The pathogenic p.(R391G) ABCC6 displays incomplete penetrance implying the necessity of an interacting partner for the development of pseudoxanthoma elasticum

ABCC6 promotes the efflux of ATP from hepatocytes to the bloodstream. ATP is then cleaved to AMP and pyrophosphate, a major inhibitor of ectopic calcification. Pathogenic variants of ABCC6 cause pseudoxanthoma elasticum, a recessive ectopic calcification disease of highly variable severity. One of the mechanisms influencing the heterogeneity of a disorder is the penetrance of pathogenic variants. Penetrance shows the proportion of carriers developing the phenotype; hence incomplete penetrance indicates that the disease does not necessarily develop in the presence of specific variants. Here, we investigated whether incomplete penetrance contributes to the heterogeneity of pseudoxanthoma elasticum. By integrating the clinical and genetic data of 589 patients, we created the largest European cohort. Based on allele frequencies compared to a reference cohort, we identified two incomplete penetrant variants, p.V787I and p.R391G, 6.5% and 2% penetrance, respectively. The characterization of the p.R391G variant suggested unaltered severity of the clinical phenotype. Based on our biochemical and localization studies, we hypothesize that the variant becomes deleterious only if an interacting partner is mutated simultaneously. Our data reveal the potential existence of the first interacting partner of ABCC6. Our data are also important for genetic counseling, as they suggest lower disease heritability of some variants.