The evaluation of Copy Number Variants in an unselected population of patients with Inherited Cardiac Conditions: The INTERACTION Study

BACKGROUND AND AIMS: The current diagnostic approach to inherited cardiac conditions (ICCs) is primarily focused on the analysis of single-nucleotide variants (SNVs) and small insertions/deletions (InDels). However, as recommended for other inherited diseases, the analysis of Copy Number Variants (CNVs) should be equally considered. In cardiology, the diagnostic contribution of CNVs remains insufficiently studied, with limited evidence and no standardized recommendations for analytical workflows.This study aims to assess the prevalence of pathogenic CNVs in an Italian multicenter cohort of ICC patients, providing recommendations for integrating CNV analysis into routine genetic testing. METHODS: A total of 203 ICC probands with prior negative or inconclusive results for SNVs and InDels testing were included. The tertiary bioinformatic analysis was performed by eVai enGenome software, and putative CNVs were validated by Multiplex Ligation-dependent Probe Amplification (MLPA) assays. RESULTS: MLPA confirmed only one of the five initially suspected CNVs, identifying a deletion in MYBPC3 gene classified as pathogenic according to ACMG/AMP guidelines. This result confirmed a limited diagnostic yield of 0,50%. Considering the substantial costs, time constraints, and specialized expertise required, we propose a strategy to prioritize selected ICC patients for CNV analysis. CONCLUSIONS: Evidence from this real-world cohort suggests the incorporation of CNV analysis as a second-tier test in patients with ICC and specific clinical or molecular indications.