{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T11:57:53Z","timestamp":1794052673638,"version":"4.8.0"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T00:00:00Z","timestamp":1763942400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>This study assessed the diagnostic effectiveness of trio-WES compared to CMA in fetuses with ultrasound anomalies and explored optimal prenatal testing strategies. A retrospective review included 454 fetuses who underwent trio-WES and\/or CMA between 2020 and 2023. Cases were divided into four groups and 19 subgroups based on improvements in diagnosing ultrasound anomalies, demonstrating that trio-WES offers greater diagnostic value than CMA\u2014especially for skeletal and multisystem defects, as well as ultrasound findings used to determine diagnostic yields. Trio-WES achieved a diagnostic yield of 22.7% (103\/454), exceeding CMA by 17%. The highest diagnostic rates were observed in skeletal anomalies (39.2%) and multisystem anomalies (29.1%). Subgroup analysis showed higher yields in crystalline lens anomalies (60.0%) and cardiac rhabdomyoma (57.1%). Trio-WES significantly enhances prenatal diagnosis of ultrasound anomalies and provides additional diagnostic insights over CMA, particularly for skeletal, multisystem defects, and specific structural subgroups. Importantly, trio-WES helps clarify the mechanisms of ROH and assess its pathogenicity, aiding in detecting imprinted disorders. These findings support including trio-WES in prenatal testing protocols for congenital malformations and establish a framework for its clinical application.<\/jats:p>","DOI":"10.3389\/fgene.2025.1662801","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T06:29:03Z","timestamp":1763965743000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Application of trio-based whole-exome sequencing in fetal ultrasound anomalies: a single-center retrospective study of 454 cases"],"prefix":"10.3389","volume":"16","author":[{"given":"Dongyi","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dairong","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangbo","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Nie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenzhen","family":"An","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuying","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2014","DOI":"10.1056\/NEJMc2216144","article-title":"High-resolution and noninvasive fetal exome screening","volume":"389","author":"Brand","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"B2","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1002\/uog.1819","article-title":"Ultrasound antenatal diagnosis of cleft palate by a new technique: the 3D 'reverse face' view","volume":"25","author":"Campbell","year":"2005","journal-title":"Ultrasound Obstetrics Gynecol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1038\/nrg2933","article-title":"Cleft lip and palate: understanding genetic and environmental influences","volume":"12","author":"Dixon","year":"2011","journal-title":"Nat. Rev. Genet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1517","DOI":"10.3390\/genes13091517","article-title":"Next generation sequencing after invasive prenatal testing in fetuses with congenital malformations: prenatal or neonatal investigation","volume":"13","author":"Emms","year":"2022","journal-title":"Genes"},{"key":"B5","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1186\/s13073-022-01130-x","article-title":"Application of exome sequencing for prenatal diagnosis of fetal structural anomalies: clinical experience and lessons learned from a cohort of 1618 fetuses","volume":"14","author":"Fu","year":"2022","journal-title":"Genome Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1097\/OGX.0000000000000787","article-title":"Exome sequencing and its emerging role in prenatal genetic diagnosis","volume":"75","author":"Hopkins","year":"2020","journal-title":"Obstetrical and Gynecol. Surv."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1007\/s00439-021-02268-1","article-title":"Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland","volume":"140","author":"Jarvela","year":"2021","journal-title":"Hum. Genet."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2521","DOI":"10.3390\/healthcare10122521","article-title":"Application of prenatal whole exome sequencing for structural congenital anomalies-experience from a local prenatal diagnostic laboratory","volume":"10","author":"Lai","year":"2022","journal-title":"Healthc. (Basel)"},{"key":"B9","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/j.fertnstert.2018.01.005","article-title":"Prenatal diagnosis by chromosomal microarray analysis","volume":"109","author":"Levy","year":"2018","journal-title":"Fertil. Steril."},{"key":"B10","doi-asserted-by":"publisher","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":"B11","doi-asserted-by":"publisher","first-page":"3209","DOI":"10.3390\/cimb46040201","article-title":"Prenatal diagnosis by trio clinical exome sequencing: Single center experience","volume":"46","author":"Margiotti","year":"2024","journal-title":"Curr. Issues Mol. Biol."},{"key":"B12","doi-asserted-by":"publisher","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)","volume":"22","author":"Monaghan","year":"2020","journal-title":"Genet. Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1007\/s13258-022-01341-x","article-title":"Pitfalls of whole exome sequencing in undefined clinical conditions with a suspected genetic etiology","volume":"45","author":"Moresco","year":"2022","journal-title":"Genes and Genomics"},{"key":"B14","doi-asserted-by":"publisher","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":"B15","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1056\/NEJMoa1516767","article-title":"Resolution of disease phenotypes resulting from multilocus genomic variation","volume":"376","author":"Posey","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1186\/s12920-023-01697-3","article-title":"Prenatal whole-exome sequencing for fetal structural anomalies: a retrospective analysis of 145 Chinese cases","volume":"16","author":"Qin","year":"2023","journal-title":"BMC Med. Genomics"},{"key":"B17","doi-asserted-by":"publisher","first-page":"147688","DOI":"10.1016\/j.gene.2023.147688","article-title":"Detection of complex chromosome rearrangements using optical genome mapping","volume":"884","author":"Qu","year":"2023","journal-title":"Gene"},{"key":"B18","volume-title":"Evaluation of array comparative genomic hybridisation in prenatal diagnosis of fetal anomalies: a multicentre cohort study with cost analysis and assessment of patient, health professional and commissioner preferences for array comparative genomic hybridisation","author":"Robson","year":"2017"},{"key":"B19","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/j.ajog.2024.05.042","article-title":"Stillbirth: we can do better","volume":"231","author":"Silver","year":"2024","journal-title":"Am. J. Obstet. Gynecol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1107","DOI":"10.1056\/NEJMoa1908753","article-title":"Causal genetic variants in stillbirth","volume":"383","author":"Stanley","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"B21","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1016\/S0140-6736(19)30193-X","article-title":"Introduction of genomics into prenatal diagnostics","volume":"393","author":"Talkowski","year":"2019","journal-title":"Lancet"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1301439","DOI":"10.3389\/fgene.2023.1301439","article-title":"Prenatal diagnosis of fetuses with ultrasound anomalies by whole-exome sequencing in luoyang city, China","volume":"14","author":"Wang","year":"2023","journal-title":"Front. Genet."},{"key":"B23","doi-asserted-by":"publisher","first-page":"2399317","DOI":"10.1080\/07853890.2024.2399317","article-title":"Detection of genomic variants by genome sequencing in foetuses with central nervous system abnormalities","volume":"56","author":"Wang","year":"2024","journal-title":"Ann. Med."},{"key":"B24","doi-asserted-by":"publisher","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":"B25","volume-title":"Congenital disorders","year":"2023"},{"key":"B26","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1186\/s13023-024-03340-5","article-title":"Genetic analysis of pregnancy loss and fetal structural anomalies by whole exome sequencing","volume":"19","author":"Xiang","year":"2024","journal-title":"Orphanet J. Rare Dis."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1004","DOI":"10.1002\/ijgo.14620","article-title":"Genetic causes of isolated and severe fetal growth restriction in normal chromosomal microarray analysis","volume":"161","author":"Zhou","year":"2023","journal-title":"Int. J. Gynecol. and Obstetrics"}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2025.1662801\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T06:29:05Z","timestamp":1763965745000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2025.1662801\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,24]]},"references-count":27,"alternative-id":["10.3389\/fgene.2025.1662801"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2025.1662801","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,24]]},"article-number":"1662801"}}