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Background Mitral valve (MV) pathology, including prolapse and regurgitation, is a well-known cardiovascular manifestation associated with the genes that predispose to Heritable Thoracic Aortic Disease (HTAD). The extent to which there are differences in prevalence, presentation and severity of MV pathology as a function of the underlying genetic cause has not been investigated in detail. Purpose Assess the prevalence, presenting features and outcome of mitral valve pathology according to the underlying genetic defect in patients with HTAD. Study design We leveraged clinical and genetic data of a large international multicenter retrospective cohort study. Probands and relatives with a validated (likely) pathogenic (LP/P) variant in 8 HTAD genes were included. Genes were categorized in 2 groups: Group 1 encoding for components of the TGFβ pathway (TGFBR1, TGFBR2, SMAD3 and TGFB2) and Group 2 encoding for proteins involved in vascular smooth muscle cell contraction (VSMC) (ACTA2, MYLK, PRKG1, MYH11). Comparison between these groups was performed. MV pathology was defined as at least moderate MV regurgitation, MV prolapse and past MV surgeries. Results A total of 459 patients. 68.8% of the patients carried a variant in one of the Group 1 genes and 31.2% had a Group 2 gene variant. 52 patients (11.3%) presented MV pathology. Significant differences in MV status according to the gene group were present: 15.5% of the patients in group 1 presented MV disease, versus 2.1% in group 2, (p Compared to patients without MV pathology, patients with MV pathology more often underwent aortic aneurysm repair (34.6% vs 15.5%, p Conclusion Patients with HTAD carrying LP/P variants in genes encoding TGFβ components present more frequently with MV pathology than patients carrying variants in genes encoding proteins involved in VSMC contraction. In the latter group, only patients carrying ACTA2 variants presented MV pathology. Patients with MV pathology are more likely to undergo aortic aneurysm repair and present less frequently with aortic dissection/rupture. Whether the presence of MV pathology accelerates the diagnosis and hence leads to a more aggressive management/stricter surveillance in these patients and/or whether biological differences between these genetic entities explain these differences requires further study. These data provide tools for developing improved, gene-tailored management of patients with HTAD. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Baillet Latour FoundationFunds for Scientific Research Flanders

Objectives To inform the design of a clinical trial of a targeted screening programme for relatives of individuals affected by thoracic aortic disease, we performed a consensus exercise as to the acceptability of screening, the optimal sequence and choice of tests, long-term patient management, and choice of trial design. Methods Working with the Aortic Dissection Awareness UK & Ireland patient association, we performed a Delphi exercise with clinical experts, patients, and carers, consisting of three rounds of consultation followed by a final multi-stakeholder face-to-face workshop. Results Thirty-five experts and 84 members of the public took part in the surveys, with 164 patients and clinicians attending the final workshop. There was substantial agreement on the need for a targeted screening pathway that would employ a combined approach (imaging + genetic testing). The target population would include the first- and second-degree adult (> 15 years) relatives, with no upper age limit of affected patients. Disagreement persisted about the screening process, sequence, personnel, the imaging method to adopt, computed tomography (CT) scan vs magnetic resonance imaging (MRI), and the specifics of a potential trial, including willingness to undergo randomisation, and measures of effectiveness and acceptability. Conclusion A Delphi process, initiated by patients, identified areas of uncertainty with respect to behaviour, process, and the design of a targeted screening programme for thoracic aortic disease that requires further research prior to any future trial.

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Experimental and animal studies, as well as genetic mutations in man, have indicated that the development of dentition is under the control of several genes. So far, mutations in MSX1 and PAX9 have been associated with dominantly inherited forms of human tooth agenesis that mainly involve posterior teeth. We identified a large kindred with several individuals affected with molar oligodontia that was transmitted as an isolated autosomal-dominant trait. Two-point linkage analysis using DNA from the family and polymorphic marker D14S288 in chromosome 14q12 produced a maximum lod score of 2.29 at theta = 0.1. Direct sequencing of exons 2 to 4 of PAX9 revealed a cytosine insertion mutation at nucleotide 793, leading to a premature termination of translation at aa 315. Our results support the conclusion that molar oligodontia is due to allelic heterogeneity in PAX9, and these data further corroborate the role of PAX9 as an important regulator of molar development.