ArticleFrontiers in pediatrics2026
Phenotypic spectrum and molecular characteristics of variants of uncertain significance in copy number variations associated with fetal cardiac malformations: a case series of 9 patients.
Article in Frontiers in pediatrics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Copy number variants of uncertain significance (VUS-CNVs) pose significant challenges in prenatal counseling for congenital heart malformations (CHMs). Their clinical relevance remains poorly defined, particularly in the absence of postnatal validation. Objective: To characterize the phenotypic and molecular features of VUS-CNVs in CHM fetuses and evaluate their clinical implications. Methods: From a cohort of 644 fetuses with CHMs undergoing chromosomal microarray analysis (CMA), we identified 9 VUS-CNV cases. All reportable CNVs (≥200 kb or in known pathogenic regions such as 22q11.21) were validated by TaqMan qPCR. Detailed prenatal echocardiography, trio CMA ( Results: VUS-CNVs were identified in 9 of 644 (1.40%) CMA-tested fetuses with CHMs. These included 3 in isolated CHM, 1 in complex CHM, 3 in CHM with extracardiac structural anomalies, and 2 in CHM with isolated soft markers. VUS-CNVs in non-isolated cases were larger (median: 2.5 Mb vs. 0.72 Mb in isolated CHM) and encompassed more OMIM-listed genes (mean: 3.8 vs. 1.5 in isolated CHM) than those in isolated CHM. Trio analysis reclassified 3 of 7 tested VUS-CNVs (2 as likely benign, 1 as likely pathogenic). Six pregnancies continued to term-3 with isolated and 3 with non-isolated CHM-and all live-born infants showed no major postnatal abnormalities. The three terminations involved non-isolated phenotypes; decisions were primarily driven by structural anomaly severity, though the VUS amplified prognostic uncertainty. Conclusion: Although VUS-CNVs are uncommon in fetuses with CHMs, they occur more frequently in non-isolated phenotypes and carry the potential for future reclassification-posing significant challenges in prenatal genetic counseling. These two aspects underscore the necessity of trio-based genomic testing, cautious interpretation of results, and longitudinal follow-up. Given the limited sample size of this study, no causal relationship between VUS-CNVs and clinical phenotypes can be inferred; however, our findings support a risk-stratified management framework that integrates detailed fetal phenotyping, trio analysis, and postnatal follow-up to enable accurate variant interpretation and informed decision-making.
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