Four-generation Australian pedigree with different types of familial MPNs associated with different driver mutations. Full symbols indicate affected individuals. In this pedigree, a germ line mutation (R1569H) in the RBBP6 gene segregated with an MPN phenotype. The RBBP6 protein is a RING finger E3 ubiquitin ligase that contributes to ubiquitinate and degrade p53 in association with MDM2: mutant RBBP6 may cause an elevation in somatic mutagenesis rates through inhibition of p53 function and deregulation of cell cycle. The fact that individuals with the germ line mutation acquired somatic mutations in different genes supports the notion of genetic predisposition. Modified from Harutyunyan et al³⁹  with permission.