Targeted exon capture and sequencing in sporadic amyotrophic lateral sclerosis.
Targeted exon capture and sequencing in sporadic amyotrophic lateral sclerosis.
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DOI：
10.1371/journal.pgen.1004704
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发表时间：
2014-10
期刊：
影响因子：
4.5
通讯作者：
Gitler AD
中科院分区：
文献类型：
--
作者：
Couthouis J;Raphael AR;Daneshjou R;Gitler AD
肌萎缩性侧索硬化症（ALS）是一种毁灭性的神经退行性疾病，导致运动神经元进行性变性，最终导致瘫痪和死亡。大约10%的ALS病例是家族性的，其余90%的病例是散发的。家族性ALS病例的遗传研究在确定ALS背后的致病突变方面提供了极其丰富的信息，特别是在家族性ALS中发现的相同突变也可能导致散发疾病。然而，在大约30%的家族性病例和大多数散发病例中，ALS的病因仍然未知。散发的ALS病例是ALS遗传信息的未充分利用的资源；因此，我们对242例散发性ALS病例和129例匹配对照的169个已知和候选ALS疾病基因进行了靶向测序，试图确定与ALS相关的新变异。我们发现，与对照组相比，病例中新的和罕见的变异显著丰富，这表明我们可能正在识别与疾病相关的突变。这项研究强调了下一代测序技术与功能研究和罕见变异分析工具相结合的效用，以提供对异质性散发疾病遗传病因的深入了解。肌萎缩性侧索硬化症（ALS），也被称为Charcot病或Lou Gehrig病，是世界上最常见的神经肌肉疾病之一。这种疾病的特征是运动神经元的进行性变性，导致患者在发病后几年内死亡。尽管大多数ALS病例是散发性的，但大多数ALS基因研究都集中在家族性形式，导致70%的家族性ALS病例的基因确定病因，而只有10%的散发性ALS病例。这一点，再加上可用于研究的家庭的缺乏，表明研究人员应该开始挖掘相对未被触及的可用散发性样本库，以确定散发性ALS的新遗传原因。在这里，我们利用高通量靶标测序技术来测试关于散发性ALS遗传原因的四种不同假设，并发现与ALS有关的新的候选基因和途径。
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that results in progressive degeneration of motor neurons, ultimately leading to paralysis and death. Approximately 10% of ALS cases are familial, with the remaining 90% of cases being sporadic. Genetic studies in familial cases of ALS have been extremely informative in determining the causative mutations behind ALS, especially as the same mutations identified in familial ALS can also cause sporadic disease. However, the cause of ALS in approximately 30% of familial cases and in the majority of sporadic cases remains unknown. Sporadic ALS cases represent an underutilized resource for genetic information about ALS; therefore, we undertook a targeted sequencing approach of 169 known and candidate ALS disease genes in 242 sporadic ALS cases and 129 matched controls to try to identify novel variants linked to ALS. We found a significant enrichment in novel and rare variants in cases versus controls, indicating that we are likely identifying disease associated mutations. This study highlights the utility of next generation sequencing techniques combined with functional studies and rare variant analysis tools to provide insight into the genetic etiology of a heterogeneous sporadic disease. Amyotrophic lateral sclerosis (ALS), also known as Charcot disease or Lou Gehrig's disease, is one of the most common neuromuscular diseases worldwide. This disease is characterized by a progressive degeneration of motor neurons, leading to patient death within a few years after onset. Despite the fact that most ALS cases are sporadic, most of the ALS genetic studies have focused on familial forms, leading to the genetic determination of cause for 70% of cases of familial ALS but for only 10% of sporadic ALS cases. This, coupled with the dearth of families available for study, suggests that researchers should begin tapping into the relatively untouched reservoir of available sporadic samples to identify novel genetic causes of sporadic ALS. Here we take advantage of high-throughput target sequencing techniques to test four different hypotheses about the genetic causes of ALS in sporadic ALS and uncover new candidate genes and pathways implicated in ALS.
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影响因子：
48
作者：
Craig, David W.;Pearson, John V.;Szelinger, Szabolcs;Sekar, Aswin;Redman, Margot;Corneveaux, Jason J.;Pawlowski, Traci L.;Laub, Trisha;Nunn, Gary;Stephan, Dietrich A.;Homer, Nils;Huentelman, Matthew J.
通讯作者：
Huentelman, Matthew J.
影响因子：
4.2
作者：
Chio, Adriano;Restagno, Gabriella;Brunetti, Maura;Ossola, Irene;Calvo, Andrea;Mora, Gabriele;Sabatelli, Mario;Monsurro, Maria Rosaria;Battistini, Stefania;Mandrioli, Jessica;Salvi, Fabrizio;Spataro, Rossella;Schymick, Jennifer;Traynor, Bryan J.;La Bella, Vincenzo
通讯作者：
La Bella, Vincenzo
影响因子：
4.4
作者：
Daneshjou, Roxana;Tatonetti, Nicholas P.;Altman, Russ B.
通讯作者：
Altman, Russ B.
影响因子：
25
作者：
Chesi, Alessandra;Staahl, Brett T.;Jovicic, Ana;Couthouis, Julien;Fasolino, Maria;Raphael, Alya R.;Yamazaki, Tomohiro;Elias, Laura;Polak, Meraida;Kelly, Crystal;Williams, Kelly L.;Fifita, Jennifer A.;Maragakis, Nicholas J.;Nicholson, Garth A.;King, Oliver D.;Reed, Robin;Crabtree, Gerald R.;Blair, Ian P.;Glass, Jonathan D.;Gitler, Aaron D.
通讯作者：
Gitler, Aaron D.
影响因子：
--
作者：
Andersson MK;Ståhlberg A;Arvidsson Y;Olofsson A;Semb H;Stenman G;Nilsson O;Aman P
通讯作者：
Aman P