title: Low-pass whole-genome sequencing in clinical cytogenetics: a validated approach.
abstract: Chromosomal microarray analysis is the gold standard for copy-number variant (CNV) detection in prenatal and postnatal diagnosis. We aimed to determine whether next-generation sequencing (NGS) technology could be an alternative method for CNV detection in routine clinical application.
  
  
  
  Genome-wide CNV analysis (>50 kb) was performed on a multicenter group of 570 patients using a low-coverage whole-genome sequencing pipeline. These samples were referred for chromosomal analysis; CNVs (i.e., pathogenic CNVs, pCNVs) were classified according to the American College of Medical Genetics and Genomics guidelines.
  
  
  
  Overall, a total of 198 abortuses, 37 stillbirths, 149 prenatal, and 186 postnatal samples were tested. Our approach yielded results in 549 samples (96.3%). In addition to 119 subjects with aneuploidies, 103 pCNVs (74 losses and 29 gains) were identified in 82 samples, giving diagnostic yields of 53.2% (95% confidence interval: 45.8, 60.5), 14.7% (5.0, 31.1), 28.5% (21.1, 36.6), and 30.1% (23.6, 37.3) in each group, respectively. Mosaicism was observed at a level as low as 25%.
  
  
  
  Patients with chromosomal diseases or microdeletion/microduplication syndromes were diagnosed using a high-resolution genome-wide method. Our study revealed the potential of NGS to facilitate genetic diagnoses that were not evident in the prenatal and postnatal groups.Genet Med 18 9, 940-948.
authors.affiliation: BGI-Shenzhen, Shenzhen, China.|Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, China.|Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
authors.forename: Zirui
authors.identifier: 0000-0002-3626-6500
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Department of Obstetrics, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Prenatal Diagnosis, Nanjing Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Hu
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Haixiao
authors.initials: H
authors.lastname: Chen
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Jinjin
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Obstetrics, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Tian
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Prenatal Diagnosis, Nanjing Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Meng
authors.affiliation: Department of Obstetrics, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Yanchou
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Clinical Laboratory of BGI Health, BGI-Shenzhen, Shenzhen, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Clinical Laboratory of BGI Health, BGI-Shenzhen, Shenzhen, China.
authors.forename: Meiyan
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Clinical Laboratory of BGI Health, BGI-Shenzhen, Shenzhen, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, China.|Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
authors.forename: Huilin
authors.initials: H
authors.lastname: Wang
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Yu
authors.affiliation: BGI-Shenzhen, Shenzhen, China.|Shenzhen Birth Defect Screening Project Lab, BGI-Shenzhen, Shenzhen, China.|BGI-Nanjing, Nanjing, China.|The Guangdong Enterprise Key Laboratory of Human Disease Genomics, BGI-Shenzhen, Shenzhen, China.|Shenzhen Key Laboratory of Transomics Biotechnologies, BGI-Shenzhen, Shenzhen, China.|Section of Molecular Disease Biology, Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
authors.affiliation: Shenzhen Maternal and Child Health Care Hospital, Shenzhen, China.
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Xie
authors.affiliation: BGI-Shenzhen, Shenzhen, China.|The Guangdong Enterprise Key Laboratory of Human Disease Genomics, BGI-Shenzhen, Shenzhen, China.|Shenzhen Key Laboratory of Transomics Biotechnologies, BGI-Shenzhen, Shenzhen, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Jiang
authors.affiliation: BGI-Shenzhen, Shenzhen, China.|Clinical Laboratory of BGI Health, BGI-Shenzhen, Shenzhen, China.|BGI-Nanjing, Nanjing, China.|The Guangdong Enterprise Key Laboratory of Human Disease Genomics, BGI-Shenzhen, Shenzhen, China.|Shenzhen Key Laboratory of Transomics Biotechnologies, BGI-Shenzhen, Shenzhen, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, China.|Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
