Prioritizing de novo potential non-canonical splicing variants in neurodevelopmental disordersResearch in context

Kuokuo Li; Jifang Xiao; Zhengbao Ling; Tengfei Luo; Jingyu Xiong; Qian Chen; Lijie Dong; Yijing Wang; Xiaomeng Wang; Zhaowei Jiang; Lu Xia; Zhen Yu; Rong Hua; Rui Guo; Dongdong Tang; Mingrong Lv; Aojie Lian; Bin Li; GuiHu Zhao; Xiaojin He; Kun Xia; Yunxia Cao; Jinchen Li

EBioMedicine (Jan 2024)

Prioritizing de novo potential non-canonical splicing variants in neurodevelopmental disordersResearch in context

Kuokuo Li,
Jifang Xiao,
Zhengbao Ling,
Tengfei Luo,
Jingyu Xiong,
Qian Chen,
Lijie Dong,
Yijing Wang,
Xiaomeng Wang,
Zhaowei Jiang,
Lu Xia,
Zhen Yu,
Rong Hua,
Rui Guo,
Dongdong Tang,
Mingrong Lv,
Aojie Lian,
Bin Li,
GuiHu Zhao,
Xiaojin He,
Kun Xia,
Yunxia Cao,
Jinchen Li

Affiliations

Kuokuo Li: Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei, 230032, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei, 230032, Anhui, China
Jifang Xiao: Bioinformatics Center, National Clinical Research Centre for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China; Bioinformatics Center, Furong Laboratory, Central South University, Changsha, Hunan, China
Zhengbao Ling: Centre for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
Tengfei Luo: Centre for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
Jingyu Xiong: Centre for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
Qian Chen: Bioinformatics Center, National Clinical Research Centre for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China; Bioinformatics Center, Furong Laboratory, Central South University, Changsha, Hunan, China
Lijie Dong: Centre for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China; Bioinformatics Center, Furong Laboratory, Central South University, Changsha, Hunan, China
Yijing Wang: Bioinformatics Center, National Clinical Research Centre for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China; Centre for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China; Bioinformatics Center, Furong Laboratory, Central South University, Changsha, Hunan, China
Xiaomeng Wang: Centre for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China; Bioinformatics Center, Furong Laboratory, Central South University, Changsha, Hunan, China
Zhaowei Jiang: Centre for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
Lu Xia: Centre for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
Zhen Yu: Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei, 230032, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei, 230032, Anhui, China
Rong Hua: Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei, 230032, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei, 230032, Anhui, China
Rui Guo: Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei, 230032, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei, 230032, Anhui, China
Dongdong Tang: Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei, 230032, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei, 230032, Anhui, China
Mingrong Lv: Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei, 230032, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei, 230032, Anhui, China
Aojie Lian: National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, China
Bin Li: Bioinformatics Center, National Clinical Research Centre for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China; Bioinformatics Center, Furong Laboratory, Central South University, Changsha, Hunan, China
GuiHu Zhao: Bioinformatics Center, National Clinical Research Centre for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China; Bioinformatics Center, Furong Laboratory, Central South University, Changsha, Hunan, China
Xiaojin He: Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei, 230032, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei, 230032, Anhui, China; Anhui Provincial Human Sperm Bank, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China; Corresponding author. Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
Kun Xia: Centre for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China; Corresponding author.
Yunxia Cao: Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No 81 Meishan Road, Hefei, 230032, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, No 81 Meishan Road, Hefei, 230032, Anhui, China; Corresponding author. Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
Jinchen Li: Bioinformatics Center, National Clinical Research Centre for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China; Centre for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China; Bioinformatics Center, Furong Laboratory, Central South University, Changsha, Hunan, China; Corresponding author. Bioinformatics Center, National Clinical Research Centre for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Journal volume & issue: Vol. 99
p. 104928

Abstract

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Summary: Background: Genomic variants outside of the canonical splicing site (±2) may generate abnormal mRNA splicing, which are defined as non-canonical splicing variants (NCSVs). However, the clinical interpretation of NCSVs in neurodevelopmental disorders (NDDs) is largely unknown. Methods: We investigated the contribution of NCSVs to NDDs from 345,787 de novo variants (DNVs) in 47,574 patients with NDDs. We performed functional enrichment and protein–protein interaction analysis to assess the association between genes carrying prioritised NCSVs and NDDs. Minigene was used to validate the impact of NCSVs on mRNA splicing. Findings: We observed significantly more NCSVs (p = 0.02, odds ratio [OR] = 2.05) among patients with NDD than in controls. Both canonical splicing variants (CSVs) and NCSVs contributed to an equal proportion of patients with NDD (0.76% vs. 0.82%). The candidate genes carrying NCSVs were associated with glutamatergic synapse and chromatin remodelling. Minigene successfully validated 59 of 79 (74.68%) NCSVs that led to abnormal splicing in 40 candidate genes, and 9 of the genes (ARID1B, KAT6B, TCF4, SMARCA2, SHANK3, PDHA1, WDR45, SCN2A, SYNGAP1) harboured recurrent NCSVs with the same variant present in more than two unrelated patients with NDD. Moreover, 36 of 59 (61.02%) NCSVs are novel clinically relevant variants, including 34 unreported and 2 clinically conflicting interpretations or of uncertain significance NCSVs in the ClinVar database. Interpretation: This study highlights the common pathology and clinical importance of NCSVs in unsolved patients with NDD. Funding: The present study was funded by grants from the National Natural Science Foundation of China, China Postdoctoral Science Foundation, the Hunan Youth Science and Technology Innovation Talent Project, the Provincial Natural Science Foundation of Hunan, The Scientific Research Program of FuRong laboratory, and the Natural Science Project of the University of Anhui Province

Published in EBioMedicine

ISSN: 2352-3964 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General)
Website: http://www.journals.elsevier.com/ebiomedicine/

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