Several paralogue pairs exist within the ERN including ARID1A/ARID1B, CREBBP/EP300, KAT2A/KAT2B, and SUV39H1/SUV39H2, and while loss of one paralogue is tolerated—and in fact often selected for in cancer [16]—the combined loss of the gene pair has deleterious effects of varying magnitude, depending on context [13, 17–20]. The gene discussed is ARID1A; the disease is cancer.