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Genome sequencing demonstrates high diagnostic yield in children with undiagnosed global developmental delay/intellectual disability: a prospective study
  • +26
  • Yu Sun,
  • Jing Peng,
  • Desheng Liang,
  • Xiantao Ye,
  • Na Xu,
  • Linlin Chen,
  • Dan Yan,
  • Huiwen Zhang,
  • Bing Xiao,
  • Wenjuan Qiu,
  • yiping shen,
  • Nan Pang,
  • Yingdi Liu,
  • Chen Liang,
  • Zailong Qin,
  • Jingsi Luo,
  • Fei Chen,
  • Jing-Min Wang,
  • Zhixin Zhang,
  • Haiyan Wei,
  • Juan Du,
  • Huifang Yan,
  • Ruoyu Duan,
  • Junyu Wang,
  • Yu Zhang,
  • Shixiu Liao,
  • Kun Sun,
  • Lingqian Wu,
  • Yongguo Yu
Yu Sun
Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine

Corresponding Author:[email protected]

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Jing Peng
Xiangya Hospital Central South University
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Desheng Liang
China Central South University
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Xiantao Ye
Shanghai Jiaotong University School of Medicine Xinhua Hospital
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Na Xu
Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research
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Linlin Chen
Shanghai Jiaotong University School of Medicine Xinhua Hospital
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Dan Yan
Shanghai Jiaotong University School of Medicine Xinhua Hospital
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Huiwen Zhang
Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research
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Bing Xiao
Center for Clinical Genetics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,
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Wenjuan Qiu
Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine
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yiping shen
Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region
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Nan Pang
Xiangya Hospital Central South University
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Yingdi Liu
Central South University
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Chen Liang
Jiangmen Maternity and Child Health Care Hospital
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Zailong Qin
Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region
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Jingsi Luo
Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region
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Fei Chen
Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region
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Jing-Min Wang
Peking University
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Zhixin Zhang
China-Japan Friendship Hospital
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Haiyan Wei
Department of Pediatric Endocrinology and Genetics, Children’s Hospital Affiliated to Zhengzhou University
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Juan Du
Central South University Xiangya School of Medicine
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Huifang Yan
Peking University First Hospital
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Ruoyu Duan
Peking University First Hospital
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Junyu Wang
Peking University First Hospital
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Yu Zhang
Peking University First Hospital
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Shixiu Liao
Henan Provincial People's Hospital
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Kun Sun
Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine
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Lingqian Wu
Central South University
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Yongguo Yu
Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research
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Abstract

Genome sequencing(GS) has been applied in the diagnosis of global developmental delay(GDD)/intellectual disability(ID). However, the performance in those with inconclusive results from chromosomal microarray analysis(CMA) and exome sequencing(ES) is unknown. We recruited 100 pediatric GDD/ID patients from multiple sites in China from February 2018 to August 2020 for GS. Patients have received at least one genomic diagnostic test prior to enrollment. Reanalysis of CMA/ES data was performed. The yield of GS was calculated and explanations for missed diagnoses by CMA/ES were investigated. Clinical utility was assessed by interviewing the parents by phone. The overall diagnostic yield of GS was 23%. Seven families could have been solved with reanalysis of ES data. 13 families were missed by previous CMA/ES due to improper method. Three remained unsolved after ES reanalysis due to allele dropout, complex variants missed by ES, and a CNV in untranslated regions. Follow-up of the diagnosed families revealed that nine families experienced changes in clinical management, including identification of targeted treatments, cessation of unnecessary treatment, and considerations for family planning. GS demonstrated high diagnostic yield and clinical utility in this cohort of undiagnosed GDD/ID patients, detecting a wide range of variant types of different sizes in a single workflow.
20 Aug 2021Submitted to Human Mutation
25 Aug 2021Submission Checks Completed
25 Aug 2021Assigned to Editor
28 Aug 2021Reviewer(s) Assigned
07 Oct 2021Review(s) Completed, Editorial Evaluation Pending
29 Oct 2021Editorial Decision: Revise Major
17 Dec 20211st Revision Received
22 Dec 2021Submission Checks Completed
22 Dec 2021Assigned to Editor
06 Jan 2022Reviewer(s) Assigned
10 Jan 2022Review(s) Completed, Editorial Evaluation Pending
18 Jan 2022Editorial Decision: Revise Minor
25 Jan 20222nd Revision Received
27 Jan 2022Submission Checks Completed
27 Jan 2022Assigned to Editor
29 Jan 2022Reviewer(s) Assigned
04 Feb 2022Review(s) Completed, Editorial Evaluation Pending
08 Feb 2022Editorial Decision: Accept
May 2022Published in Human Mutation volume 43 issue 5 on pages 568-581. 10.1002/humu.24347