The A to B location of miRNA biogenesis 22q11.2 genes DGCR14 and DGCR8, acknowledged functional importance of this miRNA regulation of development and homeostasis, and requirement for DGCR14 and DGCR8 for nervous system and heart development establishes these two genes as prime suspects for understanding 22q11DS phenotypes and their variability. This evidence concerns the gene ESS2 and 22q11.2 deletion syndrome.