From gene-discovery to gene-tailored clinical management: 25 years of research in channelopathies and cardiomyopathies

Abstract

In the early nineties, few years before the birth of Europace, the clinical and scientific world of familial arrhythmogenic conditions was revolutionized by the identification of the first disease-causing genes. The explosion of genetic studies over a 15-year period led to the discovery of major disease-causing genes in practically all channelopathies and cardiomyopathies, bringing insight into the pathophysiological mechanisms of these conditions. The birth of next generation sequencing allowed a further step forward and other significant genes, as CALM1-3 in channelopathies and FLN C and TTN in cardiomyopathies were identified. Genotype-phenotype studies allowed the implementation of the genetic results in diagnosis, risk stratification, and therapeutic management with a different level of evidence in different arrhythmogenic conditions. The influence of common genetic variants, i.e. SNPs, on disease manifestation was proved in mid-twenties, and in the last 10 years with the advent of genome-wide association studies performed in familial arrhythmogenic diseases, the concept of polygenic risk score has been consolidated. Now, we are at the start of another amazing phase, i.e. the initiation of first gene therapy clinical trials.

Keywords: Cardiomyopathies; Channelopathies; Gene therapy; Genetics; Polygenic risk score; Sudden cardiac death.

Graphical abstract

The upper panel on the left shows feature of all major channelopathies (LQTS, long QT syndrome; BrS, Brugada syndrome; CPVT, catecholaminergic polymorphic ventricular tachycardia) and cardiomyopathies (HCM, hypertrophic cardiomyopathy; ACM, arrhythmogenic cardiomyopathy; DCM, dilated cardiomyopathy) and two family trees. The other panels show how discovery of disease-causing genes and common variants influencing the phenotype (PRS, polygenic risk score) have an impact on clinical management. Lower panel of the left also shows the near future of gene therapy clinical trial.

Figure 1

The pathway for the application of genetic and clinical evaluation following unexpected cardiac arrest or sudden death. Broken arrow indicates weaker evidence. *Predictive genetic testing will identify family members for clinical evaluation who harbour a pathogenic or likely pathogenic variant when this has been identified in a family. Otherwise, all first-degree relatives should be offered clinical evaluation. +Only genes with robust disease associations should be included. (Adapted from Behrhttps://doi.org/10.1093/eurheartj/ehac172.)