{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:48:39Z","timestamp":1790596119512,"version":"4.1.0"},"reference-count":54,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,8,24]],"date-time":"2022-08-24T00:00:00Z","timestamp":1661299200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Congenital malformations diagnosed by ultrasound screening complicate 3\u20135% of pregnancies and many of these have an underlying genetic cause. Approximately 40% of prenatally diagnosed fetal malformations are associated with aneuploidy or copy number variants, detected by conventional karyotyping, QF-PCR and microarray techniques, however monogenic disorders are not diagnosed by these tests. Next generation sequencing as a secondary prenatal genetic test offers additional diagnostic yield for congenital abnormalities deemed to be potentially associated with an underlying genetic aetiology, as demonstrated by two large cohorts: the \u2018Prenatal assessment of genomes and exomes\u2019 (PAGE) study and \u2018Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study\u2019 performed at Columbia University in the US. These were large and prospective studies but relatively \u2018unselected\u2019 congenital malformations, with little Clinical Genetics input to the pre-test selection process. This review focuses on the incremental yield of next generation sequencing in single system congenital malformations, using evidence from the PAGE, Columbia and subsequent cohorts, with particularly high yields in those fetuses with cardiac and neurological anomalies, large nuchal translucency and non-immune fetal hydrops (of unknown aetiology). The total additional yield gained by exome sequencing in congenital heart disease was 12.7%, for neurological malformations 13.8%, 13.1% in increased nuchal translucency and 29% in non-immune fetal hydrops. This demonstrates significant incremental yield with exome sequencing in single-system anomalies and supports next generation sequencing as a secondary genetic test in routine clinical care of fetuses with congenital abnormalities.<\/jats:p>","DOI":"10.3390\/genes13091517","type":"journal-article","created":{"date-parts":[[2022,8,24]],"date-time":"2022-08-24T21:03:51Z","timestamp":1661375031000},"page":"1517","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Next Generation Sequencing after Invasive Prenatal Testing in Fetuses with Congenital Malformations: Prenatal or Neonatal Investigation"],"prefix":"10.3390","volume":"13","author":[{"given":"Alexandra","family":"Emms","sequence":"first","affiliation":[{"name":"West Midlands Fetal Medicine Centre, Birmingham Women\u2019s and Children\u2019s NHS Foundation Trust, Birmingham B15 2TG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Castleman","sequence":"additional","affiliation":[{"name":"West Midlands Fetal Medicine Centre, Birmingham Women\u2019s and Children\u2019s NHS Foundation Trust, Birmingham B15 2TG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Allen","sequence":"additional","affiliation":[{"name":"West Midlands Regional Genetics Laboratory, Birmingham Women\u2019s and Children\u2019s NHS Foundation Trust, Mindelsohn Way, Edgbaston, Birmingham B15 2TG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Williams","sequence":"additional","affiliation":[{"name":"Clinical Genetics Service, Birmingham Women\u2019s and Children\u2019s NHS Foundation Trust, Birmingham B15 2TG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Kinning","sequence":"additional","affiliation":[{"name":"Clinical Genetics Service, Birmingham Women\u2019s and Children\u2019s NHS Foundation Trust, Birmingham B15 2TG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9987-4223","authenticated-orcid":false,"given":"Mark","family":"Kilby","sequence":"additional","affiliation":[{"name":"West Midlands Fetal Medicine Centre, Birmingham Women\u2019s and Children\u2019s NHS Foundation Trust, Birmingham B15 2TG, UK"},{"name":"Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,24]]},"reference":[{"key":"ref_1","first-page":"e39","article-title":"Fetal Genomics Steering Group of the British Society for Genetic Medicine; on behalf of the Royal College of Obstetricians and Gynaecologists. 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