We propose the 10 NPX genes—five of which have divergent NPY homologs—as potential drivers of (1) differences in health and disease between 46,XY and 46,XX cohorts and (2) the distinctive phenotypes associated with sex chromosome aneuploidies, including Turner syndrome (45,X) and Klinefelter syndrome (47,XXY). Here, NPY is linked to Klinefelter syndrome.