{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T11:26:20Z","timestamp":1791890780259,"version":"4.3.4"},"reference-count":37,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,3,6]],"date-time":"2021-03-06T00:00:00Z","timestamp":1614988800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2018YFC1002900"],"award-info":[{"award-number":["2018YFC1002900"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Whole genome sequencing (WGS) is a powerful tool for postnatal genetic diagnosis, but relevant clinical studies in the field of prenatal diagnosis are limited. The present study aimed to prospectively evaluate the utility of WGS compared with chromosomal microarray (CMA) and whole exome sequencing (WES) in the prenatal diagnosis of fetal structural anomalies. We performed trio WGS (\u224840-fold) in parallel with CMA in 111 fetuses with structural or growth anomalies, and sequentially performed WES when CMA was negative (CMA plus WES). In comparison, WGS not only detected all pathogenic genetic variants in 22 diagnosed cases identified by CMA plus WES, yielding a diagnostic rate of 19.8% (22\/110), but also provided additional and clinically significant information, including a case of balanced translocations and a case of intrauterine infection, which might not be detectable by CMA or WES. WGS also required less DNA (100 ng) as input and could provide a rapid turnaround time (TAT, 18 \u00b1 6 days) compared with that (31 \u00b1 8 days) of the CMA plus WES. Our results showed that WGS provided more comprehensive and precise genetic information with a rapid TAT and less DNA required than CMA plus WES, which enables it as an alternative prenatal diagnosis test for fetal structural anomalies.<\/jats:p>","DOI":"10.3390\/genes12030376","type":"journal-article","created":{"date-parts":[[2021,3,7]],"date-time":"2021-03-07T20:20:43Z","timestamp":1615148443000},"page":"376","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":78,"title":["Whole Genome Sequencing in the Evaluation of Fetal Structural Anomalies: A Parallel Test with Chromosomal Microarray Plus Whole Exome Sequencing"],"prefix":"10.3390","volume":"12","author":[{"given":"Jia","family":"Zhou","sequence":"first","affiliation":[{"name":"Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziying","family":"Yang","sequence":"additional","affiliation":[{"name":"BGI Genomics, BGI-Shenzhen, Shenzhen 518083, China"},{"name":"Tianjin Medical Laboratory, BGI-Tianjin, BGI-Shenzhen, Tianjin 300308, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Sun","sequence":"additional","affiliation":[{"name":"BGI Genomics, BGI-Shenzhen, Shenzhen 518083, China"},{"name":"Tianjin Medical Laboratory, BGI-Tianjin, BGI-Shenzhen, Tianjin 300308, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lipei","family":"Liu","sequence":"additional","affiliation":[{"name":"BGI Genomics, BGI-Shenzhen, Shenzhen 518083, China"},{"name":"Tianjin Medical Laboratory, BGI-Tianjin, BGI-Shenzhen, Tianjin 300308, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengxia","family":"Liu","sequence":"additional","affiliation":[{"name":"BGI Genomics, BGI-Shenzhen, Shenzhen 518083, China"},{"name":"Tianjin Medical Laboratory, BGI-Tianjin, BGI-Shenzhen, Tianjin 300308, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya","family":"Xing","sequence":"additional","affiliation":[{"name":"Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuge","family":"Cui","sequence":"additional","affiliation":[{"name":"BGI Genomics, BGI-Shenzhen, Shenzhen 518083, China"},{"name":"Tianjin Medical Laboratory, BGI-Tianjin, BGI-Shenzhen, Tianjin 300308, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyi","family":"Xiong","sequence":"additional","affiliation":[{"name":"Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Liu","sequence":"additional","affiliation":[{"name":"BGI Genomics, BGI-Shenzhen, Shenzhen 518083, China"},{"name":"Tianjin Medical Laboratory, BGI-Tianjin, BGI-Shenzhen, Tianjin 300308, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingjun","family":"Yang","sequence":"additional","affiliation":[{"name":"Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuxiu","family":"Wei","sequence":"additional","affiliation":[{"name":"BGI Genomics, BGI-Shenzhen, Shenzhen 518083, China"},{"name":"Tianjin Medical Laboratory, 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2034-3855","authenticated-orcid":false,"given":"Yaoshen","family":"Wang","sequence":"additional","affiliation":[{"name":"BGI Genomics, BGI-Shenzhen, Shenzhen 518083, China"},{"name":"Tianjin Medical Laboratory, BGI-Tianjin, BGI-Shenzhen, Tianjin 300308, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saiying","family":"Yan","sequence":"additional","affiliation":[{"name":"BGI Genomics, BGI-Shenzhen, Shenzhen 518083, China"},{"name":"Tianjin Medical Laboratory, BGI-Tianjin, BGI-Shenzhen, Tianjin 300308, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengyu","family":"Wu","sequence":"additional","affiliation":[{"name":"Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanwei","family":"Zeng","sequence":"additional","affiliation":[{"name":"BGI