Genetic risk stratification in cardiac arrhythmias

The current article provides a concise summary of the possibilities and limitations of genotype-based risk stratification of cardiac arrhythmias. We will outline the most important findings of the recent years in the light of their chronological and conceptual development.

Genotype-phenotype association studies in families with single-gene disorders as well as in the general population led to the discovery of several DNA variants significantly associated with the risk of sudden death or life-threatening arrhythmias. In genetic (monogenic) diseases, the disease-causing mutations modulate the risk of events and response to antiarrhythmic therapy according to the specific gene involved, to their position of the mutation and to their functional effects. These causal relationships have been quite well characterized in the case of long QT syndrome but are still less defined in the case of other inherited conditions. Quantitatively, the risk associated with a single genetic variant is large for DNA variants that cause monogenic inherited arrhythmias. Much different is the case of more common variants associated with the risk of arrhythmias in the general population as they are generally associated with a small effect size.

Genetic profiling identifies arrhythmogenic risk even if a complete picture allowing high-granularity risk stratification is yet to come.