Using whole exome sequencing of extreme phenotypes and mixture of effects analyses, SKAT-O and C-alpha, a panel of 86 novel candidate modifier genes were identified, among which four candidate genes, i.e., NLRP1, SELE, CSF1R, and TRPV1, could be prioritized for the cardiovascular phenotype of PXE. Here, NLRP1 is linked to pseudoxanthoma elasticum (inherited or acquired).