Rare variants in genes encoding structural myocyte contribute to a thickened ventricular septum in sudden death population without ventricular alterations

Unexpected cardiac deaths are a current challenge to healthcare systems. In adults, coronary artery disease and acquired cardiomyopathies are the most frequent causes of sudden cardiac death while in younger than 35 years old, the main cause is represented by non-ischemic diseases, usually inherited. Nowadays, around 10%-15% of unexpected deaths remain without a definite cause of decease after a complete autopsy, then classified as deaths potentially due to an inherited arrhythmia. Discrete abnormalities in some of the heart measures have been considered as potential predictors or risk factors for sudden cardiac death. However, role of non-benign genetic variants in these scattered heart alterations remains to be clarified, especially if variants are classified of ambiguous role. Clinicians usually only take into consideration pathogenic variants for decision-making. It is yet unclear what the role of VUS genetic variants in modifying the anatomical parameters of the heart. We hypothesize that some heart measures might be influenced by polygenic components as some variants may individually confer minor risk but may actually produce additive effects when combined with others. Our aim was to investigate whether carrying non-benign rare variants in genes related to inherited arrhythmias may contribute to scattered cardiac alterations in anatomical normal hearts. The study is composed by 761 samples collected from autopsies of SD suffered by adults from 18 to 50 years of age who occurred in Catalonia (Spain) in a 9-year period. Complete medico-legal autopsy was performed to determine the cause of death. Molecular autopsy was performed as part of our forensic protocol, including genes associated with inherited diseases.To evaluate the effect of genetic rare variants into hearts measures we performed a linear regression model and data were presented as regression. This study showed, for the first time, that rare variants, regardless of significance (pathogenic, probably pathogenic or uncertain significance), may contribute to interventricular septum width in the structurally normal heart. While the cohort is based on sudden death cases, further studies and case-control studies will be necessary to conclude that the genetic determinants of septal thickness contributes to sudden cardiac death. We conclude that non-benign rare variants contribute to modify scattered septum width in structural normal hearts, being a potential risk factor of arrhythmia in genetic harbors. These evidence support the current recommendation in forensic protocols of including histologic analysis of septum when inherited arrhythmogenic disease is suspicious cause of decease.

Automated summary

Unexpected cardiac deaths pose a challenge to healthcare systems, with around 10%-15% remaining unexplained and potentially due to inherited arrhythmias. This study investigates the effect of non-benign genetic variants on heart measures and finds that they may modify certain measures in structurally normal hearts.