Damaging de novo mutations diminish motor skills in children on the autism spectrum.
Damaging de novo mutations diminish motor skills in children on the autism spectrum.
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DOI：
10.1073/pnas.1715427115
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发表时间：
2018-02-20
影响因子：
11.1
通讯作者：
Iossifov I
中科院分区：
文献类型：
--
作者：
Buja A;Volfovsky N;Krieger AM;Lord C;Lash AE;Wigler M;Iossifov I
遗传学是自闭症谱系障碍（ASD）的一个主要决定因素。到目前为止，只有最严重的一类新生突变，即可能的基因破坏性（LGD）突变，与智商相关联，智商是一种与ASD相关的表型特征，但不是核心特征。一类不太严重的新生突变，即错义突变，虽然在ASD患者中富集，但一直难以与任何ASD表型特征相关联。在本报告中，我们证明按靶基因易感性评分的新生LGD突变和错义突变都与运动技能下降显著相关。
在自闭症谱系障碍（ASD）患者中，先前已表明新生突变与较低的智商显著相关，但与ASD的核心特征无关：社交沟通和互动缺陷以及兴趣狭窄和重复行为模式。我们通过在西蒙斯单纯集（Simons Simplex Collection）中证明ASD患者中具有破坏性的新生突变也与运动技能受损的指标显著且令人信服地相关联，从而扩展了这些发现。这种相关性不能用智商和运动技能之间的相关性来解释。我们发现智商和运动技能与破坏性突变有明显的关联，特别是，根据突变类型和靶基因判断，运动技能是比智商更敏感的突变严重程度指标。我们利用这一发现提出了一种表型严重程度的综合分类：轻度（两者都几乎无损伤）、中度（主要是运动技能损伤）和重度（智商和运动技能都损伤）。
Genetics is a major determining factor in autism spectrum disorder (ASD). To date, only the most severe class of de novo mutation, likely gene disruptive (LGD), has been correlated with IQ, a phenotypic characteristic associated with ASD, but not a core feature. A less severe class of de novo mutation, missense, while enriched in individuals with ASD, has been refractory to correlation with any ASD phenotypic feature. In this report, we demonstrate that de novo LGD and missense mutations scored by target gene vulnerability both show significant associations with diminished motor skills. In individuals with autism spectrum disorder (ASD), de novo mutations have previously been shown to be significantly correlated with lower IQ but not with the core characteristics of ASD: deficits in social communication and interaction and restricted interests and repetitive patterns of behavior. We extend these findings by demonstrating in the Simons Simplex Collection that damaging de novo mutations in ASD individuals are also significantly and convincingly correlated with measures of impaired motor skills. This correlation is not explained by a correlation between IQ and motor skills. We find that IQ and motor skills are distinctly associated with damaging mutations and, in particular, that motor skills are a more sensitive indicator of mutational severity than is IQ, as judged by mutational type and target gene. We use this finding to propose a combined classification of phenotypic severity: mild (little impairment of either), moderate (impairment mainly to motor skills), and severe (impairment of both IQ and motor skills).
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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：
30.8
作者：
Krumm, Niklas;Turner, Tychele N.;Baker, Carl;Vives, Laura;Mohajeri, Kiana;Witherspoon, Kali;Raja, Archana;Coe, Bradley P.;Stessman, Holly A.;He, Zong-Xiao;Leal, Suzanne M.;Bernier, Raphael;Eichler, Evan E.
通讯作者：
Eichler, Evan E.
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
DOI：
10.1111/j.1469-7610.2006.01531.x
发表时间：
2006-06-01
影响因子：
7.6
作者：
Landa, Rebecca;Garrett-Mayer, Elizabeth
通讯作者：
Garrett-Mayer, Elizabeth
DOI：
10.1111/j.1469-7610.2011.02398.x
发表时间：
2011-07-01
影响因子：
7.6
作者：
Hus, Vanessa;Taylor, Amanda;Lord, Catherine
通讯作者：
Lord, Catherine