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Purpose: Vascular Ehlers-Danlos syndrome (vEDS) is a rare inherited autosomal dominant disorder caused by COL3A1 pathogenic variants. A high percentage of de novo cases has been suggested. Part of it could be due to parental mosaicism, but its frequency is unknown., Methods: This retrospective study included a large series of COL3A1-confirmed vEDS probands with family information. The frequency of de novo cases was evaluated and the distribution of the type of variants was compared according to the mode of inheritance. The COL3A1 mosaicism was studied by deep targeted next- generation sequencing (NGS) from parental blood DNA., Results: Out of 177 vEDS probands, 90 had a negative family history, suggesting a high rate (50.8%) of de novo pathogenic variants, enriched in the more severe COL3A1 variants (no null variant). Among those, both parental DNA were available in 36 cases and one parental DNA in 18 cases. NGS detected only one mosaicism from maternal blood DNA (allelic ratio 18%), which was confirmed in saliva (allelic ratio 22%)., Conclusion: vEDS is characterized by a high frequency of de novo pathogenic variants. Parental mosaicism is rare (2-3%), but should be systematically searched with targeted NGS, taking into account its importance in genetic counseling.

Purpose: Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder caused by variants in the ABCC6 gene. Ectopic mineralization of connective tissues leads to skin, eye, and cardiovascular manifestations with considerable phenotypic variability of unknown cause. We aimed to identify genotype-phenotype correlations in PXE., Methods: A molecular analysis was performed on 458 French PXE probands clinically evaluated using the Phenodex score (PS). Variant topographic analysis and genotype-phenotype correlation analysis were performed according to the number and type of identified variants., Results: Complete molecular analysis of 306 cases allowed the identification of 538 mutational events (88% detection rate) with 142 distinct variants, of which 66 were novel. Missense variant distribution was specific to some regions and residues of ABCC6. For the 220 cases with a complete PS, there was a higher prevalence of eye features in Caucasian patients (P = 0.03) and more severe eye and vascular phenotype in patients with loss-of-function variants (P = 0.02 and 0.05, respectively). Nephrolithiases and strokes, absent from the PS, were prevalent features of the disorder (11 and 10%, respectively)., Conclusion: We propose an updated PS including renal and neurological features and adaptation of follow-up according to the genetic and ethnic status of PXE-affected patients.Genet Med advance online publication 19 January 2017.