Since PKP2 is relevant for the development of ACM in both families, we assumed that the second unknown gene is directly related to PKP2 . Following the probable mechanisms of digenic inheritance described by Cooper et al. , a set of PKP2-related genes was compiled based on the following five criteria. (i) The two gene products form a protein complex. Gene complex data were downloaded from the BioPlex database  version 4. Genes that interacted with PKP2 with a confidence of at least 0.7 were selected. (ii) The two gene products interact functionally. PKP2 interactors were downloaded from the STRING database  version 10 and the mentha database  version 2016–08-07. STRING interactions were restricted to those with a confidence of at least 0.7. The union of PKP2 interactors from the two databases was selected. (iii) The two gene products are transcription factor and target gene. The Ensembl database  version 84 and ORegAnno database  (release 2015.12.22) were manually reviewed for transcription factors of PKP2. (iv) The two gene products participate in the same pathway. “Biological process” (BP) gene annotations from the Gene Ontology  (GO) were used as an approximation. All biological process annotations of PKP2 and all their annotated proteins were queried from the GO database version 2016.7 using the Dintor GOAnnotator tool . Processes were restricted to those where at least half of their annotated genes were expressed in the heart and all genes annotated to these processes were selected, creating a set of genes that share a biological function with PKP2. (v) The two genes are paralogs. Though not specifically listed as a mechanism of digenic inheritance, Cooper et al. discussed that paralogous genes might provide a level of redundancy by resuming gene function in case of a disruption . Therefore, genes paralogous to PKP2 were queried from Ensembl 86.