Novel rare missense variations and risk of autism spectrum disorder: whole-exome sequencing in two families with affected siblings and a two-stage follow-up study in a Japanese population.
Novel rare missense variations and risk of autism spectrum disorder: whole-exome sequencing in two families with affected siblings and a two-stage follow-up study in a Japanese population.
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DOI：
10.1371/journal.pone.0119413
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Someya T
中科院分区：
文献类型：
--
作者：
Egawa J;Watanabe Y;Wang C;Inoue E;Sugimoto A;Sugiyama T;Igeta H;Nunokawa A;Shibuya M;Kushima I;Orime N;Hayashi T;Okada T;Uno Y;Ozaki N;Someya T
患有自闭症谱系障碍 (ASD) 的多重家族中罕见的遗传变异被认为在 ASD 的遗传病因学中发挥着重要作用。为了进一步研究罕见遗传变异的作用，我们对两个家庭进行了全外显子组测序（WES），每个家庭都有三个受影响的兄弟姐妹。我们还在日本人群中进行了一项两阶段随访病例对照研究。对六名受影响的兄弟姐妹进行了 WES 鉴定，发现了六种新颖的罕见错义变异。在这些变异中，CLN8 R24H 在一个家庭中由受影响的父亲的三个受影响的兄弟姐妹遗传，因此与 ASD 共分离。在后续研究的第一阶段，我们对 241 名患者和 667 名对照者（新泻样本）中通过 WES 鉴定出的 6 种新型罕见错义变异进行了基因分型。与对照组 (1/1334) 相比，仅 CLN8 R24H 在患者 (1/482) 中具有更高的突变等位基因频率。在第二阶段，这种变异被进一步基因分型，但在 309 名患者和 350 名对照样本（名古屋样本）中并未检测到。在新泻和名古屋的合并样本中，没有显着关联（比值比 = 1.8，95% 置信区间 = 0.1–29.6）。这些结果表明 CLN8 R24H 在 ASD 的遗传病因学中发挥作用，至少在一部分 ASD 患者中是这样。
Rare inherited variations in multiplex families with autism spectrum disorder (ASD) are suggested to play a major role in the genetic etiology of ASD. To further investigate the role of rare inherited variations, we performed whole-exome sequencing (WES) in two families, each with three affected siblings. We also performed a two-stage follow-up case-control study in a Japanese population. WES of the six affected siblings identified six novel rare missense variations. Among these variations, CLN8 R24H was inherited in one family by three affected siblings from an affected father and thus co-segregated with ASD. In the first stage of the follow-up study, we genotyped the six novel rare missense variations identified by WES in 241 patients and 667 controls (the Niigata sample). Only CLN8 R24H had higher mutant allele frequencies in patients (1/482) compared with controls (1/1334). In the second stage, this variation was further genotyped, yet was not detected in a sample of 309 patients and 350 controls (the Nagoya sample). In the combined Niigata and Nagoya samples, there was no significant association (odds ratio = 1.8, 95% confidence interval = 0.1–29.6). These results suggest that CLN8 R24H plays a role in the genetic etiology of ASD, at least in a subset of ASD patients.
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影响因子：
64.8
作者：
Iossifov, Ivan;O'Roak, Brian J.;Sanders, Stephan J.;Ronemus, Michael;Krumm, Niklas;Levy, Dan;Stessman, Holly A.;Witherspoon, Kali T.;Vives, Laura;Patterson, Karynne E.;Smith, Joshua D.;Paeper, Bryan;Nickerson, Deborah A.;Dea, Jeanselle;Dong, Shan;Gonzalez, Luis E.;Mandell, Jeffrey D.;Mane, Shrikant M.;Murtha, Michael T.;Sullivan, Catherine A.;Walker, Michael F.;Waqar, Zainulabedin;Wei, Liping;Willsey, A. Jeremy;Yamrom, Boris;Lee, Yoon-ha;Grabowska, Ewa;Dalkic, Ertugrul;Wang, Zihua;Marks, Steven;Andrews, Peter;Leotta, Anthony;Kendall, Jude;Hakker, Inessa;Rosenbaum, Julie;Ma, Beicong;Rodgers, Linda;Troge, Jennifer;Narzisi, Giuseppe;Yoon, Seungtai;Schatz, Michael C.;Ye, Kenny;McCombie, W. Richard;Shendure, Jay;Eichler, Evan E.;State, Matthew W.;Wigler, Michael
通讯作者：
Wigler, Michael
影响因子：
4.2
作者：
Lonka, L;Salonen, T;Jalanko, A
通讯作者：
Jalanko, A
影响因子：
3.9
作者：
Vantaggiato, Chiara;Redaelli, Francesca;Bassi, Maria T.
通讯作者：
Bassi, Maria T.
影响因子：
30.8
作者：
Ranta, S;Zhang, YH;Lehesjoki, AE
通讯作者：
Lehesjoki, AE
影响因子：
7.6
作者：
Fein, Deborah;Barton, Marianne;Tyson, Katherine
通讯作者：
Tyson, Katherine