耶鲁大学医学院Kristopher T. Kahle课题组发现，外显子组测序显示散发性先天性脑积水（CH）个体的产前神经胶质发生遗传破坏。相关研究成果发表在2020年10月19日的《自然-医学》上。

通过对381例（232例三例）接受神经外科治疗的散发性CH患者进行全外显子测序，研究人员发现破坏性从头突变占病例总数17％以上，其中五个不同的基因表现出显著的从头突变负担。总体而言，罕见的、破坏性较大的突变在散发性CH病例中约占22％。多个CH基因是神经干细胞生物学的关键调节因子，并在与胎儿神经胶质发生有关的人类转录网络和细胞类型中融合。

这些数据暗示了早期大脑发育的遗传破坏而不是CSF动力学损伤是大量散发性CH患者主要的发病原因。

据悉，以脑室扩大为特征的先天性脑积水被认为是由脑脊液（CSF）过多积聚造成的疾病，因此可通过神经外科CSF转移治疗，但该疗法具有高发病率和失败率。一些患者术存在神经发育不良以及脑室肥大，这突出了人类对该疾病的发病机制了解有限。

附：英文原文

Title: Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus

Author: Sheng Chih Jin, Weilai Dong, Adam J. Kundishora, Shreyas Panchagnula, Andres Moreno-De-Luca, Charuta G. Furey, August A. Allocco, Rebecca L. Walker, Carol Nelson-Williams, Hannah Smith, Ashley Dunbar, Sierra Conine, Qiongshi Lu, Xue Zeng, Michael C. Sierant, James R. Knight, William Sullivan, Phan Q. Duy, Tyrone DeSpenza, Benjamin C. Reeves, Jason K. Karimy, Arnaud Marlier, Christopher Castaldi, Irina R. Tikhonova, Boyang Li, Helena Perez Pea, James R. Broach, Edith M. Kabachelor, Peter Ssenyonga, Christine Hehnly, Li Ge, Boris Keren, Andrew T. Timberlake, June Goto, Francesco T. Mangano, James M. Johnston, William E. Butler, Benjamin C. Warf, Edward R. Smith, Steven J. Schiff, David D. Limbrick, Gregory Heuer, Eric M. Jackson, Bermans J. Iskandar, Shrikant Mane, Shozeb Haider, Bulent Guclu, Yasar Bayri, Yener Sahin, Charles C. Duncan, Michael L. J. Apuzzo, Michael L. DiLuna, Ellen J. Hoffman, Nenad Sestan, Laura R. Ment, Seth L. Alper, Kaya Bilguvar, Daniel H. Geschwind, Murat Gnel, Richard P. Lifton, Kristopher T. Kahle

Issue&Volume: 2020-10-19

Abstract: 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. The largest whole-exome sequencing study of sporadic congenital hydrocephalus identities mutations associated with disrupted fetal neuro-gliogenesis as the primary pathophysiological event in a significant number of cases.

DOI: 10.1038/s41591-020-1090-2

Source: https://www.nature.com/articles/s41591-020-1090-2