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In this study, we compared the diagnostic yield of exome sequencing (ES) and chromosomal microarray analysis (CMA) in fetuses with a major CNS anomaly.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This was a retrospective study of 114 cases referred for genetic evaluation following termination of pregnancy (TOP) due to a major CNS anomaly detected on prenatal ultrasound. All fetuses were first analyzed by CMA. All CMA\u2010negative cases were offered ES. CMA\u2010positive cases were reanalyzed using ES to assess its ability to detect copy\u2010number variants (CNVs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CMA identified a pathogenic or likely pathogenic (P\/LP) CNV in 11\/114 (10%) cases. Eighty\u2010six CMA\u2010negative cases were analyzed using ES, which detected P\/LP sequence variants in 38\/86 (44%). Among recurrent cases (i.e. cases with a previously affected pregnancy), the incidence of P\/LP sequence variants was non\u2010significantly higher compared with non\u2010recurrent ones (12\/19 (63%) <jats:italic>vs<\/jats:italic> 26\/67 (39%); <jats:italic>P<\/jats:italic>\u2009=\u20090.06). Among the 38 cases with an ES diagnosis, 20 (53%) were inherited and carried a significant risk of recurrence. Reanalysis of 10 CMA\u2010positive cases by ES demonstrated that the bioinformatics pipeline used for sequence variant analysis also detected all P\/LP CNVs, as well as three previously known non\u2010causative CNVs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In our study, ES provided a high diagnostic yield (&gt;\u200950%) in fetuses with severe CNS structural anomalies, which may have been partly due to the highly selected case series that included post\u2010TOP cases from a specialist referral center. These data suggest that ES may be considered as a first\u2010tier test for the prenatal diagnosis of major fetal CNS anomalies, detecting both P\/LP sequence variants and CNVs. This is of particular importance given the time constraints of an ongoing pregnancy and the risk of recurrence in future pregnancies. \u00a9 2022 The Authors. Ultrasound in Obstetrics &amp; Gynecology published by John Wiley &amp; Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.<\/jats:p><\/jats:sec>","DOI":"10.1002\/uog.24885","type":"journal-article","created":{"date-parts":[[2022,3,1]],"date-time":"2022-03-01T11:29:22Z","timestamp":1646134162000},"page":"59-67","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":81,"title":["Exome sequencing as first\u2010tier test for fetuses with severe central nervous system structural anomalies"],"prefix":"10.1002","volume":"60","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8622-7668","authenticated-orcid":false,"given":"Y.","family":"Yaron","sequence":"first","affiliation":[{"name":"Prenatal Genetic Diagnosis Unit Genetics Institute, Tel Aviv Sourasky Medical Center  Tel Aviv Israel"},{"name":"Sackler Faculty of Medicine Tel Aviv University  Tel Aviv 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