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The pathogenic c.1171AG (p.Arg391Gly) and c.2359GA (p.Val787Ile) ABCC6 variants display incomplete penetrance causing pseudoxanthoma elasticum in a subset of individuals
- Source :
- HUMAN MUTATION
- Publication Year :
- 2022
-
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.
- Subjects :
- pyrophosphate
incomplete penetrance
Biology and Life Sciences
rare disease
GENE
SEQUENCE
calcification
MUTATION DETECTION
pseudoxanthoma
genetic diagnosis
BINDING
Medicine and Health Sciences
INFANCY
Genetics
pseudoxanthoma elasticum
CFTR
elasticum
GENERALIZED ARTERIAL CALCIFICATION
MINERALIZATION
Genetics (clinical)
Subjects
Details
- ISSN :
- 10981004 and 10597794
- Database :
- OpenAIRE
- Journal :
- Human mutationREFERENCES
- Accession number :
- edsair.doi.dedup.....00e67013d39a32d8b60c1cbda932675a