Genomics, BGI-Shenzhen, Shenzhen 518083, China"},{"name":"Department of Biology, Faculty of Science, University of Copenhagen, DK-2200 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children\u2019s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, 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(2017). Annual Summary of Vital Statistics: 2013-2014. Pediatrics, 139.","DOI":"10.1542\/peds.2016-3239"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2175","DOI":"10.1056\/NEJMoa1203382","article-title":"Chromosomal microarray versus karyotyping for prenatal diagnosis","volume":"367","author":"Wapner","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1002\/pd.4209","article-title":"The clinical utility of microarray technologies applied to prenatal cytogenetics in the presence of a normal conventional karyotype: A review of the literature","volume":"33","author":"Callaway","year":"2013","journal-title":"Prenat. Diagn."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1038\/s41431-018-0324-y","article-title":"Exome sequencing of fetal anomaly syndromes: Novel phenotype-genotype discoveries","volume":"27","author":"Meier","year":"2019","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1038\/gim.2017.33","article-title":"Prenatal exome sequencing in anomalous fetuses: New opportunities and challenges","volume":"19","author":"Vora","year":"2017","journal-title":"Genet Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1002\/pd.4675","article-title":"Exome sequencing for prenatal diagnosis of fetuses with sonographic abnormalities","volume":"35","author":"Drury","year":"2015","journal-title":"Prenat. Diagn."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1186\/s13073-018-0582-x","article-title":"Clinical exome sequencing for fetuses with ultrasound abnormalities and a suspected Mendelian disorder","volume":"10","author":"Normand","year":"2018","journal-title":"Genome Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/S0140-6736(18)31940-8","article-title":"Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): A cohort study","volume":"393","author":"Lord","year":"2019","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/S0140-6736(18)32042-7","article-title":"Whole-exome sequencing in the evaluation of fetal structural anomalies: A prospective cohort study","volume":"393","author":"Petrovski","year":"2019","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s13073-019-0639-5","article-title":"Copy number variant and runs of homozygosity detection by microarrays enabled more precise molecular diagnoses in 11,020 clinical exome cases","volume":"11","author":"Dharmadhikari","year":"2019","journal-title":"Genome Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1002\/uog.18915","article-title":"Whole exome sequencing as a diagnostic adjunct to clinical testing in fetuses with structural abnormalities","volume":"51","author":"Fu","year":"2018","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"154ra135","DOI":"10.1126\/scitranslmed.3004041","article-title":"Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units","volume":"4","author":"Saunders","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/S2213-2600(15)00139-3","article-title":"Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: A retrospective analysis of diagnostic and clinical findings","volume":"3","author":"Willig","year":"2015","journal-title":"Lancet Respir. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2226","DOI":"10.1056\/NEJMoa1208594","article-title":"Clinical diagnosis by whole-genome sequencing of a prenatal sample","volume":"367","author":"Talkowski","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"761","DOI":"10.3389\/fgene.2019.00761","article-title":"Prenatal Diagnosis of Fetuses With Increased Nuchal Translucency by Genome Sequencing Analysis","volume":"10","author":"Choy","year":"2019","journal-title":"Front. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/gigascience\/gix024","article-title":"A reference human genome dataset of the BGISEQ-500 sequencer","volume":"6","author":"Huang","year":"2017","journal-title":"Gigascience"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.jcma.2015.03.010","article-title":"Improved assay performance of single nucleotide polymorphism array over conventional karyotyping in analyzing products of conception","volume":"78","author":"Lin","year":"2015","journal-title":"J. Chin. Med. Assoc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/gim.2017.142","article-title":"Comprehensive use of extended exome analysis improves diagnostic yield in rare disease: A retrospective survey in 1059 cases","volume":"20","author":"Bergant","year":"2018","journal-title":"Genet. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/s41436-019-0686-8","article-title":"Technical standards for the interpretation and reporting of constitutional copy-number variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen)","volume":"22","author":"Riggs","year":"2020","journal-title":"Genet. