PITX2 and Arrhythmia: An upstream regulator analysis of the 179 DE genes in IPA identified significant down-regulation of PITX2 gene (FC = −2.6) in the MACE-affected sibship and dysregulated expression of its downstream targets (54 genes significantly DE between the MACE-affected and unaffected sibships), and several of them were enriched in arrhythmia (Figure 4A).