Usefulness of PPi levels to interpret variants of unknown significance and incomplete penetrant alleles in the ABCC6 gene.

Pseudoxanthoma elasticum is usually caused by biallelic pathogenic variants in ABCC6, leading to reduced ATP transport and decreased levels of circulating calcification inhibitor inorganic pyrophosphate. Variants of unknown significance and incomplete penetrant variants complicate genetic counseling. This study assessed whether plasma pyrophosphate levels can aid in interpreting their pathogenicity or penetrance. Blood samples were collected from 90 patients, 139 carriers, and 31 healthy volunteers. Demographic, clinical, imaging, and biochemical data were collected. ABCC6 variants were classified according to Sherloc guidelines into (likely) pathogenic, variant of unknown significance, or variant with incomplete penetrance. The latter two were further classified as 'Likely causal' or 'No arguments for causality'. Participants were grouped accordingly for comparative analysis of plasma pyrophosphate levels. Plasma pyrophosphate levels were significantly decreased in patients compared to carriers and controls. However, large variability persisted within cohorts and individual families. No differences in plasma pyrophosphate levels were observed between the variant types. In carriers, no significant differences were observed between presumed penetrant versus non-penetrant variants or between presumed causal versus non-causal variants of unknown significance. Although pyrophosphate levels are reduced in patients, ABCC6 variant classification does not affect pyrophosphate levels. Our results show that plasma pyrophosphate levels have no added value for interpreting causality of variants of unknown significance or penetrance of incomplete penetrant alleles in ABCC6.