biostudies-literatureRalph DNational Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMS NIH HHSe1010192https://www.ebi.ac.uk/biostudies/studies/S-EPMC9089899biostudies-literatureUnknown18(4)Pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI) are clinically distinct genetic entities of ectopic calcification associated with differentially reduced circulating levels of inorganic pyrophosphate (PPi), a potent endogenous inhibitor of calcification. Variants in ENPP1, the gene mutated in GACI, have not been associated with classic PXE. Here we report the clinical, laboratory, and molecular evaluations of ten GACI and two PXE patients from five and two unrelated families registered in GACI Global and PXE International databases, respectively. All patients were found to carry biallelic variants in ENPP1. Among ten ENPP1 variants, one homozygous variant demonstrated uniparental disomy inheritance. Functional assessment of five previously unreported PLoS geneticsENPP1 variants in patients with GACI and PXE expand the clinical and genetic heterogeneity of heritable disorders of ectopic calcification.PMC9089899R21 AR077332R01 AR072695R21AR077332R01AR072695Nitschke YLevine MARalph DUitto JRutsch FTerry SFWurst TYoussefian LSaeidian AHLi QCaffet MVahidnezhad HfalseENPP1 variants in patients with GACI and PXE expand the clinical and genetic heterogeneity of heritable disorders of ectopic calcification.Pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI) are clinically distinct genetic entities of ectopic calcification associated with differentially reduced circulating levels of inorganic pyrophosphate (PPi), a potent endogenous inhibitor of calcification. Variants in ENPP1, the gene mutated in GACI, have not been associated with classic PXE. Here we report the clinical, laboratory, and molecular evaluations of ten GACI and two PXE patients from five and two unrelated families registered in GACI Global and PXE International databases, respectively. All patients were found to carry biallelic variants in ENPP1. Among ten ENPP1 variants, one homozygous variant demonstrated uniparental disomy inheritance. Functional assessment of five previously unreported 2022-01-01T00:00:00Z2022 Apr2026-05-31T12:59:25.069Z2025-04-06T21:51:00.322ZS-EPMC90898993548284810.1371/journal.pgen.1010192