{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T21:16:41Z","timestamp":1790457401000,"version":"4.1.0"},"reference-count":44,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T00:00:00Z","timestamp":1633046400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["obgyn.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ultrasound in Obstet &amp;amp; Gyne"],"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To determine the incremental yield of exome sequencing (ES) over chromosomal microarray analysis (CMA) or karyotyping in prenatally diagnosed non\u2010immune hydrops fetalis (NIHF).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A prospective cohort study (comprising an extended group of the Prenatal Assessment of Genomes and Exomes (PAGE) study) was performed which included 28 cases of prenatally diagnosed NIHF undergoing trio ES following negative CMA or karyotyping. These cases were combined with data from a systematic review of the literature. MEDLINE, EMBASE, CINAHL and\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/ClinicalTrials.gov\">ClinicalTrials.gov<\/jats:ext-link>\n                      databases were searched electronically (January 2000 to October 2020) for studies reporting on the incremental yield of ES over CMA or karyotyping in fetuses with prenatally detected NIHF. Inclusion criteria for the systematic review were: (i) at least two cases of NIHF undergoing sequencing; (ii) testing initiated based on prenatal ultrasound\u2010based phenotype; and (iii) negative CMA or karyotyping result. The incremental diagnostic yield of ES was assessed in: (i) all cases of NIHF; (ii) isolated NIHF; (iii) NIHF associated with an additional fetal structural anomaly; and (iv) NIHF according to severity (i.e. two\n                      <jats:italic>vs<\/jats:italic>\n                      three or more cavities affected).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In the extended PAGE study cohort, the additional diagnostic yield of ES over CMA or karyotyping was 25.0% (7\/28) in all NIHF cases, 21.4% (3\/14) in those with isolated NIHF and 28.6% (4\/14) in those with non\u2010isolated NIHF. In the meta\u2010analysis, the pooled incremental yield based on 21 studies (306 cases) was 29% (95%\u2009CI, 24\u201334%;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.00001;\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      \u2009=\u20090%) in all NIHF, 21% (95%\u2009CI, 13\u201330%;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.00001;\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      \u2009=\u20090%) in isolated NIHF and 39% (95%\u2009CI, 30\u201349%;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.00001;\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      \u2009=\u20091%) in NIHF associated with an additional fetal structural anomaly. In the latter group, congenital limb contractures were the most prevalent additional structural anomaly associated with a causative pathogenic variant, occurring in 17.3% (19\/110) of cases. The incremental yield did not differ significantly according to hydrops severity. The most common genetic disorders identified were RASopathies, occurring in 30.3% (27\/89) of cases with a causative pathogenic variant, most frequently due to a\n                      <jats:italic>PTPN11<\/jats:italic>\n                      variant (44.4%; 12\/27). The predominant inheritance pattern in causative pathogenic variants was autosomal dominant in monoallelic disease genes (57.3%; 51\/89), with most being\n                      <jats:italic>de novo<\/jats:italic>\n                      (86.3%; 44\/51).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Use of prenatal next\u2010generation sequencing in both isolated and non\u2010isolated NIHF should be considered in the development of clinical pathways. Given the wide range of potential syndromic diagnoses and heterogeneity in the prenatal phenotype of NIHF, exome or whole\u2010genome sequencing may prove to be a more appropriate testing approach than a targeted gene panel testing strategy. \u00a9 2021 The Authors.\n                      <jats:italic>Ultrasound in Obstetrics &amp; Gynecology<\/jats:italic>\n                      published by John Wiley &amp; Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/uog.23652","type":"journal-article","created":{"date-parts":[[2021,4,13]],"date-time":"2021-04-13T14:45:51Z","timestamp":1618325151000},"page":"509-518","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":61,"title":["Fetal hydrops and the Incremental yield of Next\u2010generation sequencing over standard prenatal Diagnostic testing (\n                    <scp>FIND<\/scp>\n                    ) study: prospective cohort study and meta\u2010analysis"],"prefix":"10.1002","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0718-7547","authenticated-orcid":false,"given":"F.","family":"Mone","sequence":"first","affiliation":[{"name":"Institute of Metabolism and Systems Research College of Medical &amp; Dental Sciences, University of Birmingham, Edgbaston  Birmingham UK"},{"name":"Fetal Medicine Centre Birmingham Women's and Children's NHS Foundation Trust  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Y.","family":"Eberhardt","sequence":"additional","affiliation":[{"name":"Wellcome Sanger Institute  Hinxton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. E.","family":"Hurles","sequence":"additional","affiliation":[{"name":"Wellcome Sanger Institute  Hinxton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. J.","family":"Mcmullan","sequence":"additional","affiliation":[{"name":"West Midlands Regional Genetics Service Birmingham Women's and Children's NHS Foundation Trust  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. R.","family":"Maher","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics University of Cambridge  Cambridge UK"},{"name":"NIHR Cambridge Biomedical Research Centre  Cambridge UK"},{"name":"Department of Clinical Genetics Cambridge University Hospitals NHS Foundation Trust  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Lord","sequence":"additional","affiliation":[{"name":"Wellcome Sanger Institute  Hinxton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L. S.","family":"Chitty","sequence":"additional","affiliation":[{"name":"North Thames Genomic Laboratory Hub Great Ormond Street NHS Foundation Trust  London UK"},{"name":"UCL Great Ormond Street Institute of Child Health  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7653-4653","authenticated-orcid":false,"given":"E.","family":"Dempsey","sequence":"additional","affiliation":[{"name":"Molecular and Clinical Sciences St George's University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Homfray","sequence":"additional","affiliation":[{"name":"SW Thames Regional Genetics Department St George's University Hospitals NHS Foundation Trust  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. L.","family":"Giordano","sequence":"additional","affiliation":[{"name":"Institute for Genomic Medicine Columbia University Medical Center  New York NY USA"},{"name":"Division of Maternal\u2013Fetal Medicine, Department of Obstetrics and Gynecology Columbia University Vagelos Medical Center  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. J.","family":"Wapner","sequence":"additional","affiliation":[{"name":"Institute for Genomic Medicine Columbia University Medical Center  New York NY USA"},{"name":"Division of Maternal\u2013Fetal Medicine, Department of Obstetrics and Gynecology Columbia University Vagelos Medical Center  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8467-0383","authenticated-orcid":false,"given":"L.","family":"Sun","sequence":"additional","affiliation":[{"name":"Fetal Medicine Unit and Prenatal Diagnosis Center Shanghai First Maternity and Infant Hospital of Tongji University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8593-2186","authenticated-orcid":false,"given":"T. N.","family":"Sparks","sequence":"additional","affiliation":[{"name":"Center for Maternal\u2013Fetal Precision Medicine, Division of Maternal\u2013Fetal Medicine University of California  San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. E.","family":"Norton","sequence":"additional","affiliation":[{"name":"Center for Maternal\u2013Fetal Precision Medicine, Division of Maternal\u2013Fetal Medicine University of California  San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9987-4223","authenticated-orcid":false,"given":"M. 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