Genetic analysis of 18 families with tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is mainly caused by variants in TSC1 and TSC2, which encodes hamartin protein and tuberin protein, respectively. Here, we report clinical and molecular characteristics of 18 families with TSC. High-throughput DNA sequencing was employed to detect variants in all the exons and flanking region of TSC1 and TSC2. TA clone and real-time PCR were performed to verify the pathogenicity of candidate variants. A total of 17 mutations were identified, including 13 mutations in TSC2 and 4 mutations in TSC1. Fifty-six percent (10/18) of the families carried de novo mutations, and 8 of these mutations were not reported previously. Most mutations detected were loss-of-function mutations (15/17). One splice-site mutation (TSC2 c.599 + 5G > A) caused abnormal splicing and was confirmed by in vitro analysis. Facial angiofibromas (94%) and epilepsy (89%) were the most prevalent clinical features in our patients. Treatment with anti-seizure medication (ASM) or in combination with rapamycin results in clinical remission in most patients with TSC-associated seizures (14/15). For genotype-phenotype correlation, patients in our cohort with TSC2 mutations had an earlier onset age and patients with TSC1 showed better response to ASM. Our study has expanded the spectrum of TSC1 and TSC2 causing TSC.