Investigation of a Large Kindred Reveals Cardiac Calsequestrin ( CASQ2 ) as a Cause of Brugada Syndrome

• Published in: Genes 2024-07, Vol.15 (7), p.822
• Main Authors: d'Apolito, Maria, Santoro, Francesco, Ranaldi, Alessandra, Ragnatela, Ilaria, Colia, Anna Laura, Cannito, Sara, Margaglione, Alessandra, D'Arienzo, Girolamo, D'Andrea, Giovanna, Pellegrino, PierLuigi, Santacroce, Rosa, Brunetti, Natale Daniele, Margaglione, Maurizio
• Format: Article
• Language: English
• Subjects: Calcium-binding protein; Calcium-binding proteins; Calsequestrin; Cardiac arrhythmia; Cardiac muscle; Channelopathy; Electrocardiography; Emergency medical care; Filamentation; Genes; Genetic analysis; Genetic aspects; Genomes; Heart; Investigations; Mutation; Pathogenicity; Patients; Potassium; Proteins; Proteomics; Sarcoplasmic reticulum; Syncope; Variation
• ISSN: 2073-4425; 2073-4425
• DOI: 10.3390/genes15070822

Brugada syndrome (BrS) is an inherited primary channelopathy syndrome associated with the risk of ventricular fibrillation (VF) and sudden cardiac death in a structurally normal heart. The aim of this study was to clinically and genetically evaluate a large family with severe autosomal dominant Brugada syndrome. Clinical and genetic studies were performed. Genetic analysis was conducted with NGS technologies (WES) using the Illumina instrument. According to the standard procedure, variants found by WES were confirmed in all available families by Sanger sequencing. The effect of the variants was studied by using in silico prediction of pathogenicity. The proband was a 52-year-old man who was admitted to the emergency department for syncope at rest. WES of the index case identified a heterozygous VUS , c.532T>C, p.(Tyr178His). We studied the segregation of the variation in all pedigree members. All the patients were heterozygous for the variation p.(Tyr178His), whereas the remaining healthy individuals in the family were homozygous for the normal allele. Structural analysis of p.(Tyr178His) was performed and revealed an important effect of the missense variation on monomer stability. The Tyr180 residue is located inside the sarcoplasmic reticulum (SR) junctional face membrane interaction domain and is predicted to disrupt filamentation. Our data suggest that the p.Tyr178His substitution is associated with BrS in the family investigated, affecting the stability of the protein, disrupting filamentation at the interdimer interface, and affecting the subsequent formation of tetramers and polymers that contain calcium-binding sites.