Explaining disease variability in Pseudoxanthoma elasticum and related disorders

PXE is a rare autosomal recessive ectopic mineralization disease, leading to multi-organ manifestations, including the skin, eyes and cardiovascular system. When taking into account an estimated prevalence of one in 50’000, at least 140’000 individuals are affected worldwide. This number probably is an underestimation, given the disease’s later onset and distinct clinical variability. The observed absence of strong genotype-phenotype correlations in PXE is considered a major limitation for personalized patient care. Hence, a central aim of this dissertation was to contribute to unraveling disease variability in PXE and in this way pave the way for a more personalized approach for PXE patient follow-up. In addition, PXE was used as a starting point to expand what is known about variability of related rare phenotypes and more common, complex diseases. This multi-layered approach emphasizes the relevance of rare disease research and demonstrates how this acquired knowledge can have implications at a larger scale. A first part of this dissertation focused on the identification and validation of modifier genes for the clinical manifestations of PXE. We were able to validate VEGFA as a genetic modifier for the PXE retinopathy and identify NLRP1, SELE, CSF1R and TRPV1 as candidate modifier genes for the cardiovascular phenotype. Additionally, IL1B-related signaling was suggested as a new player in the PXE pathophysiology. Further research is necessary to ascertain the clinical usefulness of these findings for patient follow-up and treatment in patient-centered translational studies. A second part was dedicated to other mechanisms to explain disease variability in PXE and GGCXrelated disorders. Our finding of germline mosaicism as a possible inheritance pattern for PXE and other autosomal recessive genodermatoses can affect patient counseling, especially preconception counseling, as it influences the recurrence risk for future children of affected couples and it is a caveat for implementation of expanded carrier screening programs in the general population. Next, we are the first to suggest genotype-phenotype correlations for GGCX-related disease phenotypes, which led to new research hypotheses and may in the future guide counseling of affected patients. A third part of this dissertation investigated ABCC6 beyond the classic PXE triad, also in more common diseases. Our finding of heterozygous pathogenic ABCC6 variants as risk factors for ischemic stroke is new evidence for the versatility of the protein and emphasizes the importance of carrier detection and follow up. We suggested a proischemic state in the brain as a possible rationale for the increased stroke risk in the presence of ABCC6 deficiency– a novel finding in PXE research – and hinted towards a potential role for soluble Endoglin as a biomarker for vascular disease in PXE, which may give rise to translational research projects. These results underline the importance of research in the field of PXE specifically and rare diseases in general, as advances will lead to a better understanding not only for rare diseases but will have an impact on common diseases, of which vascular disease is just one example. In conclusion, this work contributed to increase what is known about disease variability in PXE and related ectopic mineralization disorders and paved the way for further translational research, with an improved patient care and outcome as ultimate goal