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Molecular diagnoses were systematically analyzed. Subgroup analyses were performed on the ES diagnostic yield based on gestational age, HC\n                      <jats:italic>Z<\/jats:italic>\n                      \u2010scores, associated anomalies, and growth parameters.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Molecular diagnoses were established in 34 out of 87 macrocephalic fetuses (39.1%) through trio\u2010ES. These diagnoses revealed that the variants predominantly affect key signaling pathways, including mTOR, RASopathies and Sotos syndrome. The detection rate was significantly higher in non\u2010isolated compared to isolated macrocephaly cases (65.0%, 26\/40 vs. 17.0%, 8\/47;\n                      <jats:italic>p<\/jats:italic>\n                      &lt;\u00a00.001). The most frequent anomalies associated with genetic diagnoses included micromelia (100.0%, 14\/14), megalencephaly (100.0%, 2\/2), and ventriculomegaly (60.0%, 6\/10). Subgroup analysis identified higher diagnostic yields in fetuses diagnosed before 32 gestational weeks, with HC\n                      <jats:italic>Z<\/jats:italic>\n                      \u2010scores \u2265 +3 SD, micromelia, and absence of large\u2010for\u2010gestational\u2010age (LGA).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Exome sequencing significantly enhances the detection of monogenic disorders in macrocephalic fetuses compared with CMA, irrespective of isolated or non\u2010isolated cases. These clinical features and phenotypes are essential for assessing monogenic disorders and for prenatal counseling and evaluations of macrocephalic fetuses.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/pd.6818","type":"journal-article","created":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T21:23:51Z","timestamp":1747949031000},"page":"819-831","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Prenatal Exome Sequencing for Fetal Macrocephaly: A Large Prospective Observational Cohort Study"],"prefix":"10.1002","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1233-5065","authenticated-orcid":false,"given":"Hang","family":"Zhou","sequence":"first","affiliation":[{"name":"Prenatal Diagnostic Center Guangzhou Women and Children's Medical Center Guangzhou Medical University  Guangzhou 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