We are aware of limitations in our study. Both families have relatively few members, which resulted in a large set of variants and genes as possible candidates for digenic inheritance. Only 85% of the exome was covered with at least 10X. Since we required a minimum coverage of 10X to accept a variant call, 15% of the exome could not be investigated. However, coverage at the ACM genes was well above average, so it is unlikely that variants were missed in these genes. Due to the large number of candidate genes in each family, we restricted our analysis to ACM or PKP2-related genes, potentially removing causative digenic genes with unknown associations. Even though the TTN variants in Fam2 were confirmed by Sanger sequencing, no functional validation of the variant effects was performed. Therefore, it still needs to be shown if TTN or any of the candidate genes in Fam1 truly cause ACM together with PKP2 in the respective family. A functional validation could be performed based on induced pluripotent stem cell (iPSC) models from the ACM-affected individuals, where the PKP2 variant or the TTN/Fam1 variants are reversed . In the iPSC derived cardiomyocytes the effect of the genetic variants could be investigated by comparing fat accumulation and cell electrophysiology to the double mutant cells. Other cell models that could be employed for validation are progenitor cells (they differentiate easily in vitro), non-contractile cardiac mesenchymal stromal cells (ideal for studying lipid metabolism), or primary or immortalized cardiomyocytes (enable investigation of gap-junctions and ion-channels) . Yet, even if successful, such experiments would demonstrate the mode of effect in the respective family, while general conclusions about the role of TTN/Fam1 genes in ACM could not necessarily be drawn from them. To evaluate the roles of these genes in ACM more generally, other ACM patients carrying desmosomal variants could be checked for rare variants in the respective genes. Unfortunately, we currently do not have additional ACM patients for testing and the NCBI Sequence Read Archive does not contain public whole exome or whole genome sequence data of ACM patients. The search for genes with a digenic effect is a considerable challenge since variants in both relevant genes do not necessarily have a pathogenic effect when occurring individually . The functional or structural change caused by the variant in either protein may be subtle, and may for example lead to a change at a protein binding affinity or a change in gene expression. Therefore, standard criteria usually applied to evaluate the likelihood of variant pathogenicity like rarity and computational predictions might not be well suited. Consequently, we did not exclude variants based on these criteria, yet in the absence of functional validation and more appropriate models, we prioritized and discussed our results according to these methods. We would like to recall that we did not distinguish between variants that were present in the affected and not in the carriers and variants present in the carriers but not in the affected, since we were interested in genes whose function might differ between affected individuals and carriers due to the variants. However, we point out that of the 17 variants listed in Table 2, only three (Ile339Val in MKKS, His558Arg in SCN5A, and Ser321Leu in DROSHA) are present in the carriers and not in the affected individuals, suggesting that our strategy of prioritizing based on rarity and predicted pathogenicity is appropriate. Finally, we acknowledge the possibility that more than two genes could be involved in the pathogenesis (oligogenic inheritance) or, contrarily, that environmental factors could influence the penetrance of the PKP2 variants without other genetic variants having an effect on the development of ACM. However, in our study, the main non-genetic disease modulators (age, sex, and physical exercise) are not sufficient to explain the different phenotypic expression in affected individuals and carriers in the two analyzed families (see Table 1). In Fam1, both the carrier Fam1.III.1 and the affected Fam1.III.2 are male and are close in age, and carrier Fam1.III.1 and the affected Fam1.III.3 are both physically active. In Fam2, both the affected Fam2.II.1 and the carrier Fam2.II.2 are male, physically active, and relatively close in age.