De novo mutations in moderate or severe intellectual disability.
De novo mutations in moderate or severe intellectual disability.
复制标题
DOI：
10.1371/journal.pgen.1004772
复制
发表时间：
2014-10
期刊：
影响因子：
4.5
通讯作者：
Michaud JL
中科院分区：
文献类型：
--
作者：
Hamdan FF;Srour M;Capo-Chichi JM;Daoud H;Nassif C;Patry L;Massicotte C;Ambalavanan A;Spiegelman D;Diallo O;Henrion E;Dionne-Laporte A;Fougerat A;Pshezhetsky AV;Venkateswaran S;Rouleau GA;Michaud JL
遗传学被认为在智力障碍（ID）中发挥着重要作用。最近的研究强调了 ID 中新生突变 (DNM) 的参与，但它们对其发病机制的贡献程度以及相应基因的身份仍然很大程度上未知。在这里，我们报告了中度或重度 ID 受试者的 DNM 筛查。我们对 41 个先证者及其父母的外显子组进行了测序，并确认了 81 个影响编码序列或共有剪接位点的 DNM（1.98 个 DNM/先证者）。与对照受试者相比，我们观察到这些病例中明显过量的从头单核苷酸取代和功能丧失突变，表明这些变异中至少有一部分是致病性的。在先前与 ID 相关的基因（ARID1B、CHD2、FOXG1、GABRB3、GATAD2B、GRIN2B、MBD5、MED13L、SETBP1、TBR1、TCF4、WDR45）中总共鉴定出了 12 种可能致病的 DNM，诊断率约为 29%。我们还在基因（HNRNPU、WAC、RYR2、SET、EGR1、MYH10、EIF2C1、COL4A3BP、CHMP2A、PPP1CB、VPS4A、PPP2R2B）中鉴定了 12 种可能致病的 DNM，这些基因此前并未与 ID 存在因果关系。有趣的是，没有任何病例可以用遗传突变来解释。蛋白质网络分析表明，许多已知基因和候选基因的产物彼此相互作用，或与其他 ID 相关基因的产物相互作用，进一步支持它们参与 ID。我们得出的结论是，DNM 是中度或重度 ID 的主要原因。智力障碍（ID）是儿童时期最常见的严重障碍。一些观察结果表明，遗传因素可以解释大部分智力障碍病例。我们和其他人最近发现新生突变（DNM；不是从父母遗传的基因变化）是导致智力障碍的常见原因。为了进一步评估 DNM 对 ID 发展的贡献，我们询问了 41 名患有中度或重度 ID 的受影响儿童及其健康父母的几乎所有基因组基因。在其中 12 个病例中，我们在已知与 ID 相关的基因中鉴定出了致病 DNM，分子诊断率为 29%。我们还在基因中发现了 12 种可能致病的 DNM，这些 DNM 以前与 ID 没有因果关系。有趣的是，这项研究发现的许多具有有害 DNM 的基因编码的蛋白质彼此相互作用并影响脑细胞的特定过程。相比之下，我们没有发现任何可以解释我们的病例的遗传突变。我们得出的结论是，DNM 在中度或重度 ID 中起主导作用。
Genetics is believed to have an important role in intellectual disability (ID). Recent studies have emphasized the involvement of de novo mutations (DNMs) in ID but the extent to which they contribute to its pathogenesis and the identity of the corresponding genes remain largely unknown. Here, we report a screen for DNMs in subjects with moderate or severe ID. We sequenced the exomes of 41 probands and their parents, and confirmed 81 DNMs affecting the coding sequence or consensus splice sites (1.98 DNMs/proband). We observed a significant excess of de novo single nucleotide substitutions and loss-of-function mutations in these cases compared to control subjects, suggesting that at least a subset of these variations are pathogenic. A total of 12 likely pathogenic DNMs were identified in genes previously associated with ID (ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5, MED13L, SETBP1, TBR1, TCF4, WDR45), resulting in a diagnostic yield of ∼29%. We also identified 12 possibly pathogenic DNMs in genes (HNRNPU, WAC, RYR2, SET, EGR1, MYH10, EIF2C1, COL4A3BP, CHMP2A, PPP1CB, VPS4A, PPP2R2B) that have not previously been causally linked to ID. Interestingly, no case was explained by inherited mutations. Protein network analysis indicated that the products of many of these known and candidate genes interact with each other or with products of other ID-associated genes further supporting their involvement in ID. We conclude that DNMs represent a major cause of moderate or severe ID. Intellectual disability (ID) is the most frequent severe handicap of childhood. Several observations indicate that genetic factors explain a large fraction of cases with ID. We and others have recently found that de novo mutations (DNMs; genetic changes not transmitted from the parents) represent a common cause of ID. To further assess the contribution of DNMs to the development of ID, we interrogated virtually all the genes of the genome in 41 affected children with moderate or severe ID and in their healthy parents. In 12 of the cases, we identified disease-causing DNMs in genes known to be associated with ID, resulting in a molecular diagnostic yield of 29%. We also found 12 possibly disease-causing DNMs in genes that were not previously causally linked to ID. Interestingly, many of the genes with deleterious DNMs uncovered by this study encode proteins that interact with each other and affect specific processes in brain cells. In contrast, we did not identify any inherited mutations that could explain our cases. We conclude that DNMs play a predominant role in moderate or severe ID.
登录
查看更多内容
FOXG1 综合征的核心表型包括出生后小头畸形、严重智力低下、语言缺失、运动障碍和胼胝体发育不全。
影响因子：
4
作者：
Kortüm F;Das S;Flindt M;Morris-Rosendahl DJ;Stefanova I;Goldstein A;Horn D;Klopocki E;Kluger G;Martin P;Rauch A;Roumer A;Saitta S;Walsh LE;Wieczorek D;Uyanik G;Kutsche K;Dobyns WB
通讯作者：
Dobyns WB
影响因子：
16.2
作者：
Iossifov I;Ronemus M;Levy D;Wang Z;Hakker I;Rosenbaum J;Yamrom B;Lee YH;Narzisi G;Leotta A;Kendall J;Grabowska E;Ma B;Marks S;Rodgers L;Stepansky A;Troge J;Andrews P;Bekritsky M;Pradhan K;Ghiban E;Kramer M;Parla J;Demeter R;Fulton LL;Fulton RS;Magrini VJ;Ye K;Darnell JC;Darnell RB;Mardis ER;Wilson RK;Schatz MC;McCombie WR;Wigler M
通讯作者：
Wigler M
影响因子：
9.8
作者：
Froyen, Guy;Corbett, Mark;Gecz, Jozef
通讯作者：
Gecz, Jozef
影响因子：
30.8
作者：
Hoischen, Alexander;van Bon, Bregje W. M.;Veltman, Joris A.
通讯作者：
Veltman, Joris A.
影响因子：
9.8
作者：
Haack, Tobias B.;Hogarth, Penelope;Hayflick, Susan J.
通讯作者：
Hayflick, Susan J.