Phenotype Analysis of Chinese Children With Tuberous Sclerosis Complex: A Pediatric Cohort Study

Abstract

Tuberous sclerosis complex (TSC) is a genetic condition characterized by the occurrence of hamartomatous wounds stemming from the dysfunction of the mammalian target of rapamycin (mTOR) pathway. We investigated the clinical phenotypes and genetic variants in 243 unrelated probands and their families in China. Exome sequencing, targeted sequencing or multiplex ligation-dependent probe amplification (MLPA) was performed in 174 children with TSC, among whom 31 (17.82%) patients/families were identified as having pathogenic or likely pathogenic variants in the <i>TSC1</i> gene, 120 (68.97%) as having pathogenic or likely pathogenic variants in the <i>TSC2</i> gene and 23 (13.21%) as having no pathogenic or likely pathogenic variants identified (NMI). In the 31 patients with pathogenic or likely pathogenic <i>TSC1</i> variants, 10 novel variants were detected among 26 different variants. In all 120 patients with <i>TSC2</i> variants, 39 novel variants were found among a total of 107 different variants. We compared the phenotypes of the individuals with <i>TSC1</i> pathogenic variants, <i>TSC2</i> pathogenic variants and NMI. Patients with <i>TSC2</i> variants were first diagnosed at a younger age (<i>p</i> = 0.003) and had more retinal hamartomas (<i>p</i> = 0.003) and facial angiofibromas (<i>p</i> = 0.027) (age ≥ 3 years) than individuals with <i>TSC1</i> variants. Compared with individuals with <i>TSC1/TSC2</i> pathogenic variants, NMI individuals had fewer cortical tubers (<i>p</i> = 0.003). Compared with individuals with <i>TSC1</i> pathogenic variants, NMI patients had more retinal hamartomas (<i>p</i> = 0.035), and compared with individuals with <i>TSC2</i> pathogenic variants, they had less epilepsy (<i>p</i> = 0.003) and fewer subependymal nodules (SENs) (<i>p</i> = 0.004).