authors.forename: Kwong Wai
authors.initials: KW
authors.lastname: Choy
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Prenatal Diagnosis, Nanjing Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing, China.
authors.forename: Zhengfeng
authors.initials: Z
authors.lastname: Xu
mesh_terms: D000022:Abortion, Spontaneous / Q000235:genetics; D025063:Chromosome Disorders / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D003582:Cytogenetics / Q000379:methods; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D015894:Genome, Human / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D046228:Microarray Analysis; D011296:Prenatal Diagnosis; D050497:Stillbirth / Q000235:genetics
references.citation: Bioinformatics. 2009 Aug 1;25(15):1966-7
references.pmid: 19497933
references.citation: Genome Res. 2008 Nov;18(11):1851-8
references.pmid: 18714091
references.citation: J Med Genet. 2003 Aug;40(8):575-84
references.pmid: 12920066
references.citation: Nature. 2012 Nov 1;491(7422):56-65
references.pmid: 23128226
references.citation: Am J Hum Genet. 1993 Apr;52(4):668-76
references.pmid: 8460633
references.citation: Genet Med. 2011 Jul;13(7):680-5
references.pmid: 21681106
references.citation: Nat Rev Genet. 2009 Apr;10(4):241-51
references.pmid: 19293820
references.citation: Hum Genet. 2011 Dec;130(6):725-33
references.pmid: 21626137
references.citation: Ultrasound Obstet Gynecol. 2011 Sep;38(3):314-9
references.pmid: 21400624
references.citation: BMC Med Genet. 2013 Sep 25;14 :99
references.pmid: 24063657
references.citation: N Engl J Med. 2012 Dec 6;367(23):2175-84
references.pmid: 23215555
references.citation: Hum Mutat. 2014 May;35(5):625-36
references.pmid: 24610732
references.citation: Cell. 2013 Jan 31;152(3):394-405
references.pmid: 23374337
references.citation: J Med Genet. 2009 Feb;46(2):123-31
references.pmid: 19015223
references.citation: Nucleic Acids Res. 2013 Feb 1;41(3):1519-32
references.pmid: 23275535
references.citation: Nat Genet. 2008 Mar;40(3):322-8
references.pmid: 18278044
references.citation: J Med Genet. 2006 Jul;43(7):609-12
references.pmid: 16236813
references.citation: PLoS One. 2013;8(3):e59128
references.pmid: 23527109
references.citation: Cell. 2010 Mar 5;140(5):704-16
references.pmid: 20211139
references.citation: Ultrasound Obstet Gynecol. 2015 Oct;46(4):472-7
references.pmid: 25767059
references.citation: Genet Res Int. 2011;2011:976398
references.pmid: 22567372
references.citation: Biol Psychiatry. 2014 Mar 1;75(5):351-60
references.pmid: 23992925
references.citation: Nature. 2008 Nov 6;456(7218):60-5
references.pmid: 18987735
references.citation: J Mol Diagn. 2014 Sep;16(5):519-26
references.pmid: 24998187
references.citation: Fetal Diagn Ther. 2014;36(4):326-32
references.pmid: 25059832
references.citation: Methods Mol Biol. 2011;688:97-126
references.pmid: 20938835
references.citation: Mol Cytogenet. 2015 Jan 22;8(1):3
references.pmid: 25628759
references.citation: Nat Biotechnol. 2011 May 08;29(6):512-20
references.pmid: 21552272
references.citation: Prenat Diagn. 2013 Jan;33(1):32-41
references.pmid: 23168908
references.citation: Nat Genet. 2005 May;37(5):549-54
references.pmid: 15838508
references.citation: Am J Hum Genet. 2009 Apr;84(4):468-76
references.pmid: 19285295
references.citation: PLoS One. 2014 Jan 21;9(1):e85096
references.pmid: 24465483
references.citation: PLoS One. 2012;7(3):e31282
references.pmid: 22403611
references.citation: N Engl J Med. 2012 Dec 6;367(23):2185-93
references.pmid: 23215556
references.citation: BMC Bioinformatics. 2013;14 Suppl 11:S1
references.pmid: 24564169
references.citation: Prenat Diagn. 2013 Jan;33(1):42-9
references.pmid: 23168997
references.citation: Prenat Diagn. 2015 Sep;35(9):841-7
references.pmid: 25976239
references.citation: Prenat Diagn. 2013 Mar;33(3):232-7
references.pmid: 23359364
references.citation: Nature. 2011 Feb 3;470(7332):59-65
references.pmid: 21293372
references.citation: Mol Cytogenet. 2014 May 23;7:34
references.pmid: 24926319