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

作　　者：Siqi Dong Xianhong Yin Kun Wang Wenbo Yang Jiatong Li Yi Wang Yanni Zhou Xiaoni Liu Jiucun Wang Xiangjun Chen 

机构地区：[1]Department of Neurology,Huashan Hospital and Institute of Neurology,Fudan University,Shanghai 200040,China [2]National Center for Neurological Disorders,Shanghai 200040,China [3]Department of Anthropology and Human Genetics,School of Life Sciences,Fudan University,Shanghai 200438,China [4]Human Phenome Institute,Fudan University,Shanghai 200433,China

出　　处：《Phenomics》2023年第2期167-181,共15页表型组学（英文）

基　　金：This work was supported by 2020 Central Transfer Payment Medical Siege Institutions Capacity Building Project(National and Provincial Multi-scientific Cooperation Diagnosis and Treatment of Major Diseases Capacity Building Project);Shanghai Fudan University Education Development Foundation and State Key Laboratory of Genetic Engineering,Human Phenome Institute,Zhangjiang Fudan International Innovation Center,Fudan University;Shanghai Municipal Science and Technology Major Project 2017HZDZX01.

摘　　要：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 cor-relation.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.

关 键 词：Amyotrophic lateral sclerosis Oligogenic inheritance SURVIVAL Superoxide dismutase 1 TANK-binding kinase 1 OPTINEURIN 

分 类 号：R746.4[医药卫生—神经病学与精神病学]