[P2-162] Mutational Analysis of TSC1 and TSC2 in Japanese Patients with Tuberous Sclerosis Complex
[Introduction] Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by multiple hamartias and hamartomas involving throughout the body. To date, many TSC1 and TSC2 mutations have been reported all over the world. However, few mutation studies have been performed and genetic characteristics are not yet clear in Japanese patients with TSC. In this study, we performed large scale mutational cohort study in Japan. [Methodology] 114 Japanese families with TSC were evaluated their phenotypes and genotypes. These patients were clinically diagnosed according to established criteria (Northrup et al. 2012). TSC1 and TSC2 point mutations were screened by CHIPS (CEL endonuclease mediated heteroduplex incision with polyacrylamide gel electrophoresis and silver staining) and confirmed by direct sequencing. Large deletion and insertion were analyzed by long PCR and DNA microarray. [Results] We identified 80 mutations (70.2%), including 22 TSC1 mutations and 58 TSC2 mutations. Detected mutation types of TSC1/TSC2 were frame shift 9/18, in-frame deletion 0/7, missense 1/15, nonsense 7/9, splicing 3/6, stop codon mutation 0/1 and large deletion 2/2 respectively. Comparing clinical manifestations, the incidences of developmental delay and/or mental retardation and cardiac rhabdomyoma were significantly lower in TSC1 patients than TSC2 patients, with p = 0.003 and 0.016 respectively. Our study demonstrates significantly higher incidence of TSC1 patients in the Japanese population compared to US and European studies. Also 15 of 22 TSC1 mutations were not reported before. [Conclusions] Japanese patients with TSC have unique mutational pool and higher incidence of TSC1 mutations comparing to US and European patients.