Unraveling genetic cardiomyopathies: From gene discovery to mechanistic insights and clinical implications

Cardiomyopathy is a disease of the myocardium, involving cellular and structural alterations that affect the heart its ability to contract and to pump blood efficiently.
It represents a heterogenous group of conditions with diverse clinical presentations
and underlying genetic etiologies. Disease-causing variants have been identified in
over 100 genes, encoding for proteins playing diverse roles within the cardiomyocyte.
However, despite these insights, diagnostic yield in genetic testing remains low,
leaving many patients worldwide classified as idiopathic. This suggests the presence
of yet undiscovered genetic variants and disease mechanisms, and underscores the
need for further research. Also, the pathogenic mechanisms by which numerous
established disease-causing variants lead to clinical manifestations remain incompletely
understood. When left untreated, cardiomyopathy can cause serious complications
such as arrhythmias, heart failure, and sudden cardiac death. To improve outcomes
for patients with genetic cardiomyopathy, we need to develop personalized treatment
strategies that tackle the root cause of the disease. To accomplish this, we need to
deepen our understanding of the genetic factors and disease mechanisms involved.
This includes the discovery of new genetic causes and refining how genetic variants
lead to and correlate with clinical manifestations. These insights will enable clinicians
to establish more accurate diagnosis and risk prediction contributing to better patient
care, and can ultimately drive the development of efficient targeted therapeutics.This thesis aims to address these challenges and to offer valuable insights in both the
molecular and clinical aspects of genetic cardiomyopathy.