Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus.
Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus.
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DOI：
10.1038/s41591-020-1090-2
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发表时间：
2020-11
期刊：
影响因子：
82.9
通讯作者：
Kahle KT
中科院分区：
文献类型：
--
作者：
Jin SC;Dong W;Kundishora AJ;Panchagnula S;Moreno-De-Luca A;Furey CG;Allocco AA;Walker RL;Nelson-Williams C;Smith H;Dunbar A;Conine S;Lu Q;Zeng X;Sierant MC;Knight JR;Sullivan W;Duy PQ;DeSpenza T;Reeves BC;Karimy JK;Marlier A;Castaldi C;Tikhonova IR;Li B;Peña HP;Broach JR;Kabachelor EM;Ssenyonga P;Hehnly C;Ge L;Keren B;Timberlake AT;Goto J;Mangano FT;Johnston JM;Butler WE;Warf BC;Smith ER;Schiff SJ;Limbrick DD Jr;Heuer G;Jackson EM;Iskandar BJ;Mane S;Haider S;Guclu B;Bayri Y;Sahin Y;Duncan CC;Apuzzo MLJ;DiLuna ML;Hoffman EJ;Sestan N;Ment LR;Alper SL;Bilguvar K;Geschwind DH;Günel M;Lifton RP;Kahle KT
先天性脑积水（CH），其特征在于脑室扩大，被认为是一种脑脊液（CSF）过度积聚的疾病，因此采用神经外科CSF分流术治疗具有较高的发病率和失败率。一些术后患者神经发育不良和持续性脑室扩大突出了我们对疾病机制的认识有限。通过对381例散发性神经外科治疗CH患者（232个三联体）进行全外显子组测序，我们发现损伤性新生突变占病例的17%以上，其中5个不同的基因表现出显著的新生突变负担。总的来说，约22%的散发性CH病例是由具有较大影响的罕见破坏性突变引起的。多个CH基因是神经干细胞生物学的关键调节因子，并且在与胎儿神经胶质形成相关的人类转录网络和细胞类型中会聚。这些数据暗示早期脑发育的遗传破坏，而不是CSF动力学受损，是大量散发性CH患者的主要病理机制。
Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.
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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：
4.5
作者：
Gilmore, JH;van Tol, JJ;Chescheir, NC
通讯作者：
Chescheir, NC
影响因子：
5.2
作者：
Divina, Petr;Kvitkovicova, Andrea;Vorechovsky, Igor
通讯作者：
Vorechovsky, Igor
影响因子：
16.2
作者：
Duran, Daniel;Zeng, Xue;Kahle, Kristopher T.
通讯作者：
Kahle, Kristopher T.
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G