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Background: Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder with a high risk for arterial, bowel, and uterine rupture, caused by heterozygous pathogenic variants in COL3A1 . The aim of this cohort study is to provide further insights into the natural history of vEDS and describe genotype-phenotype correlations in a Dutch multicenter cohort to optimize patient care and increase awareness of the disease., Methods: Individuals with vEDS throughout the Netherlands were included. The phenotype was charted by retrospective analysis of molecular and clinical data, combined with a one-time physical examination., Results: A total of 142 individuals (50% female) participated the study, including 46 index patients (32%). The overall median age at genetic diagnosis was 41.0 years. More than half of the index patients (54.3%) and relatives (53.1%) had a physical appearance highly suggestive of vEDS. In these individuals, major events were not more frequent ( P =0.90), but occurred at a younger age ( P =0.01). A major event occurred more often and at a younger age in men compared with women ( P <0.001 and P =0.004, respectively). Aortic aneurysms ( P =0.003) and pneumothoraces ( P =0.029) were more frequent in men. Aortic dissection was more frequent in individuals with a COL3A1 variant in the first quarter of the collagen helical domain ( P =0.03)., Conclusions: Male sex, type and location of the COL3A1 variant, and physical appearance highly suggestive of vEDS are risk factors for the occurrence and early age of onset of major events. This national multicenter cohort study of Dutch individuals with vEDS provides a valuable basis for improving guidelines for the diagnosing, follow-up, and treatment of individuals with vEDS., Competing Interests: Disclosures None.

Lynch syndrome patients are susceptible to colorectal and endometrial cancers owing to inactivating germline mutations in mismatch repair genes, including MSH2 (ref. 1). Here we describe patients from Dutch and Chinese families with MSH2-deficient tumors carrying heterozygous germline deletions of the last exons of TACSTD1, a gene directly upstream of MSH2 encoding Ep-CAM. Due to these deletions, transcription of TACSTD1 extends into MSH2. The MSH2 promoter in cis with the deletion is methylated in Ep-CAM positive but not in Ep-CAM negative normal tissues, thus revealing a correlation between activity of the mutated TACSTD1 allele and epigenetic inactivation of the corresponding MSH2 allele. Gene silencing by transcriptional read-through of a neighboring gene in either sense, as demonstrated here, or antisense direction, could represent a general mutational mechanism. Depending on the expression pattern of the neighboring gene that lacks its normal polyadenylation signal, this may cause either generalized or mosaic patterns of epigenetic inactivation.

Purpose: To investigate the prevalence of unmet demands concerning autonomy and participation and to identify risk factors related to these unmet demands in patients with chronic stroke., Method: A cross-sectional study of 147 patients three years after stroke. We assessed perceived unmet care demands in relation to problems of participation and autonomy measured by the Impact on Participation and Autonomy Questionnaire (IPAQ). Socio-demographic and health characteristics were analysed as potential risk factors for the prevalence of unmet demands, using multivariate regression analysis., Results: A total of 33% of the patients perceived at least one unmet demand in one of the IPAQ subdomains. Risk factors significantly related to the presence of unmet demands were younger age, motor impairment, fatigue and depressive symptoms. Findings indicate that the model including these factors was fairly accurate in identifying patients having unmet demands and those not having unmet demands., Conclusions: Unmet care demands were present in a substantial proportion of the stroke patients. The risk factors identified are helpful for clinicians and health care providers to recognize patients who are at risk of perceiving unmet care demands and to optimize care to patients with chronic stroke.