Prenatal exome sequencing analysis in fetuses with central nervous system anomalies

• Published in: Ultrasound in obstetrics & gynecology Vol. 62; no. 5; pp. 721 - 726
• Main Authors: Zhi, Y, Liu, L, Wang, H, Chen, X, Lv, Y, Cui, X, Chang, H, Wang, Y, Cui, S
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.11.2023
• Subjects: Abnormalities; Aneuploidy; Anomalies; Central nervous system; Central Nervous System Diseases; Chromosome Aberrations; Decision making; Diagnostic systems; Exome Sequencing; Female; Fetus - abnormalities; Fetus - diagnostic imaging; Fetuses; Genetic disorders; Gynecology; Humans; Magnetic resonance imaging; Medical diagnosis; Medical prognosis; Microarray Analysis - methods; Mutation; Nervous system; Nervous System Malformations - diagnostic imaging; Nervous System Malformations - genetics; Obstetrics; Pregnancy; Prenatal Diagnosis - methods; Retrospective Studies; Sequence analysis; Sequences; Ultrasonic imaging; Ultrasonography, Prenatal - methods; Ultrasound; abnormality; congenital; prenatal diagnosis; prenatal exome sequencing; prognosis; central nervous system
• ISSN: 0960-7692; 1469-0705
• DOI: 10.1002/uog.26254

To evaluate the utility of prenatal exome sequencing (pES) in fetuses with central nervous system (CNS) abnormalities. This was a retrospective cohort study of fetuses identified to have CNS abnormality on prenatal ultrasound and/or magnetic resonance imaging. All fetuses were first analyzed by chromosomal microarray analysis (CMA). Fetuses with a confirmed aneuploidy or causal pathogenic copy-number variant (CNV) on CMA did not undergo pES analysis and were excluded, while those with a negative CMA result were offered pES testing. Of the 167 pregnancies included in the study, 42 (25.1%) were identified to have a pathogenic or likely pathogenic (P/LP) variant. The diagnostic rate was significantly higher in fetuses with a non-isolated CNS abnormality than in those with a single CNS abnormality (35.7% (20/56) vs 14.5% (8/55); P = 0.010). Moreover, when a fetus had three or more CNS abnormalities, the positive diagnostic rate increased to 42.9%. A total of 25/42 (59.5%) cases had de-novo mutations, while, in the remaining cases, mutations were inherited and carried a significant risk of recurrence. Families whose fetus carried a P/LP mutation were more likely to choose advanced pregnancy termination than those with a variant of uncertain significance, secondary/incidental finding or negative pES result (83.3% (25/30) vs 41.3% (38/92); P < 0.001). pES improved the identification of genetic disorders in fetuses with CNS anomalies without a chromosomal abnormality or CNV identified on CMA, regardless of the number of CNS anomalies and presence of extracranial abnormality. We also demonstrated that pES findings can significantly impact parental decision-making. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.