Targeted sequencing and integrative analysis to prioritize candidate genes in neurodevelopmental disorders

doi:10.1007/s12035-021-02377-y

. 2021 Aug;58(8):3863-3873.

doi: 10.1007/s12035-021-02377-y. Epub 2021 Apr 15.

Targeted sequencing and integrative analysis to prioritize candidate genes in neurodevelopmental disorders

Yi Zhang^#¹, Tao Wang^#^{2

3

4}, Yan Wang³, Kun Xia^{5

6

7}, Jinchen Li^{8

9

10}, Zhongsheng Sun^{11

12

13

14}

Affiliations

¹ National Clinical Research Centre for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, 410083, Hunan, China.
² Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410083, Hunan, China.
³ Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, 100101, China.
⁴ DIAGenes Precision Medicine, Beijing, 102600, China.
⁵ Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410083, Hunan, China. xiakun@sklmg.edu.cn.
⁶ CAS Center for Excellence in Brain Science and Intelligences Technology (CEBSIT), Shanghai, 200031, China. xiakun@sklmg.edu.cn.
⁷ School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China. xiakun@sklmg.edu.cn.
⁸ National Clinical Research Centre for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, 410083, Hunan, China. lijinchen@csu.edu.cn.
⁹ Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410083, Hunan, China. lijinchen@csu.edu.cn.
¹⁰ Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. lijinchen@csu.edu.cn.
¹¹ Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, 100101, China. sunzs@biols.ac.cn.
¹² Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, 325035, China. sunzs@biols.ac.cn.
¹³ CAS Center for Excellence in Biotic Interactions, University of Chinese Academy of Sciences, Beijing, 100049, China. sunzs@biols.ac.cn.
¹⁴ State Key Laboratory of Integrated Management of Pest Insects and Rodents, Chinese Academy of Sciences, Beijing, 100101, China. sunzs@biols.ac.cn.

^# Contributed equally.

PMID: 33860439
PMCID: PMC8280036
DOI: 10.1007/s12035-021-02377-y

Targeted sequencing and integrative analysis to prioritize candidate genes in neurodevelopmental disorders

Yi Zhang et al. Mol Neurobiol. 2021 Aug.

. 2021 Aug;58(8):3863-3873.

doi: 10.1007/s12035-021-02377-y. Epub 2021 Apr 15.

Authors

Yi Zhang^#¹, Tao Wang^#^{2

3

4}, Yan Wang³, Kun Xia^{5

6

7}, Jinchen Li^{8

9

10}, Zhongsheng Sun^{11

12

13

14}

Affiliations

¹ National Clinical Research Centre for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, 410083, Hunan, China.
² Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410083, Hunan, China.
³ Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, 100101, China.
⁴ DIAGenes Precision Medicine, Beijing, 102600, China.
⁵ Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410083, Hunan, China. xiakun@sklmg.edu.cn.
⁶ CAS Center for Excellence in Brain Science and Intelligences Technology (CEBSIT), Shanghai, 200031, China. xiakun@sklmg.edu.cn.
⁷ School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China. xiakun@sklmg.edu.cn.
⁸ National Clinical Research Centre for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, 410083, Hunan, China. lijinchen@csu.edu.cn.
⁹ Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410083, Hunan, China. lijinchen@csu.edu.cn.
¹⁰ Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. lijinchen@csu.edu.cn.
¹¹ Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, 100101, China. sunzs@biols.ac.cn.
¹² Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, 325035, China. sunzs@biols.ac.cn.
¹³ CAS Center for Excellence in Biotic Interactions, University of Chinese Academy of Sciences, Beijing, 100049, China. sunzs@biols.ac.cn.
¹⁴ State Key Laboratory of Integrated Management of Pest Insects and Rodents, Chinese Academy of Sciences, Beijing, 100101, China. sunzs@biols.ac.cn.

^# Contributed equally.

PMID: 33860439
PMCID: PMC8280036
DOI: 10.1007/s12035-021-02377-y

Abstract

Neurodevelopmental disorders (NDDs) are a group of diseases characterized by high heterogeneity and frequently co-occurring symptoms. The mutational spectrum in patients with NDDs is largely incomplete. Here, we sequenced 547 genes from 1102 patients with NDDs and validated 1271 potential functional variants, including 108 de novo variants (DNVs) in 78 autosomal genes and seven inherited hemizygous variants in six X chromosomal genes. Notably, 36 of these 78 genes are the first to be reported in Chinese patients with NDDs. By integrating our genetic data with public data, we prioritized 212 NDD candidate genes with FDR < 0.1, including 17 novel genes. The novel candidate genes interacted or were co-expressed with known candidate genes, forming a functional network involved in known pathways. We highlighted MSL2, which carried two de novo protein-truncating variants (p.L192Vfs*3 and p.S486Ifs*11) and was frequently connected with known candidate genes. This study provides the mutational spectrum of NDDs in China and prioritizes 212 NDD candidate genes for further functional validation and genetic counseling.

Keywords: Candidate genes; De novo variants; Neurodevelopmental disorders; Targeted sequencing.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interest.

