Abstract 367 The relevance of a complete genetic study in the diagnosis of Brugada syndrome

Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02180-w
The relevance of a complete genetic study in the diagnosis of Brugada syndrome
L. Cazón Varela¹, L. De la Higuera¹, D. García¹, M. Pérez¹, R. Peteiro¹, I. Gómez¹, P. Vélez¹, M. Sánchez¹, A. Sanluis¹, G. Smith¹, E. Maneiro¹, X. Fernández¹, A. Amor¹, M. Valverde¹, S. García¹, I. Cárdenas¹, M. Ortíz¹, J. P. Ochoa¹
¹Health in Code, A Coruña, ES;
Background: Genetic variants, mainly in the SCN5A gene, are reported in approximately 15-25% of Brugada syndrome (BrS) cases. These variants include missense, nonsense, small insertion/deletions, frameshifts, and splice-site changes that, usually, lead to loss-of-function of the NaV1.5 channel. In addition to this, it is known that a small percentage of BrS cases are carriers of copy number variations (CNVs) in this gene. Objective: To determine the relevance of a complete genetic study for the diagnosis of Brugada syndrome. Methods: Nine hundred and seventy-seven consecutive unrelated probands with suspicion of Brugada syndrome were sequenced by NGS using a panel of genes including SCN5A. Filtering and classification of NGS data was performed using a custom pipeline, and CNVs were detected using a read depth approach and confirmed by orthogonal molecular techniques. Results: The analysis of the NGS data revealed SCN5A variants associated or possibly associated with BrS in 137 probands (14%). We found 102 missense variants, 3 small in-frame deletions and 32 radical changes (including nonsense, frameshift and splice variants); eighty-six of these variants were classified as pathogenic / likely pathogenic and 51 as variants of unknown significance but favoring pathogenic. CNV analysis, performed in 888 (90.9%) probands, revealed six carriers of CNVs in SCN5A. All identified CNVs were deletions, with some affecting one or more exons of the SCN5A gene (exons 4, 8-10, 13-27, 22), others involving the adjacent gene (SCN5A exons 1-16 and SCN10A exons 15-27) and another affecting the entire SCN5A gene and 7 other genes (ACVR2B, ACVR2B-AS1, EXOG, OXSR1, SCN10A, SLC22A13, SLC22A14, and XYLB). Conclusion: In our cohort, 0.6% of the BrS cases were carriers of SCN5A CNVs. These variants represented about 7% of the identified relevant variations. This result shows that CNV analysis enhances the yield of the genetic diagnosis of BrS and emphasizes the relevance of a complete genetic study including screening for CNVs for the diagnosis of the disease.
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