**7. DCM Secondary to Cardiac Conduction Disturbances**

DCM might also develop secondary to loss-of-function variants, which leads to reduced sodium conductivity or channel availability. Classical manifestations of loss-of-function *SCN5A* variants are Brugada syndrome and PCCD (Lenège and Lev disease), but development of DCM at late disease stages, often 15 to 20 years after diagnosis, has been described in many cases. In addition, transgenic mice with 90% decreased NaV1.5 expression [19] and mice with the DCM-associated D1275N variant, have been found to display conduction slowing with progressive age-dependent changes suggestive for DCM [42]. This hypothesis, however, does not explain the development of DCM in rare *SCN5A* variant carriers with unaffected cardiac conduction. The majority of *SCN5A* variants causing cardiac conduction defects are frameshift/truncation variants, which produce a conduction phenotype proportionate to the severity of NaV1.5 dysfunction, whereas most DCM-related *SCN5A* variants are missense changes.

## **8. Mechanisms Involving Other Genetic Influences**

Genome-wide association studies (GWAS) with case-control design have shown that another *SCN5A*-mediated condition, Brugada syndrome, is more likely to develop in patients who carry multiple common variants with a small effect, referred to as small nucleotide polymorphisms (SNPs). These SNPs can modulate the expression dosage of NaV1.5 by altering mechanisms such as the dosage of the messenger RNA, the number of channels on the surface of cardiomyocyte, or even by modulating the affinity of a transcription factor for the gene regulatory element. Considering its shared genetic substrate with *SCN5A*-mediated DCM, it is likely that the DCM is also influenced by genetic modifiers, but more GWAS need to be completed before revisiting this hypothesis. Furthermore, measurements of *I*Na in HEK293 cells expressing DCM-associated variants R222Q and I1835T using whole-cell voltage clamp technique, have revealed that common polymorphisms H558R and Q1077del are relevant for their phenotypic expression and have a large impact on the NaV1.5 biophysical phenotypes [43]. It is therefore more likely that *SCN5A-*mediated phenotypes result from complex oligo-polygenic disease with some effect of post-translational and environmental factors, rather than a strict Mendelian inheritance.
