近日，美国波士顿儿童医院教授Timothy W. Yu及其课题组发现了自闭症谱系障碍的隐性基因紊乱。这一研究成果发表在2019年7月出版的国际学术期刊《Nature Genetics》上。

课题组在一个大的ASD群组中展示了过多的复等位基因功能缺失和破坏性的错义突变，其比例大约占总病例的5%的，这当中的10%是女性，与女性的保护作用相一致。研究人员记录了已知或正在出现的隐性神经发育基因(CA2, DDHD1, NSUN2, PAH, RARB, ROGDI, SLC1A1, USH2A)的复等位基因破坏，以及其他以前未涉及ASD的基因，包括FEV (FEV转录因子，ETS家族成员)，它编码血清素能回路的关键调控因子。该数据改进了对隐性突变对ASD的贡献的估计，并提出了新的途径来阐明先前未知的导致这种情况的生物学通路。

据介绍，自闭症谱系障碍(ASD)的发病率高达1/59。全基因组关联和大规模测序研究强烈提示ASD中常见的变异和罕见的新生变异。隐性突变也有牵连，但它们的作用仍不太明确。

附：英文原文

Title: Recessive gene disruptions in autism spectrum disorder

Author: Ryan N. Doan, Elaine T. Lim, Silvia De Rubeis, Catalina Betancur, David J. Cutler, Andreas G. Chiocchetti, Lynne M. Overman, Aubrie Soucy, Susanne Goetze, Christine M. Freitag, Mark J. Daly, Christopher A. Walsh, Joseph D. Buxbaum, Timothy W. Yu

Issue&Volume: Volume 51 Issue 7, July 2019

Abstract: Autism spectrum disorder (ASD) affects up to 1 in 59 individuals. Genome-wide association and large-scale sequencing studies strongly implicate both common variants and rare de novo variants in ASD. Recessive mutations have also been implicated but their contribution remains less well defined. Here we demonstrate an excess of biallelic loss-of-function and damaging missense mutations in a large ASD cohort, corresponding to approximately 5% of total cases, including 10% of females, consistent with a female protective effect. We document biallelic disruption of known or emerging recessive neurodevelopmental genes (CA2, DDHD1, NSUN2, PAH, RARB, ROGDI, SLC1A1, USH2A) as well as other genes not previously implicated in ASD including FEV (FEV transcription factor, ETS family member), which encodes a key regulator of the serotonergic circuitry. Our data refine estimates of the contribution of recessive mutation to ASD and suggest new paths for illuminating previously unknown biological pathways responsible for this condition.

DOI: 10.1038/s41588-019-0433-8

Source: https://www.nature.com/articles/s41588-019-0433-8