美国斯坦福大学Dennis P. Wall课题组和加州大学洛杉矶分校Daniel H. Geschwind课题组合作绘制了引起自闭症的遗传突变网路。2019年8月9日出版的《细胞》发表了这一最新研究成果。

通过分析来自有多个患儿家庭的2308名个体的全基因组序列，研究人员对自闭症谱系障碍（ASD）的罕见遗传变异进行了全面评估。研究人员发现69个基因具有ASD风险，包括24个通过全基因组Bonferroni校正的基因和16个新的ASD风险基因，其中大多数由罕见遗传变异获得，这是对之前发现的实质性延伸。具有遗传突变的基因所富集的生物学途径集中在细胞骨架的构成和离子转运，这与之前研究中涉及的途径不同。尽管如此，重新突变和遗传而来基因有助于共同的蛋白质-蛋白质相互作用网络的形成。

研究人员还鉴定了影响非编码区的结构突变（SV），这提示DLG2和NR3C2的启动子中的重复缺失。斑马鱼中nr3c2功能的丧失影响了睡眠和社交能力，这与人类ASD相关的表型类似。这些发现表明在ASD研究中多重家庭分析的实用性，并且这些数据可通过Hartwell自闭症研究和技术网站获得。
 

附：英文原文

Title: Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks

Author: Elizabeth K. Ruzzo, Laura Pérez-Cano, Jae-Yoon Jung, David A. Prober, Daniel H. Geschwind, Dennis P. Wall

Issue&Volume: Volume 178 Issue 4

Abstract: We performed a comprehensive assessment of rare inherited variation in autism spectrum disorder (ASD) by analyzing whole-genome sequences of 2,308 individuals from families with multiple affected children. We implicate 69 genes in ASD risk, including 24 passing genome-wide Bonferroni correction and 16 new ASD risk genes, most supported by rare inherited variants, a substantial extension of previous findings. Biological pathways enriched for genes harboring inherited variants represent cytoskeletal organization and ion transport, which are distinct from pathways implicated in previous studies. Nevertheless, the de novo and inherited genes contribute to a common protein-protein interaction network. We also identified structural variants (SVs) affecting non-coding regions, implicating recurrent deletions in the promoters of DLG2 and NR3C2. Loss of nr3c2 function in zebrafish disrupts sleep and social function, overlapping with human ASD-related phenotypes. These data support the utility of studying multiplex families in ASD and are available through the Hartwell Autism Research and Technology portal.

DOI: https://doi.org/10.1016/j.cell.2019.07.015

Source: https://www.cell.com/cell/fulltext/S0092-8674(19)30780-9