Rare Modifier Variants Alter the Severity of Cardiovascular Disease in Pseudoxanthoma Elasticum: Identification of Novel Candidate Modifier Genes and Disease Pathways Through Mixture of Effects Analysis.

Pseudoxanthoma elasticum (PXE), an ectopic mineralization disorder caused by pathogenic variants, is characterized by skin, ocular and cardiovascular (CV) symptoms. Due to striking phenotypic variability without genotype-phenotype correlations, modifier genes are thought to play a role in disease variability. In this study, we evaluated the collective modifying effect of rare variants on the cardiovascular phenotype of PXE.

VEGFA variants as prognostic markers for the retinopathy in pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive ectopic mineralization disorder, characterized by skin, eye and cardiovascular symptoms. The most devastating ocular complication is choroidal neovascularization, which is thought to be mediated by vascular endothelial growth factor (VEGF) signaling, a molecule encoded by the VEGFA gene. As early detection and treatment is essential to preserve vision, prioritization of patients at risk is crucial, but impossible because of wide phenotypic variability and a lack of genotype-phenotype correlations for PXE.

Pathogenic variants in the ABCC6 gene are associated with an increased risk for ischemic stroke.

Ischemic stroke causes a high mortality and morbidity worldwide. It results from a complex interplay of incompletely known environmental and genetic risk factors. We investigated the ABCC6 gene as a candidate risk factor for ischemic stroke because of the increased ischemic stroke incidence in the autosomal recessive disorder pseudoxanthoma elasticum, caused by biallelic pathogenic ABCC6 variants, the higher cardiovascular risk in heterozygous carriers and the established role of ABCC6 dysfunction in myocardial ischemia.

GGCX-Associated Phenotypes: An Overview in Search of Genotype-Phenotype Correlations.

Gamma-carboxylation, performed by gamma-glutamyl carboxylase (GGCX), is an enzymatic process essential for activating vitamin K-dependent proteins (VKDP) with important functions in various biological processes. Mutations in the encoding gene are associated with multiple phenotypes, amongst which vitamin K-dependent coagulation factor deficiency (VKCFD1) is best known. Other patients have skin, eye, heart or bone manifestations.

The ABCC6 Transporter as a Paradigm for Networking from an Orphan Disease to Complex Disorders.

The knowledge on the genetic etiology of complex disorders largely results from the study of rare monogenic disorders. Often these common and rare diseases show phenotypic overlap, though monogenic diseases generally have a more extreme symptomatology. ABCC6, the gene responsible for pseudoxanthoma elasticum, an autosomal recessive ectopic mineralization disorder, can be considered a paradigm gene with relevance that reaches far beyond this enigmatic orphan disease.