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

Overview

Journal Genes (Basel)

Publisher MDPI

Date 2024 Jul 27

PMID 39062601

Authors

Maria dApolito

Francesco Santoro

Alessandra Ranaldi

Ilaria Ragnatela

Anna Laura Colia

Sara Cannito

Alessandra Margaglione

Girolamo DArienzo

Giovanna DAndrea

PierLuigi Pellegrino

Rosa Santacroce

Natale Daniele Brunetti

Maurizio Margaglione

Affiliations

Soon will be listed here.

Abstract

Background: 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.

Aim Of The Study: The aim of this study was to clinically and genetically evaluate a large family with severe autosomal dominant Brugada syndrome.

Methods: 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.

Results: 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.

Conclusions: 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.

Citing Articles

Genetic Background and Clinical Phenotype in an Italian Cohort with Inherited Arrhythmia Syndromes and Arrhythmogenic Cardiomyopathy (ACM): A Whole-Exome Sequencing Study.

dApolito M, Santoro F, Ranaldi A, Cannito S, Santacroce R, Ragnatela I Int J Mol Sci. 2025; 26(3).

PMID: 39940965 PMC: 11818934. DOI: 10.3390/ijms26031200.

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