Prenatal Exome Sequencing for Fetal Macrocephaly: A Large Prospective Observational Cohort Study

To assess the diagnostic utility of exome sequencing (ES) in macrocephalic fetuses.

Fetuses with macrocephaly (head circumference (HC) ≥ +2 SD) and negative chromosomal microarray results were included, who had available trio-ES data. Molecular diagnoses were systematically analyzed. Subgroup analyses were performed on the ES diagnostic yield based on gestational age, HC Z-scores, associated anomalies, and growth parameters.

Molecular diagnoses were established in 34 out of 87 macrocephalic fetuses (39.1%) through trio-ES. 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-isolated compared to isolated macrocephaly cases (65.0%, 26/40 vs. 17.0%, 8/47; p < 0.001). 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 Z-scores ≥ +3 SD, micromelia, and absence of large-for-gestational-age (LGA).

Exome sequencing significantly enhances the detection of monogenic disorders in macrocephalic fetuses compared with CMA, irrespective of isolated or non-isolated cases. These clinical features and phenotypes are essential for assessing monogenic disorders and for prenatal counseling and evaluations of macrocephalic fetuses.