Role of genetics in amyotrophic lateral sclerosis: a large cohort study in Chinese mainland population.
Role of genetics in amyotrophic lateral sclerosis: a large cohort study in Chinese mainland population.
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DOI：
10.1136/jmedgenet-2021-107965
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发表时间：
2022-09
影响因子：
4
通讯作者：
中科院分区：
文献类型：
--
作者：
大量新的肌萎缩侧索硬化症(ALS)致病基因和危险基因已被发现，主要存在于欧洲血统的患者中。相比之下，我们对ALS在其他种族人群中的遗传学知之甚少。这项研究旨在对中国大陆史无前例的大规模ALS人群的遗传学进行全面分析，并与罕见变异携带者的临床特征相关联。对1587例家族性肌萎缩侧索硬化症(FAL)和1523例散发性肌萎缩侧索硬化症(SALS)患者和1866例家族性ALS患者进行了C9orf72基因G4C2重复序列全外显子测序和/或检测。对41个ALS相关基因进行了分析。发现155例ALS患者携带ALS致病基因的罕见致病/可能致病(P/LP)变异，其中FAL 26例(40.6%)，SALS 129例(8.5%)。SOD1是最常见的突变基因，其次是C9orf72、FUS、NEK1、TARDBP和TBK1。负荷分析表明，SOD1、FUS和TARDBP的罕见变异在基因水平上对ALS(p<；2.5E-6)的集体风险有贡献，但在等位基因水平上，TARDBP p.Gly294Val和fus p.Arg521Cys和p.Arg521His是导致ALS的最重要的单一变异。在临床上，TARDBP和C9orf72的P/LP变异与预后不良有关，C9orf72重复与发病年龄较小有关，且C9orf72重复往往影响认知。我们的数据为了解中国肌萎缩侧索硬化症的遗传和临床特征、优化基因检测设计和评估疾病预后提供了必要的信息。
A large number of new causative and risk genes for amyotrophic lateral sclerosis (ALS) have been identified mostly in patients of European ancestry. In contrast, we know relatively little regarding the genetics of ALS in other ethnic populations. This study aims to provide a comprehensive analysis of the genetics of ALS in an unprecedented large cohort of Chinese mainland population and correlate with the clinical features of rare variants carriers. A total of 1587 patients, including 64 familial ALS (FALS) and 1523 sporadic ALS (SALS), and 1866 in-house controls were analysed by whole-exome sequencing and/or testing for G4C2 repeats in C9orf72. Forty-one ALS-associated genes were analysed. 155 patients, including 26 (40.6%) FALS and 129 (8.5%) SALS, carrying rare pathogenic/likely pathogenic (P/LP) variants of ALS causative genes were identified. SOD1 was the most common mutated gene, followed by C9orf72, FUS, NEK1, TARDBP and TBK1. By burden analysis, rare variants in SOD1, FUS and TARDBP contributed to the collective risk for ALS (p<2.5e-6) at the gene level, but at the allelic level TARDBP p.Gly294Val and FUS p.Arg521Cys and p.Arg521His were the most important single variants causing ALS. Clinically, P/LP variants in TARDBP and C9orf72 were associated with poor prognosis, in FUS linked with younger age of onset, and C9orf72 repeats tended to affect cognition. Our data provide essential information for understanding the genetic and clinical features of ALS in China and for optimal design of genetic testing and evaluation of disease prognosis.
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DOI：
10.1126/science.aaa3650
发表时间：
2015-03-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cirulli ET;Lasseigne BN;Petrovski S;Sapp PC;Dion PA;Leblond CS;Couthouis J;Lu YF;Wang Q;Krueger BJ;Ren Z;Keebler J;Han Y;Levy SE;Boone BE;Wimbish JR;Waite LL;Jones AL;Carulli JP;Day-Williams AG;Staropoli JF;Xin WW;Chesi A;Raphael AR;McKenna-Yasek D;Cady J;Vianney de Jong JM;Kenna KP;Smith BN;Topp S;Miller J;Gkazi A;FALS Sequencing Consortium;Al-Chalabi A;van den Berg LH;Veldink J;Silani V;Ticozzi N;Shaw CE;Baloh RH;Appel S;Simpson E;Lagier-Tourenne C;Pulst SM;Gibson S;Trojanowski JQ;Elman L;McCluskey L;Grossman M;Shneider NA;Chung WK;Ravits JM;Glass JD;Sims KB;Van Deerlin VM;Maniatis T;Hayes SD;Ordureau A;Swarup S;Landers J;Baas F;Allen AS;Bedlack RS;Harper JW;Gitler AD;Rouleau GA;Brown R;Harms MB;Cooper GM;Harris T;Myers RM;Goldstein DB
通讯作者：
Goldstein DB
影响因子：
4
作者：
Kenna KP;McLaughlin RL;Byrne S;Elamin M;Heverin M;Kenny EM;Cormican P;Morris DW;Donaghy CG;Bradley DG;Hardiman O
通讯作者：
Hardiman O
DOI：
10.1016/s1474-4422(12)70043-1
发表时间：
2012-04
期刊：
The Lancet. Neurology
影响因子：
--
作者：
Majounie E;Renton AE;Mok K;Dopper EG;Waite A;Rollinson S;Chiò A;Restagno G;Nicolaou N;Simon-Sanchez J;van Swieten JC;Abramzon Y;Johnson JO;Sendtner M;Pamphlett R;Orrell RW;Mead S;Sidle KC;Houlden H;Rohrer JD;Morrison KE;Pall H;Talbot K;Ansorge O;Chromosome 9-ALS/FTD Consortium;French research network on FTLD/FTLD/ALS;ITALSGEN Consortium;Hernandez DG;Arepalli S;Sabatelli M;Mora G;Corbo M;Giannini F;Calvo A;Englund E;Borghero G;Floris GL;Remes AM;Laaksovirta H;McCluskey L;Trojanowski JQ;Van Deerlin VM;Schellenberg GD;Nalls MA;Drory VE;Lu CS;Yeh TH;Ishiura H;Takahashi Y;Tsuji S;Le Ber I;Brice A;Drepper C;Williams N;Kirby J;Shaw P;Hardy J;Tienari PJ;Heutink P;Morris HR;Pickering-Brown S;Traynor BJ
通讯作者：
Traynor BJ
影响因子：
25
作者：
Renton AE;Chiò A;Traynor BJ
通讯作者：
Traynor BJ
影响因子：
4
作者：
McCann, Emily P.;Henden, Lyndal;Blair, Ian P.
通讯作者：
Blair, Ian P.