Each family’s gene set was filtered to only include genes expressed in the heart. The RNA gene dataset was downloaded from the ProteinAtlas  version 15, which contains gene expression levels of 45 cell lines and 32 tissues based on RNA-seq. A gene was considered expressed in the heart, if it had an expression level of at least 5 FPKM in the heart muscle in this dataset. We call the genes/variants determined by these filtering steps Fam1 genes/variants and Fam2 genes/variants. This gene selection is visualized in Fig. 2.Fig. 2Methods summary. Whole exome sequencing and variant calling was performed for each individual in both families. For each family, genes are selected that have at least one variant with a high or moderate variant impact, that differ between healthy and affected PKP2 carriers, that have a coverage of at least 10X, and that are expressed in the heart. These genes are filtered to include only genes related to ACM or PKP2 and are computationally prioritized. Results are presented in Table 2