Figures

**Fig. 1**
Study workflow. This study consisted of four parts: (1) sample collection; (2) identification and validation of variants; (3) prioritization of candidate genes; (4) functional network analysis of novel and known candidate genes. PTVs, protein-truncating variants; Dmis, deleterious missense variants

**Fig. 2**
Functional network of novel and known candidate genes. Based on co-expression data from BrainSpan and PPI data from IntAct, 159 candidate genes formed a large interconnected functional network, mainly involving the following major functional clusters: chromatin organization, essential genes, nervous system development, FMRP targets, behavior, and synapse organization. Novel candidate genes are in red circles and known candidate genes are in green circles. Different line types between nodes represent the interactions existing in BrainSpan or IntAct or in both BrainSpan and IntAct

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References

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[1] Thapar A, Cooper M, Rutter M. Neurodevelopmental disorders. Lancet Psychiatry. 2017;4(4):339–346. doi: 10.1016/S2215-0366(16)30376-5. - DOI - PubMed

[2] Thapar A, Cooper M, Rutter M. Neurodevelopmental disorders. Lancet Psychiatry. 2017;4(4):339–346. doi: 10.1016/S2215-0366(16)30376-5. - DOI - PubMed

[3] Mullin AP, Gokhale A, Moreno-De-Luca A, et al. Neurodevelopmental disorders: mechanisms and boundary definitions from genomes, interactomes and proteomes. Transl Psychiatry. 2013;3:e329. doi: 10.1038/tp.2013.108. - DOI - PMC - PubMed

[4] Mullin AP, Gokhale A, Moreno-De-Luca A, et al. Neurodevelopmental disorders: mechanisms and boundary definitions from genomes, interactomes and proteomes. Transl Psychiatry. 2013;3:e329. doi: 10.1038/tp.2013.108. - DOI - PMC - PubMed

[5] Tarlungeanu DC, Novarino G. Genomics in neurodevelopmental disorders: an avenue to personalized medicine. Exp Mol Med. 2018;50(8):100–107. doi: 10.1038/s12276-018-0129-7. - DOI - PMC - PubMed

[6] Tarlungeanu DC, Novarino G. Genomics in neurodevelopmental disorders: an avenue to personalized medicine. Exp Mol Med. 2018;50(8):100–107. doi: 10.1038/s12276-018-0129-7. - DOI - PMC - PubMed

[7] Stessman HAF, Xiong B, Coe BP, Wang T, Hoekzema K, Fenckova M, Kvarnung M, Gerdts J, Trinh S, Cosemans N, Vives L, Lin J, Turner TN, Santen G, Ruivenkamp C, Kriek M, van Haeringen A, Aten E, Friend K, Liebelt J, Barnett C, Haan E, Shaw M, Gecz J, Anderlid BM, Nordgren A, Lindstrand A, Schwartz C, Kooy RF, Vandeweyer G, Helsmoortel C, Romano C, Alberti A, Vinci M, Avola E, Giusto S, Courchesne E, Pramparo T, Pierce K, Nalabolu S, Amaral DG, Scheffer IE, Delatycki MB, Lockhart PJ, Hormozdiari F, Harich B, Castells-Nobau A, Xia K, Peeters H, Nordenskjöld M, Schenck A, Bernier RA, Eichler EE. Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat Genet. 2017;49(4):515–526. doi: 10.1038/ng.3792. - DOI - PMC - PubMed

[8] Stessman HAF, Xiong B, Coe BP, Wang T, Hoekzema K, Fenckova M, Kvarnung M, Gerdts J, Trinh S, Cosemans N, Vives L, Lin J, Turner TN, Santen G, Ruivenkamp C, Kriek M, van Haeringen A, Aten E, Friend K, Liebelt J, Barnett C, Haan E, Shaw M, Gecz J, Anderlid BM, Nordgren A, Lindstrand A, Schwartz C, Kooy RF, Vandeweyer G, Helsmoortel C, Romano C, Alberti A, Vinci M, Avola E, Giusto S, Courchesne E, Pramparo T, Pierce K, Nalabolu S, Amaral DG, Scheffer IE, Delatycki MB, Lockhart PJ, Hormozdiari F, Harich B, Castells-Nobau A, Xia K, Peeters H, Nordenskjöld M, Schenck A, Bernier RA, Eichler EE. Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat Genet. 2017;49(4):515–526. doi: 10.1038/ng.3792. - DOI - PMC - PubMed

[9] Wilfert AB, Sulovari A, Turner TN, Coe BP, Eichler EE. Recurrent de novo mutations in neurodevelopmental disorders: properties and clinical implications. Genome Med. 2017;9(1):101. doi: 10.1186/s13073-017-0498-x. - DOI - PMC - PubMed

[10] Wilfert AB, Sulovari A, Turner TN, Coe BP, Eichler EE. Recurrent de novo mutations in neurodevelopmental disorders: properties and clinical implications. Genome Med. 2017;9(1):101. doi: 10.1186/s13073-017-0498-x. - DOI - PMC - PubMed

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Targeted sequencing and integrative analysis to prioritize candidate genes in neurodevelopmental disorders

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Targeted sequencing and integrative analysis to prioritize candidate genes in neurodevelopmental disorders

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