Fetal agenesis of the corpus callosum: Clinical and genetic analysis in a series of 40 patients

Objectives: This study aimed to explore the genetic causes of agenesis of the corpus callosum (ACC) and assess the utility of karyotype analysis, copy number variation sequencing (CNV-seq), and whole-exome sequencing (WES) to genetically diagnose fetal ACC. Methods: We retrospectively examined 40 fetuses diagnosed with ACC who underwent prenatal ultrasonography or magnetic resonance imaging between January 2019 and October 2023. Genetic tests were conducted on the fetuses using karyotype analysis or CNV-seq as the first-line diagnosis. WES was performed if aneuploid and pathogenic CNVs were excluded. Results: Among the 40 fetuses, 29 (72 %) had non-isolated ACC and 11 (28 %) had isolated ACC. Cerebellar dysplasia and hydrocephalus were the most common abnormal developments in the central nervous system. Twenty-eight patients underwent karyotype analysis, with a detection rate of 14 % (4/28). Twenty-six patients underwent CNV-seq; three patients were found to have pathogenic CNVs, with a detection rate of 12 % (3/26). Thirty-three fetuses with no findings of karyotype analysis or CNV-seq were subsequently tested using WES, with a detection rate of 36 % (12/33). Overall, the total diagnostic yield was 48 % (19/40), and monogenic etiology accounted for 30 % (12/40). The genetic detection rate of fetal non-isolated ACC (62 %, 18/29) was higher than that of isolated ACC (9 %, 1/11). Conclusion: Prenatal genetic analysis of fetuses with ACC is clinically significant, with monogenic disorders being the main cause. WES may enhance the detection rate of fetuses with ACC with negative karyotype analysis or CNV-seq results.