{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T11:26:17Z","timestamp":1791890777303,"version":"4.3.4"},"reference-count":31,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:00:00Z","timestamp":1760659200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:00:00Z","timestamp":1760659200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2021YFC1005300"],"award-info":[{"award-number":["2021YFC1005300"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2021YFC1005301"],"award-info":[{"award-number":["2021YFC1005301"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["obgyn.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Prenatal Diagnosis"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To evaluate the diagnostic value of prenatal exome sequencing (ES) integrated with copy number variant (CNV) and single nucleotide variant (SNV) analysis (ES\u2010CNV\/SNV) in fetuses with structural anomalies following negative chromosomal microarray analysis (CMA) and karyotyping, and to delineate the practical challenges encountered during its clinical implementation in prenatal settings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this multicenter prospective cohort study (2018\u20132021), 275 fetuses with structural anomalies were categorized into three groups: sporadic single\u2010system (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a0128), sporadic multisystem (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a088), and recurrent anomalies (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a059). Trio\u2010based ES\u2010CNV\/SNV analysis was used to identify SNVs, CNVs, or compound heterozygous CNV\/SNV combinations\u2014 the latter being defined as two distinct pathogenic variants (a CNV and an SNV) coexisting within the same gene, resulting in biallelic gene dysfunction, which is pivotal for autosomal recessive disorders. Incremental diagnostic yields across groups, the incidence of CNV\/SNV combinations, and expanded prenatal phenotypic\u2010genotypic correlations were analyzed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>ES\u2010CNV\/SNV analysis improved the diagnostic yield to 29.45% (81\/275) compared with conventional chromosome analysis combined with CMA in fetuses with malformations. The highest diagnostic yield was observed in the recurrent anomaly group (40.68%, 24\/59), followed by the multisystem (28.41%, 25\/88) and single\u2010system anomaly groups (25.00%, 32\/128). Notably, 1.45% of cases harbored compound CNV\/SNV combinations, underscoring the diagnostic potential of ES\u2010CNV\/SNV in autosomal recessive disorders. In addition, this study expanded prenatal phenotypic\u2010genotypic correlations for 36 variants and five genes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>ES\u2010CNV\/SNV analysis enhances prenatal diagnostic precision by detecting compound CNV\/SNV combinations that are undetectable by standard testing. Recurrent anomalies demonstrated a greater diagnostic benefit than sporadic single\u2010system or multisystem anomalies, underscoring the utility of this method in high\u2010risk cases. This study broadens the prenatal phenotypic spectrum and deepens our understanding of developmental mechanisms.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/pd.70006","type":"journal-article","created":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T04:39:46Z","timestamp":1760762386000},"page":"46-55","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Prenatal Exome Sequencing Analysis in Fetuses With Structural Anomalies: A Multicenter Prospective Cohort Study With Practical Implications"],"prefix":"10.1002","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5731-7082","authenticated-orcid":false,"given":"Yulin","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology National Clinical Research Center for Obstetric &amp; Gynecologic Diseases Chinese Academy of Medical Sciences &amp; Peking Union Medical College Peking Union Medical College Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9309-6632","authenticated-orcid":false,"given":"Haibo","family":"Li","sequence":"additional","affiliation":[{"name":"The Central Laboratory of Birth Defects Prevention and Control Ningbo Women and Children\u2019s Hospital  Ningbo Zhejiang China"},{"name":"Ningbo Key Laboratory for the Prevention and Treatment of Embryogenic Diseases Ningbo Women and Children\u2019s Hospital  Ningbo Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyu","family":"Zhu","sequence":"additional","affiliation":[{"name":"Center for Obstetrics and Gynecology Nanjing Drum Tower Hospital The Affiliated Hospital of Medical School Nanjing University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangpu","family":"Xu","sequence":"additional","affiliation":[{"name":"Medical Genetic Diagnosis and Therapy Center of Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics &amp; Gynecology and Pediatrics Fujian Provincial Key Laboratory of Prenatal Diagnosis and Birth Defect Fujian Medical University  Fuzhou Fujian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Prenatal Diagnosis Tianjin Center Hospital of Obstetrics and Gynecology  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengqun","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Fetal Heart Ultrasonography Hebei Maternity Hospital  Shijiazhuang Hebei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8403-6913","authenticated-orcid":false,"given":"Jianping","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics Wuxi Maternal and Child Health Care Hospital Nanjing Medical University  Wuxi Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Reproductive Genetics Hebei General Hospital  Shijiazhuang Hebei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4344-7924","authenticated-orcid":false,"given":"Minyue","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Reproductive Genetics School of Medicine Women\u2019s Hospital Zhejiang University  Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics National Health Commission Key Laboratory of Birth Defects Research Hunan Provincial Maternal and Child Health Care Hospital  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Jin","sequence":"additional","affiliation":[{"name":"Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Reproduction and Genetics The Affiliated Suzhou Hospital of Nanjing Medical University  Suzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxiao","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics The First Medical Center of Chinese PLA General Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Prenatal Diagnosis Center Peking University People's Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Department of Medical Genetic Zhangzhou Municipal Hospital of Fujian Province  Zhangzhou Fujian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology National Clinical Research Center for Obstetric &amp; 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