Objectives To evaluate the burden of rare variants in the causative genes for amyotrophic lateral sclerosis (ALS) on the age at onset of ALS in a Japanese case series.
Methods We conducted whole-exome sequencing analysis of 89 families with familial ALS (FALS) and 410 patients with sporadic ALS (SALS) to identify known pathogenic mutations or rare functionally predicted deleterious variants in the causative genes for ALS. Rare variants (minor allele frequency <1%) with scaled Combined Annotation-Dependent Depletion score >20 were defined as rare functionally predicted deleterious variants. The patients with ALS were classified on the basis of the number of pathogenic and/or rare functionally predicted deleterious variants, and the age at onset was compared among the classified groups.
Results Whole-exome sequencing analysis revealed known pathogenic mutations or rare functionally predicted deleterious variants in causative genes for ALS in 56 families with FALS (62.9%) and 87 patients with SALS (21.2%). Such variants in multiple genes were identified in seven probands with FALS and eight patients with SALS. The ages at onset in the patients with ALS with multiple variants were significantly earlier than those in other patients with ALS. Even when the patients with known pathogenic mutations were excluded, a significantly earlier onset of the disease was still observed in patients with multiple rare functionally predicted deleterious variants.
Conclusions A substantial number of patients carried rare variants in multiple genes, and the burden of rare variants in the known causative genes for ALS affects the age at onset in the Japanese ALS series.
Statistics from Altmetric.com
Contributors HN contributed to the study design, data acquisition, analysis and manuscript preparation. HI, JM, YT, TM, MT and JG contributed to the study design, data acquisition and analysis. KD, JY and SM contributed to data acquisition and analysis. TT and ST contributed to the study design, data acquisition, analysis and manuscript preparation.
Funding This work was supported in part by KAKENHI (Grants-in-Aid for Scientific Research on Innovative Areas Nos. 22129001 and 22129002) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and Grants-in-Aid (H23-Jitsuyoka (Nanbyo)-Ippan-004 and H26-Jitsuyoka (Nanbyo)-Ippan-080) from the Ministry of Health, Welfare and Labour, Japan, and grants (nos. 15ek0109065h0002, 16kk0205001h001, 17kk0205001h0002 and 17ek0109279h0001) from the Japan Agency for Medical Research and Development (AMED) to ST.
Competing interests None declared.
Patient consent Not required.
Ethics approval Ethical approval in this research was obtained from the institutional review board of the University of Tokyo.
Provenance and peer review Not commissioned; externally peer reviewed.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.