在一个先证者中多个新生编码变异的非随机发生表明自闭症存在一个寡基因模型。

Nonrandom occurrence of multiple de novo coding variants in a proband indicates the existence of an oligogenic model in autism.

机构信息

Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, China.

Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.

出版信息

Genet Med. 2020 Jan;22(1):170-180. doi: 10.1038/s41436-019-0610-2. Epub 2019 Jul 23.

DOI:10.1038/s41436-019-0610-2

PMID:31332282

Abstract

PURPOSE

Elucidating the genetic architecture underlying autism spectrum disorder (ASD) will aid in the understanding of its genetic etiology and clinical diagnosis.

METHODS

A comprehensive set of coding de novo variants (DNVs) from 4504 trios with ASD and 3012 control/sibling trios from several large-scale sequencing studies were collected and combined. Multiple in-depth analyses including DNVs burden, clinical phenotypes, and functional networks underlying the combined data set were used to evaluate the nonrandom occurrence of multiple extreme DNVs (loss-of-function and damaging missense variants) in the same patients.

RESULTS

We observed a significant excess of multiple extreme DNVs among patients with ASD compared with controls. Meanwhile, patients with ASD carrying 2+ extreme DNVs had significantly lower IQs than patients carrying 0 or 1 DNV. Moreover, much closer functional connectivity than expected was observed among 2 or more genes with extreme DNVs from the same individuals. In particular, we identified 56 key genes as more confident ASD genes compared with other known ASD genes. In addition, we detected 23 new ASD candidate genes with recurrent DNVs, including VIP, ZWILCH, MSL2, LRRC4, and CAPRIN1.

CONCLUSIONS

Our findings present compelling statistical evidence supporting an oligogenic model and provide new insights into the genetic architecture of ASD.

摘要

目的

阐明孤独症谱系障碍（ASD）的遗传结构将有助于理解其遗传病因和临床诊断。

方法

从来自多个大型测序研究的 4504 个 ASD 三体型和 3012 个对照/同胞三体型中收集并合并了一整套编码新生变异（DNV）。使用多种深入分析，包括 DNV 负担、临床表型和组合数据集下的功能网络，评估同一患者中多个极端 DNV（功能丧失和破坏性错义变异）的非随机发生。

结果

与对照组相比，我们观察到 ASD 患者中多个极端 DNV 的显著过剩。同时，携带 2+极端 DNV 的 ASD 患者的智商明显低于携带 0 或 1 个 DNV 的患者。此外，与其他已知的 ASD 基因相比，来自同一个体的具有极端 DNV 的 2 个或更多基因之间观察到的功能连接要紧密得多。特别是，我们确定了 56 个关键基因作为更有信心的 ASD 基因，而不是其他已知的 ASD 基因。此外，我们检测到 23 个具有反复 DNV 的新的 ASD 候选基因，包括 VIP、ZWILCH、MSL2、LRRC4 和 CAPRIN1。