Model of the role of germline vs somatic mutation of USP9X in leukemia development. In the germline, males do not tolerate LoF variants, presumably because of embryonic cells without any USP9X function. Males with hypomorphic missense variants have neurodevelopmental phenotypes with no reported B-ALL risk. Female embryos with germline LoF variants will contain a mixture of near normal USP9X levels from cells with expression from the nonmutant X and cells with small amount of USP9X from the nonmutant inactive X. They present with severe congenital anomalies, intellectual disability, and an increased risk of B-ALL. In sporadic B-ALL, somatic LoF mutations are seen in samples from both sexes.