Presence of Rare Variants is Associated with Poorer Survival in Chinese Patients with Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with phenotypic and genetic heterogeneity. Recent studies have suggested an oligogenic basis of ALS, in which the co-occurrence of two or more genetic variants has additive or synergistic deleterious effects. To assess the contribution of possible oligogenic inheritance, we profiled a panel of 43 relevant genes in 57 sporadic ALS (sALS) patients and eight familial ALS (fALS) patients from five pedigrees in east China. We filtered rare variants using the combination of the Exome Aggregation Consortium, the 1000 Genomes and the HuaBiao Project. We analyzed patients with multiple rare variants in 43 known ALS causative genes and the genotype-phenotype correlation. Overall, we detected 30 rare variants in 16 different genes and found that 16 of the sALS patients and all the fALS patients examined harbored at least one variant in the investigated genes, among which two sALS and four fALS patients harbored two or more variants. Of note, the sALS patients with one or more variants in ALS genes had worse survival than the patients with no variants. Typically, in one fALS pedigree with three variants, the family member with three variants (Superoxide dismutase 1 (SOD1) p.V48A,  Optineurin (OPTN) p.A433V and TANK binding kinase 1 (TBK1) p.R573H) exhibited much more severe disease phenotype than the member carrying one variant (TBK1 p.R573H). Our findings suggest that rare variants could exert a negative prognostic effect, thereby supporting the oligogenic inheritance of ALS.