PO91
Beyond SNVs and Indels: The Contribution of CNVs to Improve Diagnostic Outcomes in Cardiogenetics

Inherited cardiac diseases, such as cardiomyopathies and channelopathies, are among the leading causes of sudden cardiac death. Genetic testing plays a key role in their diagnosis and risk stratification. Traditionally, efforts in cardiogenetics have focused on detecting single nucleotide variants (SNVs) and small insertions/deletions (indels). However, this approach may overlook other relevant genomic alterations. Copy number variants (CNVs), now systematically assessed across all genes included in targeted panels, represent an additional and important source of pathogenic variation.

This study aims to assess the impact of an integrated screening strategy that encompasses SNVs, indels, and CNVs on overall diagnostic yield in inherited cardiomyopathies and channelopathies.

Between November 2022 and July 2025, 2342 index cases with diagnosed or suspected cardiomyopathies or channelopathies referred to our laboratory for genetic testing were analysed. Variants were identified through targeted Next-Generation Sequencing (NGS) multigene panel. CNVs were detected using a read-depth approach and subsequently confirmed by orthogonal molecular techniques, including Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Diagnostic outcomes were classified in accordance with international guidelines.

A molecular genetic diagnosis was established in 16% of patients (n = 388). Among these, 16 clinically relevant CNVs (likely pathogenic or pathogenic) were identified, representing 4% of positive findings. The distribution of CNVs varied across phenotypes, underscoring their heterogeneous contribution to different disease subtypes.

Clinically relevant CNVs represent a non-negligible proportion of molecular diagnoses in cardiogenetics. Their systematic inclusion alongside SNV and indel analysis enhances overall diagnostic yield and supports more comprehensive patient care. These findings align with recent evidence on the role of CNVs in inherited cardiovascular disorders. Advances in NGS-based CNVs detection now enable reliable integration of this methodology into routine diagnostic pipelines, although challenges in clinical interpretation sometimes remain.