Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants.
Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants.
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DOI：
10.1038/s41436-018-0266-3
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发表时间：
2019-04
期刊：
影响因子：
--
通讯作者：
Girirajan S
中科院分区：
文献类型：
--
作者：
Pizzo L;Jensen M;Polyak A;Rosenfeld JA;Mannik K;Krishnan A;McCready E;Pichon O;Le Caignec C;Van Dijck A;Pope K;Voorhoeve E;Yoon J;Stankiewicz P;Cheung SW;Pazuchanics D;Huber E;Kumar V;Kember RL;Mari F;Curró A;Castiglia L;Galesi O;Avola E;Mattina T;Fichera M;Mandarà L;Vincent M;Nizon M;Mercier S;Bénéteau C;Blesson S;Martin-Coignard D;Mosca-Boidron AL;Caberg JH;Bucan M;Zeesman S;Nowaczyk MJM;Lefebvre M;Faivre L;Callier P;Skinner C;Keren B;Perrine C;Prontera P;Marle N;Renieri A;Reymond A;Kooy RF;Isidor B;Schwartz C;Romano C;Sistermans E;Amor DJ;Andrieux J;Girirajan S
评估遗传背景中罕见变异对罕见拷贝数变异（CNVs）和基因破坏性变异个体神经发育表型变异的贡献。我们分析了来自757名先证者和233名携带疾病相关变异的父母和兄弟姐妹的定量临床信息、外显子组测序和微阵列数据。功能不耐受基因中罕见的可能有害的变异（"其他命中"）的数量与16p12.1缺失的先证者（n = 23，p = 0.004）和携带基因破坏性变异的自闭症先证者（n = 184，p = 0.03）的神经发育表型的表达相关。16p12.1缺失和强家族史的先证者与轻度/无家族史的先证者相比，表现出更严重的临床特征（p = 0.04）和更高的其他命中负担（p = 0.001）。在携带致病性CNV（n = 53）或疾病基因中的新发致病性变体（n = 290）的先证者中，其他命中的数量也与认知障碍的严重程度相关，并且在80名16p11.2缺失的先证者中与头部大小呈负相关。这些共同发生的命中涉及已知的疾病相关基因，如SETD5，AUTS 2和NRXN1，并富集细胞和发育过程。复杂疾病的准确遗传诊断将需要完整的遗传背景评估，即使在候选疾病相关的变异被确定。
To assess the contribution of rare variants in the genetic background toward variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive variants. We analyzed quantitative clinical information, exome sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated variants. The number of rare likely deleterious variants in functionally intolerant genes (“other hits”) correlated with expression of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in autism probands carrying gene-disruptive variants (n=184, p=0.03) compared with their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of other hits compared with those with mild/no family history (p=0.001). The number of other hits also correlated with severity of cognitive impairment in probands carrying pathogenic CNVs (n=53) or de novo pathogenic variants in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These co-occurring hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for cellular and developmental processes. Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified.
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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
影响因子：
25.8
作者：
Moreno-De-Luca, Andres;Evans, David W.;Ledbetter, David H.
通讯作者：
Ledbetter, David H.
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
5.6
作者：
Guerrini, Renzo;Cellini, Elena;Zamponi, Nelia
通讯作者：
Zamponi, Nelia