Yi Zhang
Liqui Liu
Yan Wang
Huiqian Chen
Tianda Fan
Jinchen Li
Kun Xia
Zhongsheng Sun
a Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410083, China;
b Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China;
c DIAGenes Precision Medicine, Beijing 102600, China;
d National Clinical Research Centre for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410083, China;
e Shanghai Adeptus Biotechnology, Shanghai 200126, China;
f Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China;
g Department of Neurology, Xiangya Hospital, Central South University, Changsha Hunan, 410083, China;
h CAS Center for Excellence in Brain Science and Intelligences Technology (CEBSIT), Shanghai 200031, China;
i School of Basic Medical Science, Central South University, Changsha, Hunan, 410083, China;
j CAS Center for Excellence in Biotic Interactions, University of Chinese Academy of Sciences, Beijing 100049, China;
k State Key Laboratory of Integrated Management of Pest Insects and Rodents, Chinese Academy of Sciences, Beijing 100101, China
Funds: This work was supported by the Guangdong Key Project in "Development of new tools for diagnosis and treatment of Autism" (2018B030335001 to Z. Sun) and "Early diagnosis and treatment of autism spectrum disorders" (202007030002 to Z. Sun), the National Natural Science Foundation of China (32070590 to Y. Wang), the National Natural Science Foundation of China (81730036 and 81525007 to K. Xia), Science and Technology Major Project of Hunan Provincial Science and Technology Department (2018SK1030 to K. Xia), the National Natural Science Foundation of China (81801133 to J. Li), the Young Elite Scientist Sponsorship Program by CAST (2018QNRC001 to J. Li), the Innovation-Driven Project of Central South University (20180033040004 to J. Li) and Natural Science Foundation of Hunan Province for outstanding Young Scholars (2020JJ3059 to J. Li).
Received Date: 2020-12-08
Accepted Date:2021-03-07
Rev Recd Date:2021-03-05
Publish Date:2021-04-20
Abstract
Abstract
Neurodevelopmental disorders (NDDs) are a set of complex disorders characterized by diverse and cooccurring clinical symptoms. The genetic contribution in patients with NDDs remains largely unknown. Here, we sequence 519 NDD-related genes in 3,195 Chinese probands with neurodevelopmental phenotypes and identify 2,522 putative functional mutations consisting of 137 de novo mutations (DNMs) in 86 genes and 2,385 rare inherited mutations (RIMs) with 22 X-linked hemizygotes in 13 genes, 2 homozygous mutations in 2 genes and 23 compound heterozygous mutations in 10 genes. Furthermore, the DNMs of 16,807 probands with NDDs are retrieved from public datasets and combine in an integrated analysis with the mutation data of our Chinese NDD probands by taking 3,582 in-house controls of Chinese origin as background. We prioritize 26 novel candidate genes. Notably, six of these genes — ITSN1, UBR3, CADM1, RYR3, FLNA, and PLXNA3 — preferably contribute to autism spectrum disorders (ASDs), as demonstrated by high co-expression and/or interaction with ASD genes confirmed via rescue experiments in a mouse model. Importantly, these genes are differentially expressed in the ASD cortex in a significant manner and involved in ASD-associated networks. Together, our study expands the genetic spectrum of Chinese NDDs, further facilitating both basic and translational research.Keywords: De novo mutations,
X-linked variants,
Rare inherited variants,
Homozygous mutations,
Neurodevelopmental disorders,
Autism spectrum disorders,
Candidate genes
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