Reanalysis of reported copy number variants with current literature data and clinical correlations in microarray-analyzed

Copy number variations (CNVs) observed throughout the genome contribute to phenotypic differences among individuals. However, the clinical impact of these variations cannot always be demonstrated with definitive evidence. Novel technologies enabling comprehensive evaluation of the human genome through multiple parameters and reanalysis of existing data reduce diagnostic uncertainty, enhancing diagnostic success. This study aimed to investigate the contribution of re-evaluating CNVs classified as likely pathogenic, pathogenic, or variant of uncertain significance (VUS), in light of patients' clinical features and current literature data to diagnostic yield. The study included 310 CNVs reported in 272 cases subjected to microarray analysis between 2017 and 2023. Upon reanalysis, among the 174 variants initially classified as VUS, 6% (11/174) were reclassified as benign, 1% (1/174) as likely pathogenic, and 1% (2/174) as pathogenic. The reclassification rate was 4.5% for the variants and 5.1% for the cases. The highest number of reclassifications was observed during initial evaluations at year 2018. Most reclassified variants were >400 kb, with the majority of benign reclassifications being inherited duplications from healthy parents (8/11). In reclassified cases, the contribution of additional molecular tests was significant, particularly recommending further analysis for VUS variants that did not correlate with clinical findings. The most frequently reclassified variant was the Xp22.31 duplication, observed in both prenatal and postnatal groups. Reclassification was most common in prenatal cases with abnormal ultrasound findings and postnatal cases with intellectual disability. In three cases, despite no change in classification, updated clinical and/or literature data provided additional support in diagnostic evaluation. Our findings demonstrate that re-evaluating CNVs based on clinical correlation and updated literature significantly enhances the diagnostic process and guides management of VUS variants.