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.

Genetic testing for inherited cardiovascular diseases. A position statement of the Polish Cardiac Society endorsed by Polish Society of Human Genetics and Cardiovascular Patient Communities

“…With the advent of next-generation sequencing (NGS), today we have over 100 established genes with definitive or strong associations to hereditary cardiac diseases and hundreds are under investigation [8]. This has improved our understanding of pathomechanisms and allowed the discovery of gene-specific therapies [9] and recognition of new cardiovascular phenotypes [10]. Most cardiac conditions are inherited in an autosomal dominant (AD) fashion and qualify for cardiomyopathies (CMP), arrhythmias, aortopathies, lipid disorders, and congenital heart defects (CHD).…”

“…These conditions frequently have overlapping phenotypes and can present differently even in one family as the effect of the same pathogenic (P)/likely pathogenic (LP) variant can be modified by common polymorphisms. Apart from strictly monogenic dominant inheritance, some cases are caused by digenic or oligogenic inheritance, with two or more rare variants located in the same or different genes, which is often associated with a more severe phenotype [9,11]. Taking into account all these complexities, molecular diagnostics requires a comprehensive approach with parallel analysis of a large number of genes with NGS.…”

Autopsy of all young sudden death cases is important to increase survival in family members left behind

“… 107 , 109 , 116 , 117 , 136–138 However, broader genetic testing increases the risk of identifying variants of uncertain significance, which is especially challenging to interpret in the setting of SADS, where correlation to the phenotype is impossible in the decedent. 81 Over-interpretation of clinical or genetic findings of unknown significance might lead to erroneous diagnosis and cause significant harm. The utility of broad panels and whole-genome sequencing, therefore, needs to be carefully tested before full implementation in clinical practice.…”

The role for ambulatory electrocardiogram monitoring in the diagnosis and prognostication of Brugada syndrome: a sub-study of the Rare Arrhythmia Syndrome Evaluation (RASE) Brugada study

“…It is also possible that different genetic substrates (single-gene SCN5A variants vs. polygenic contribution) influence the ECG phenotype variability in BrS; whether this could also have an influence in arrhythmogenesis and potential for tailored therapeutic strategies needs to be elucidated in future research. 24 Multivariate analysis using clinical and demographic parameters failed to find significant associations with events due to the low event rate.…”