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Neurobiol Aging. 2017 Oct;58:238.e9-238.e15. doi: 10.1016/j.neurobiolaging.2017.06.007. Epub 2017 Jun 20.

Burden of rare variants in ALS genes influences survival in familial and sporadic ALS.

Author information

1
Division of Neurology, Department of Medicine, University of Hong Kong, Hong Kong, P.R. China.
2
Department of Psychiatry, University of Hong Kong, Hong Kong, P.R. China; Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, P.R. China.
3
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, P.R. China.
4
Department of Orthopaedics & Traumatology, University of Hong Kong, Hong Kong, P.R. China.
5
Department of Psychiatry, University of Hong Kong, Hong Kong, P.R. China; Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, P.R. China; Department of Medical Genetics, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, P.R. China; Key Laboratory of Tropical Disease Control (SYSU), Ministry of Education, Guangzhou, P.R. China. Electronic address: limiaoxin@mail.sysu.edu.cn.
6
Department of Psychiatry, University of Hong Kong, Hong Kong, P.R. China; Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, P.R. China. Electronic address: pcsham@hku.hk.
7
Division of Neurology, Department of Medicine, University of Hong Kong, Hong Kong, P.R. China. Electronic address: slho@hku.hk.

Abstract

Genetic variants are implicated in the development of amyotrophic lateral sclerosis (ALS), but it is unclear whether the burden of rare variants in ALS genes has an effect on survival. We performed whole genome sequencing on 8 familial ALS (FALS) patients with superoxide dismutase 1 (SOD1) mutation and whole exome sequencing on 46 sporadic ALS (SALS) patients living in Hong Kong and found that 67% had at least 1 rare variant in the exons of 40 ALS genes; 22% had 2 or more. Patients with 2 or more rare variants had lower probability of survival than patients with 0 or 1 variant (p = 0.001). After adjusting for other factors, each additional rare variant increased the risk of respiratory failure or death by 60% (p = 0.0098). The presence of the rare variant was associated with the risk of ALS (Odds ratio 1.91, 95% confidence interval 1.03-3.61, p = 0.03), and ALS patients had higher rare variant burden than controls (MB, p = 0.004). Our findings support an oligogenic basis with the burden of rare variants affecting the development and survival of ALS.

KEYWORDS:

ALS; Genetics; Next generation sequencing; Survival

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