Genetic characterization of juvenile sudden cardiac arrest and death in Tuscany: The ToRSADE registry

Francesca Girolami; Valentina Spinelli; Niccolò Maurizi; Martina Focardi; Gabriella Nesi; Vincenza Maio; Rossella Grifoni; Giuseppe Albora; Bruno Bertaccini; Mattia Targetti; Raffaele Coppini; Silvia Favilli; Iacopo Olivotto; Elisabetta Cerbai

doi:10.3389/fcvm.2022.1080608

Genetic characterization of juvenile sudden cardiac arrest and death in Tuscany: The ToRSADE registry

Front Cardiovasc Med. 2022 Dec 14:9:1080608. doi: 10.3389/fcvm.2022.1080608. eCollection 2022.

Authors

Francesca Girolami¹, Valentina Spinelli², Niccolò Maurizi³, Martina Focardi^{3

4}, Gabriella Nesi^{3

5}, Vincenza Maio^{3

5}, Rossella Grifoni^{3

4}, Giuseppe Albora³, Bruno Bertaccini⁶, Mattia Targetti³, Raffaele Coppini², Silvia Favilli¹, Iacopo Olivotto^{1

7}, Elisabetta Cerbai²

Affiliations

¹ Cardiology Unit, Meyer Children's University Hospital, Florence, Italy.
² Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
³ Careggi University Hospital, Florence, Italy.
⁴ Forensic Medical Sciences, Department of Health Sciences, University of Florence, Florence, Italy.
⁵ Division of Pathological Anatomy, Department of Health Sciences, University of Florence, Florence, Italy.
⁶ Department of Statistics, Computer Science, Applications, University of Florence, Florence, Italy.
⁷ Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.

Abstract

Background: Sudden cardiac arrest (SCA) in young people represents a dramatic event, often leading to severe neurologic outcomes or sudden cardiac death (SCD), and is frequently caused by genetic heart diseases. In this study, we report the results of the Tuscany registry of sudden cardiac death (ToRSADE) registry, aimed at monitoring the incidence and investigating the genetic basis of SCA and SCD occurring in subjects < 50 years of age in Tuscany, Italy.

Methods and results: Creation of the ToRSADE registry allowed implementation of a repository for clinical, molecular and genetic data. For 22 patients, in whom a genetic substrate was documented or suspected, blood samples could be analyzed; 14 were collected at autopsy and 8 from resuscitated patients after SCA. Next generation sequencing (NGS) analysis revealed likely pathogenetic (LP) variants associated with cardiomyopathy (CM) or channelopathy in four patients (19%), while 17 (81%) carried variants of uncertain significance in relevant genes (VUS). In only one patient NGS confirmed the diagnosis obtained during autopsy: the p.(Asn480Lysfs*20) PKP2 mutation in a patient with arrhythmogenic cardiomyopathy (AC).

Conclusion: Systematic genetic screening allowed identification of LP variants in 19% of consecutive patients with SCA/SCD, including subjects carrying variants associated with hypertrophic cardiomyopathy (HCM) or AC who had SCA/SCD in the absence of structural cardiomyopathy phenotype. Genetic analysis combined with clinical information in survived patients and post-mortem evaluation represent an essential multi-disciplinary approach to manage juvenile SCD and SCA, key to providing appropriate medical and genetic assistance to families, and advancing knowledge on the basis of arrhythmogenic mechanisms in inherited cardiomyopathies and channelopathies.

Keywords: ToRSADE registry; arrhythmia; genetics; juvenile sudden cardiac death; molecular autopsy; next generation sequencing.