The pathogenic c.1171A>G (p.Arg391Gly) and c.2359G>A (p.Val787Ile) ABCC6 variants display incomplete penetrance causing pseudoxanthoma elasticum in a subset of individuals. Issue 12 (15th November 2022)

• Record Type: Journal Article
• Authors: Szeri, Flora; Miko, Agnes; Navasiolava, Nastassia; Kaposi, Ambrus; Verschuere, Shana; Molnar, Beatrix; Li, Qiaoli; Terry, Sharon F.; Boraldi, Federica; Uitto, Jouni; van de Wetering, Koen; Martin, Ludovic; Quaglino, Daniela; Vanakker, Olivier M.; Tory, Kalman; Aranyi, Tamas
• Is Part Of: Human mutation. Volume 43:Issue 12(2022)
• Page Start: 1872
• Page End: 1881
• Publication Date: 2022-11-15
• Subjects: calcification -- genetic diagnosis -- incomplete penetrance -- pseudoxanthoma elasticum -- pyrophosphate -- rare disease; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.24498
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: ABCC6 promotes ATP efflux from hepatocytes to bloodstream. ATP is metabolized to pyrophosphate, an inhibitor of ectopic calcification. Pathogenic variants of ABCC6 cause pseudoxanthoma elasticum, a highly variable recessive ectopic calcification disorder. Incomplete penetrance may initiate disease heterogeneity, hence symptoms may not, or differently manifest in carriers. Here, we investigated whether incomplete penetrance is a source of heterogeneity in pseudoxanthoma elasticum. By integrating clinical and genetic data of 589 patients, we created the largest European cohort. Based on allele frequency alterations, we identified two incomplete penetrant pathogenic variants, c.2359G>A (p.Val787Ile) and c.1171A>G (p.Arg391Gly), with 6.5% and 2% penetrance, respectively. However, when penetrant, the c.1171A>G (p.Arg391Gly) manifested a clinically unaltered severity. After applying in silico and in vitro characterization, we suggest that incomplete penetrant variants are only deleterious if a yet unknown interacting partner of ABCC6 is mutated simultaneously. The low penetrance of these variants should be contemplated in genetic counseling.