外顯子組測序揭示散發性先天性腦積水成因
作者：
小柯機器人發布時間：2020/10/20 15:36:36
耶魯大學醫學院Kristopher T. Kahle課題組發現，外顯子組測序顯示散發性先天性腦積水（CH）個體的產前神經膠質發生遺傳破壞。相關研究成果發表在2020年10月19日的《自然-醫學》上。
通過對381例（232例三例）接受神經外科治療的散發性CH患者進行全外顯子測序，研究人員發現破壞性從頭突變佔病例總數17％以上，其中五個不同的基因表現出顯著的從頭突變負擔。總體而言，罕見的、破壞性較大的突變在散發性CH病例中約佔22％。多個CH基因是神經幹細胞生物學的關鍵調節因子，並在與胎兒神經膠質發生有關的人類轉錄網絡和細胞類型中融合。
這些數據暗示了早期大腦發育的遺傳破壞而不是CSF動力學損傷是大量散發性CH患者主要的發病原因。
據悉，以腦室擴大為特徵的先天性腦積水被認為是由腦脊液（CSF）過多積聚造成的疾病，因此可通過神經外科CSF轉移治療，但該療法具有高發病率和失敗率。一些患者術存在神經發育不良以及腦室肥大，這突出了人類對該疾病的發病機制了解有限。
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