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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

Flora Szeri, Agnes Miko, Nastassia Navasiolava, Ambrus Kaposi, Shana Verschuere (UGent) , Beatrix Molnar, Qiaoli Li, Sharon F. Terry, Federica Boraldi, Jouni Uitto, et al.
(2022) HUMAN MUTATION. 43(12). p.1872-1881
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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.
Keywords
GENERALIZED ARTERIAL CALCIFICATION, MUTATION DETECTION, GENE, MINERALIZATION, PYROPHOSPHATE, SEQUENCE, BINDING, INFANCY, CFTR, calcification, genetic diagnosis, incomplete penetrance, pseudoxanthoma, elasticum, pyrophosphate, rare disease

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MLA
Szeri, Flora, et al. “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.” HUMAN MUTATION, vol. 43, no. 12, Wiley-Hindawi, 2022, pp. 1872–81, doi:10.1002/humu.24498.
APA
Szeri, F., Miko, A., Navasiolava, N., Kaposi, A., Verschuere, S., Molnar, B., … Aranyi, T. (2022). 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. HUMAN MUTATION, 43(12), 1872–1881. https://doi.org/10.1002/humu.24498
Chicago author-date
Szeri, Flora, Agnes Miko, Nastassia Navasiolava, Ambrus Kaposi, Shana Verschuere, Beatrix Molnar, Qiaoli Li, et al. 2022. “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.” HUMAN MUTATION 43 (12): 1872–81. https://doi.org/10.1002/humu.24498.
Chicago author-date (all authors)
Szeri, Flora, Agnes Miko, Nastassia Navasiolava, Ambrus Kaposi, Shana Verschuere, Beatrix Molnar, Qiaoli Li, Sharon F. Terry, Federica Boraldi, Jouni Uitto, Koen van de Wetering, Ludovic Martin, Daniela Quaglino, Olivier Vanakker, Kalman Tory, and Tamas Aranyi. 2022. “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.” HUMAN MUTATION 43 (12): 1872–1881. doi:10.1002/humu.24498.
Vancouver
1.
Szeri F, Miko A, Navasiolava N, Kaposi A, Verschuere S, Molnar B, et al. 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. HUMAN MUTATION. 2022;43(12):1872–81.
IEEE
[1]
F. Szeri et al., “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,” HUMAN MUTATION, vol. 43, no. 12, pp. 1872–1881, 2022.
@article{01GSST1TR91WCZ3RRZ5KBRRVAX,
  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.}},
  author       = {{Szeri, Flora and  Miko, Agnes and  Navasiolava, Nastassia and  Kaposi, Ambrus and Verschuere, Shana and  Molnar, Beatrix and  Li, Qiaoli and  Terry, Sharon F. and  Boraldi, Federica and  Uitto, Jouni and  van de Wetering, Koen and  Martin, Ludovic and  Quaglino, Daniela and Vanakker, Olivier and  Tory, Kalman and  Aranyi, Tamas}},
  issn         = {{1059-7794}},
  journal      = {{HUMAN MUTATION}},
  keywords     = {{GENERALIZED ARTERIAL CALCIFICATION,MUTATION DETECTION,GENE,MINERALIZATION,PYROPHOSPHATE,SEQUENCE,BINDING,INFANCY,CFTR,calcification,genetic diagnosis,incomplete penetrance,pseudoxanthoma,elasticum,pyrophosphate,rare disease}},
  language     = {{eng}},
  number       = {{12}},
  pages        = {{1872--1881}},
  publisher    = {{Wiley-Hindawi}},
  title        = {{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}},
  url          = {{http://doi.org/10.1002/humu.24498}},
  volume       = {{43}},
  year         = {{2022}},
}
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