Functional relationships between recessive inherited genes and genes with de novo variants in autism spectrum disorder
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RESEARCH
Functional relationships between recessive inherited genes and genes with de novo variants in autism spectrum disorder Lin Wang1,2†, Yi Zhang3†, Kuokuo Li1,4,5†, Zheng Wang3, Xiaomeng Wang1, Bin Li3, Guihu Zhao3, Zhenghuan Fang1, Zhengbao Ling1, Tengfei Luo1, Lu Xia1, Yanping Li2, Hui Guo1, Zhengmao Hu1, Jinchen Li3*, Zhongsheng Sun6,7* and Kun Xia1,8,9*
Abstract Background: Both de novo variants and recessive inherited variants were associated with autism spectrum disorder (ASD). This study aimed to use exome data to prioritize recessive inherited genes (RIGs) with biallelically inherited variants in autosomes or X-linked inherited variants in males and investigate the functional relationships between RIGs and genes with de novo variants (DNGs). Methods: We used a bioinformatics pipeline to analyze whole-exome sequencing data from 1799 ASD quads (containing one proband, one unaffected sibling, and their parents) from the Simons Simplex Collection and prioritize candidate RIGs with rare biallelically inherited variants in autosomes or X-linked inherited variants in males. The relationships between RIGs and DNGs were characterized based on different genetic perspectives, including genetic variants, functional networks, and brain expression patterns. Results: Among the biallelically or hemizygous constrained genes that were expressed in the brain, ASD probands carried significantly more biallelically inherited protein-truncating variants (PTVs) in autosomes (p = 0.038) and X-linked inherited PTVs in males (p = 0.026) than those in unaffected siblings. We prioritized eight autosomal, and 13 X-linked candidate RIGs, including 11 genes already associated with neurodevelopmental disorders. In total, we detected biallelically inherited variants or X-linked inherited variants of these 21 candidate RIGs in 26 (1.4%) of 1799 probands. We then integrated previously reported known or candidate genes in ASD, ultimately obtaining 70 RIGs and 87 DNGs for analysis. We found that RIGs were less likely to carry multiple recessive inherited variants than DNGs were to carry multiple de novo variants. Additionally, RIGs and DNGs were significantly co-expressed and interacted with each other, forming a network enriched in known functional ASD clusters, although RIGs were less likely to be
*Correspondence: [email protected]; [email protected]; xiakun@sklmg. edu.cn † Lin Wang, Yi Zhang and Kuokuo Li have contributed equally to this work. 1 Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China 3 National Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China 6 Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International Licens
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