Targeted sequencing and integrative analysis of 3,195 Chinese patients with neurodevelopmental disorders prioritized 26 novel candidate genes |
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| Authors: | Tao Wang Yi Zhang Liqui Liu Yan Wang Huiqian Chen Tianda Fan Jinchen Li Kun Xia Zhongsheng Sun |
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| Institution: | 1. Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410083, China;2. Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China;3. DIAGenes Precision Medicine, Beijing 102600, China;4. National Clinical Research Centre for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410083, China;5. Shanghai Adeptus Biotechnology, Shanghai 200126, China;6. Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China;7. Department of Neurology, Xiangya Hospital, Central South University, Changsha Hunan, 410083, China;8. CAS Center for Excellence in Brain Science and Intelligences Technology (CEBSIT), Shanghai 200031, China;9. School of Basic Medical Science, Central South University, Changsha, Hunan, 410083, China;10. CAS Center for Excellence in Biotic Interactions, University of Chinese Academy of Sciences, Beijing 100049, China;11. State Key Laboratory of Integrated Management of Pest Insects and Rodents, Chinese Academy of Sciences, Beijing 100101, China;1. State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100080, China;2. CAS Centre for Excellence in Biotic Interactions, University of Chinese Academy of Sciences, Beijing 100049, China;1. Eye Center of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China;2. The Institute of Translational Medicine, Zhejiang University, Hangzhou 310058, China;3. Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China;4. Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Chiba 277-8562, Japan;5. Zhejiang Provincial Key Lab of Ophthalmology, Hangzhou 310058, China;6. MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China;1. Department of Entomology and MOA Key Lab of Pest Monitoring and Green Management, College of Plant Protection, China Agricultural University, Beijing 100193, China;2. College of Life Sciences, Hebei University, Baoding 071002, China;1. Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium;2. Department of Biomolecular Medicine, Ghent University, Ghent, Belgium |
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| 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 of16,807 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 d ITSN1, UBR3, CADM1,RYR3, FLNA, and PLXNA3 d 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. |
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| Keywords: | X-linked variants Rare inherited variants Homozygous mutations Neurodevelopmental disorders Autism spectrum disorders Candidate genes |
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