Autosomal dominant mutations have only been identified in up to 60% of all ACM patients  suggesting the existence of unknown mechanisms such as higher genetic heterogeneity, modifier genes, or cross talk between genetic background and environmental factors . In fact, three loci have been mapped in ACM linkage studies, for which the causal gene has not yet been identified: ARVD3 (OMIM %602,086) at 14q12–32.3 , ARVD4 (OMIM %602,087) at 2q32.1–32.3 , and ARVD6 (OMIM %604,401) at 10p14-p12 . In addition, the frequency of variants associated with ACM has been found to be much higher than expected given the phenotype prevalence in the general population, suggesting that a high number of these variants are not monogenic causes of ACM . In fact, recent reports have suggested digenic inheritance as an alternative disease mechanism of ACM [11–14]. In digenic inheritance the presence of two variants in two different genes is required for the manifestation of a clinical phenotype; in the absence of one of these variants, the other variant might be benign. For example, Xu et al. screened 198 ACM patients for variants in the desmosomal genes. Of the 38 patients in which PKP2 variants were detected, additional variants in PKP2 itself (compound heterozygosity) were identified in nine patients; variants in other desmosomal genes (digenic inheritance) were identified in 13 patients. Related family members harboring a variant in just one of these genes were unaffected by ACM. The authors concluded that the disease was caused by compound heterozygosity or digenic inheritance in these patients . Rasmussen et al. investigated 12 families with variants in DSG2. In three of these families, additional variants were identified in the DSP gene in affected family members. Only individuals with both variants in DSG2 and DSP were affected by ACM, leading the authors to conclude that low penetrance of desomosmal variants in ACM patients may also be explained by digenic inheritance . Cooper et al. proposed that digenic inheritance may occur as a result of variants in two genes encoding different subunits of the same protein (complex); two proteins that interact functionally; are a receptor-ligand pair; are a target gene and transcription factor; or compromise the same regulatory, biosynthetic, or degradative pathway . Digenic inheritance is distinct from modifier genes: in digenic inheritance, both variants individually usually do not lead to disease, whereas in modifier genes one pathogenic variant is enhanced by a putatively contributing variant of unknown significance . Non-genetic factors known to influence ACM penetrance are age, male sex and intense physical activity [16, 17].