Of the four PKP2-related Fam1 genes, the genes homologous to DAG1, TCF25, and CTBP2 have been linked to cardiomyocyte proliferation or heart development in mice and, in case of TCF25, also in human. DAG1 and TCF25 negatively regulate heart development, while a knock out of CTBP2 leads to a lethal malformation of the heart in mice. A variant in DAB2IP has been associated with coronary heart disease in two studies, indicating that this gene might also play a crucial rule for the normal functioning of the heart. It has been reported that β-dystroglycan, a protein product of DAG1, directly binds to the Hippo pathway effector Yap to inhibit cardiomyocyte proliferation in mice . In particular, the Hippo pathway and DGC cooperatively regulate tissue growth in mouse hearts after injury. Yap and the Hippo pathway have been directly implicated in ACM pathogenesis . TCF25 (previously named NULP1) was suggested as a transcription factor that negatively regulates the serum response factor (SRF). SRF controls muscle differentiation and cellular growth and regulates cardiac genes. SRF over-expression has been shown to cause cardiomyopathy and cardiac hypertrophy in mice. Therefore, TCF25 may function as a transcriptional repressor of SRF in human heart development . DAB2IP acts as a tumor suppressor gene, and is inactivated by methylation in prostate and breast cancers. A genome-wide association study found the rs7025486 variant in DAB2IP associated with coronary heart disease, which was replicated in a second study . CTBP2 encodes two proteins, a transcriptional repressor and a major component of synaptic ribbons. Silencing the homologous Ctbp2 gene in mice causes defects in heart morphogenesis and results in early embryonic lethality . Ctbp2-null mice show similar axial truncation phenotypes as mice with mutations in some Wnt target genes, suggesting that CTBP2 may be a regulator of Wnt-mediated gene expression . Indeed, CtBP2 acts as corepressor of C/EBPα, an early regulator of adipogenesis, and target of the Wnt signaling pathway . Furthermore, Sox6 has been found to bind Ctbp2 to repress the fibroblast growth factor 3  and Sox6 to regulate the cardiac myocyte development in mice . Although none of the variants in these four genes are predicted to be deleterious and the variant in DAG1 is even predicted to stabilize protein structure, they could nevertheless affect protein stability, flexibility, and interaction with the other binding partners. However, in the present study we could not find any indication that these genes may act together with PKP2 to cause the ACM phenotype in the affected individuals of Fam1.