講演情報
[S4-1]ALSにおけるゲノム解析とrare variantsの役割
○成瀬 紘也 (東京大学 大学院医学系研究科 神経内科学)
Amyotrophic lateral sclerosis (ALS) is a devastating neurological disorder characterized by the progressive degeneration of upper and lower motor neurons. Only 5-10% of ALS cases are familial (FALS), whereas the majority of cases are sporadic (SALS). Currently, as many as 45 genes are found to be associated with ALS. In our recent comprehensive genome analysis using next-generation sequencers, pathogenic variants in FALS-causing genes, including SOD1, FUS, TARDBP, VCP, ERBB4, HNRNPA1, SETX, TBK1, KIF5A, and C9ORF72, were identified in 57% of families with FALS and 3.5% of patients with SALS in a series of Japanese ALS patients. Notably, the frequency of patients carrying expanded repeats in C9ORF72 is substantially lower in the Japanese or East-Asian series than in a series of European ancestry, showing that genetic epidemiology of ALS in Japan considerably differs from that of European ancestry. Thus, pathogenic variants in SOD1 are the most common genetic cause of ALS in the Japanese series, occurring in 36% of FALS pedigrees and 2.2% of SALS patients. Remarkably, we have shown that a substantial number of patients carried rare variants in multiple ALS-causing genes, and the burden of rare variants in these genes affects the age at onset in the Japanese case series. In this session, we show the result of genetic analysis of ALS cases on the basis of whole-exome sequence (WES) or whole-genome sequence (WGS) data and the role of rare variants in ALS-causing genes contributing to the disease expression including the age at onset.