Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA.
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital (TCH), Houston, TX 77030, USA; Program in Developmental Biology, BCM, Houston, TX 77030, USA.
Cell Rep. 2022 Mar 15;38(11):110517. doi: 10.1016/j.celrep.2022.110517.
Individuals with autism spectrum disorder (ASD) exhibit an increased burden of de novo mutations (DNMs) in a broadening range of genes. While these studies have implicated hundreds of genes in ASD pathogenesis, which DNMs cause functional consequences in vivo remains unclear. We functionally test the effects of ASD missense DNMs using Drosophila through "humanization" rescue and overexpression-based strategies. We examine 79 ASD variants in 74 genes identified in the Simons Simplex Collection and find 38% of them to cause functional alterations. Moreover, we identify GLRA2 as the cause of a spectrum of neurodevelopmental phenotypes beyond ASD in 13 previously undiagnosed subjects. Functional characterization of variants in ASD candidate genes points to conserved neurobiological mechanisms and facilitates gene discovery for rare neurodevelopmental diseases.
自闭症谱系障碍（ASD）个体在不断扩大的基因范围内表现出新生突变（DNMs）的负担增加。虽然这些研究已经在 ASD 发病机制中涉及数百个基因，但哪些 DNMs 在体内引起功能后果尚不清楚。我们通过“人源化”拯救和基于过表达的策略，使用果蝇来对 ASD 错义 DNMs 的功能影响进行测试。我们检查了西蒙斯单基因家族中确定的 74 个基因中的 79 个 ASD 变体，发现其中 38%导致功能改变。此外，我们还发现 GLRA2 是 13 个以前未确诊的受试者的 ASD 以外的一系列神经发育表型的原因。对 ASD 候选基因中的变体进行功能表征，指向保守的神经生物学机制，并为罕见神经发育疾病的基因发现提供了便利。