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1002\/humu.23626","article-title":"Recommendations for interpreting the loss of function PVS1 ACMG\/AMP variant criterion","volume":"39","author":"Pesaran","year":"2018","journal-title":"Hum Mutat."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1038\/s41436-019-0655-2","article-title":"Adapting ACMG\/AMP sequence variant classification guidelines for single-gene copy number variants","volume":"22","author":"Brandt","year":"2019","journal-title":"Genet. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1038\/gim.2016.190","article-title":"Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): A policy statement of the American College of Medical Genetics and Genomics","volume":"19","author":"Kalia","year":"2017","journal-title":"Genet. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1038\/s41436-019-0731-7","article-title":"The use of fetal exome sequencing in prenatal diagnosis: A points to consider document of the American College of Medical Genetics and Genomics (ACMG). 2020, 10","volume":"22","author":"Monaghan","year":"2020","journal-title":"Genet. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1002\/ajmg.a.35767","article-title":"8p23.1 duplication syndrome; common, confirmed, and novel features in six further patients","volume":"161","author":"Barber","year":"2013","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1038\/ejhg.2013.268","article-title":"Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1","volume":"22","author":"Prokudin","year":"2014","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_27","first-page":"190","article-title":"Novel mutations in GJA8 associated with autosomal dominant congenital cataract and microcornea","volume":"12","author":"Devi","year":"2006","journal-title":"Mol. Vis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1128\/CMR.00062-12","article-title":"The \u201csilent\u201d global burden of congenital cytomegalovirus","volume":"26","author":"Manicklal","year":"2013","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"493.e1","DOI":"10.1016\/j.ajog.2019.06.007","article-title":"Characteristics and mode of inheritance of pathogenic copy number variants in prenatal diagnosis","volume":"221","author":"Chau","year":"2019","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"571219","DOI":"10.3389\/fgene.2020.571219","article-title":"Clinical Utility of SNP Array Analysis in Prenatal Diagnosis: A Cohort Study of 5000 Pregnancies","volume":"11","author":"Xiang","year":"2020","journal-title":"Front Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1002\/pd.5781","article-title":"A prospective study on rapid exome sequencing as a diagnostic test for multiple congenital anomalies on fetal ultrasound","volume":"40","author":"Bouman","year":"2020","journal-title":"Prenat. Diagn."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Eisfeldt, J., Pettersson, M., Vezzi, F., Wincent, J., Kaller, M., Gruselius, J., Nilsson, D., Syk Lundberg, E., Carvalho, C.M.B., and Lindstrand, A. (2019). Comprehensive structural variation genome map of individuals carrying complex chromosomal rearrangements. PLoS Genet., 15.","DOI":"10.1371\/journal.pgen.1007858"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1159\/000499893","article-title":"Complete Paternal Uniparental Disomy of Chromosome 2 in an Asian Female Identified by Short Tandem Repeats and Whole Genome Sequencing","volume":"157","author":"Zhang","year":"2019","journal-title":"Cytogenet. Genome Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/s13073-019-0675-1","article-title":"From cytogenetics to cytogenomics: Whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability","volume":"11","author":"Lindstrand","year":"2019","journal-title":"Genome Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1126\/science.1186802","article-title":"Analysis of genetic inheritance in a family quartet by whole-genome sequencing","volume":"328","author":"Roach","year":"2010","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/ng.2826","article-title":"Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis","volume":"46","author":"Weedon","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1002\/pd.5375","article-title":"Effects of platforms, size filter cutoffs, and targeted regions of cytogenomic microarray on detection of copy number variants and uniparental disomy in prenatal diagnosis: Results from 5026 pregnancies","volume":"39","author":"Wang","year":"2019","journal-title":"Prenat. Diagn."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/3\/376\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:34:12Z","timestamp":1760160852000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/3\/376"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,6]]},"references-count":37,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["genes12030376"],"URL":"https:\/\/doi.org\/10.3390\/genes12030376","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,6]]}}}