Delineating the genetic heterogeneity of ALS using targeted high-throughput sequencing.
Delineating the genetic heterogeneity of ALS using targeted high-throughput sequencing.
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DOI：
10.1136/jmedgenet-2013-101795
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发表时间：
2013-11
影响因子：
4
通讯作者：
Hardiman O
中科院分区：
文献类型：
--
作者：
Kenna KP;McLaughlin RL;Byrne S;Elamin M;Heverin M;Kenny EM;Cormican P;Morris DW;Donaghy CG;Bradley DG;Hardiman O
已有100多个基因与肌萎缩侧索硬化症(ALS)的病因学有关。详细了解他们对疾病负担的独立和累积贡献可能有助于指导各种临床和研究工作。使用定向高通量测序，我们表征了444例爱尔兰ALS患者(50例FALS，394例SAL)和311名年龄匹配和地理匹配的对照人群中10个孟德尔基因和23个低外显性/暂定ALS基因的变异。在17.1%的患者中(38%的FAL，14.5%的SALS)发现了已知的或潜在的高外显性ALS变异。携带孟德尔病基因变异的占12.8%(C9orf72 8.78%；SETX 2.48%；als2 1.58%；FUS 0.45%；TARDBP 0.45%；OPTN 0.23%；VCP 0.23%)。ANG、SOD、VAPB分别为0%、4.7%和9.7%(30%的FAL、7.1%的SAL)，分别为8.78%、0.45%、0.45%。1.6%的患者携带多种已知/潜在疾病变异，包括所有已确定的ALS变异携带者(P<；0.01)；TARDBP：C.859G>；A(p.[G287S])(n=2/2 SAL)。将我们的结果与其他欧洲人群的研究结果进行比较，发现疾病变异谱有显著差异(p=1.7x10−4)。高达17%的爱尔兰肌萎缩侧索硬化症病例可能在被调查的基因中携带高外显性变异。然而，遗传易感性的确切性质与其他欧洲人群中报告的显著不同。某些变异在隔离的情况下可能不会导致疾病，伴随而来的疾病基因分析可能被证明非常重要。
Over 100 genes have been implicated in the aetiology of amyotrophic lateral sclerosis (ALS). A detailed understanding of their independent and cumulative contributions to disease burden may help guide various clinical and research efforts. Using targeted high-throughput sequencing, we characterised the variation of 10 Mendelian and 23 low penetrance/tentative ALS genes within a population-based cohort of 444 Irish ALS cases (50 fALS, 394 sALS) and 311 age-matched and geographically matched controls. Known or potential high-penetrance ALS variants were identified within 17.1% of patients (38% of fALS, 14.5% of sALS). 12.8% carried variants of Mendelian disease genes (C9orf72 8.78%; SETX 2.48%; ALS2 1.58%; FUS 0.45%; TARDBP 0.45%; OPTN 0.23%; VCP 0.23%. ANG, SOD1, VAPB 0%), 4.7% carried variants of low penetrance/tentative ALS genes and 9.7% (30% of fALS, 7.1% of sALS) carried previously described ALS variants (C9orf72 8.78%; FUS 0.45%; TARDBP 0.45%). 1.6% of patients carried multiple known/potential disease variants, including all identified carriers of an established ALS variant (p<0.01); TARDBP:c.859G>A(p.[G287S]) (n=2/2 sALS). Comparison of our results with those from studies of other European populations revealed significant differences in the spectrum of disease variation (p=1.7×10−4). Up to 17% of Irish ALS cases may carry high-penetrance variants within the investigated genes. However, the precise nature of genetic susceptibility differs significantly from that reported within other European populations. Certain variants may not cause disease in isolation and concomitant analysis of disease genes may prove highly important.
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来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
4.2
作者：
Harms, Matthew B.;Cady, Janet;Baloh, Robert H.
通讯作者：
Baloh, Robert H.
影响因子：
14.8
作者：
Kumar, Prateek;Henikoff, Steven;Ng, Pauline C.
通讯作者：
Ng, Pauline C.
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：
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.