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Chromosomal microarray analysis and exome sequencing provide substantial diagnostic yields (23.8% and 39.0%, respectively) in fetuses with central nervous system anomalies, and the identification of pathogenic variants strongly correlates with long-term global developmental delay. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

June 4, 2026Open Access

Diagnostic yield of chromosomal microarray analysis and exome sequencing in fetuses with central nervous system anomalies, with long-term follow-up: a single-center study over a 17-year period

Key Points

To evaluate the diagnostic yield of chromosomal microarray analysis and exome sequencing in fetuses with CNS anomalies and assess long-term outcomes.
Retrospective analysis over 17 years with 780 cases of fetal CNS anomalies
Invasive testing by G-banded karyotyping, CMA, and ES in selected cases
Cases classified into four groups based on the type of anomalies.
Causative findings identified in 23.8% by CMA and 39.0% by ES
CMA/ES use increased from 16.3% to 59.7% with more pathogenic findings (26 to 72 cases)
Higher ES yield in multisystem anomalies, with isolated CNS plus cases showing better yields compared to isolated cases.

Abstract

Abstract Objective To assess the diagnostic yield of chromosomal microarray analysis (CMA) and exome sequencing (ES) in fetuses with central nervous system (CNS) anomalies across two study periods (January 2008 to June 2016 and July 2016 to December 2024), and to evaluate long-term outcomes. Methods This retrospective study included cases with fetal CNS anomalies undergoing invasive testing by G-banded karyotyping and, in selected cases, additional CMA and/or ES. Fetuses were classified into four groups: isolated CNS malformations, isolated CNS plus (additional minor abnormalities and dynamic findings), complex CNS anomalies, and multisystem malformations. Results Among 780 cases, causative findings were identified in 23.8% (25/105) by CMA and 39.0% (73/187) by ES. Use of CMA/ES increased in the second study period (16.3% vs. 59.7%), resulting in more pathogenic findings (26 vs. 72 cases), whereas diagnostic yield among tested cases decreased without significance. The highest ES yield was observed in multisystem CNS anomalies; isolated CNS plus cases showed higher yields than truly isolated CNS cases. In an exploratory subgroup analysis, isolated CNS plus cases with polyhydramnios had a higher CMA/ES yield than truly isolated cases. Among 91 live-born children with follow-up, 49.5% (45/91) had global developmental delay, which was more frequent with pathogenic findings (90.0%, 18/20; p = 0.002) and increasing anomaly complexity (11.1 to 81.8%; p < 0.001). Conclusion Uptake of CMA and ES increased over time and resulted in more etiologic diagnoses. In tested cases, both methods provided meaningful diagnostic yield in fetuses with CNS anomalies and may contribute to prognostic assessment and prenatal counseling.

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