Novel molecular and cellular mechanisms of genetic arrhythmogenic disease Insights into the pathobiology of TNNI3K and HCN4

Synchronized beating and proper contraction of the heart is essential for efficient blood flow through the body. These physiological processes can be affected by genetic cardiac disorders. Since the rapid rise in genetic sequencing methods, there has been a strong increase in identification of genetic variants and disease-related genes. The molecular disease mechanisms of many genetic variants, and genetic cardiac disorders are still not well understood. In this thesis we assess and reclassify variants in KCNH2 and HCN4, and we investigate the (patho)biology of HCN4 and TNNI3K.
For genetic variants to be classified, substantial evidence is needed. Thorough investigation may identify additional causes of disease within a family, or broaden the gene-related phenotype. Furthermore, functional analysis of the cellular electrophysiology, is a pivotal tool for the assessment of variants' pathogenicity. This also offers insights into disease mechanisms which are essential for the identification of drug targets, and personalizing treatment strategies.
In this thesis we also provide molecular and functional evidence for the pathogenicity of variants in TNNI3K. With this knowledge, the incorporation of TNNI3K in arrhythmogenic disease and cardiomyopathy panels should be further pressured. This will improve the diagnosis and counseling of patients. In return, increase in clinical reports will aid in better understanding the full clinical phenotype. Furthermore, we identified and functionally assessed Cx45 and HCN4 as targets of TNNI3K, providing pivotal molecular insights into the disease mechanism. With combined understanding of the clinical phenotype and molecular disease mechanism, new treatment strategies and targets can arise.