👤 Lisa Geist

Genetic defects associated with bicuspid aortopathy have been infrequently analysed. Our goal was to examine the prevalence of rare genetic variants in patients with a bicuspid aortic valve (BAV) with a root phenotype using next-generation sequencing technology. We investigated a total of 124 patients with BAV with a root dilatation phenotype who underwent aortic valve ± proximal aortic surgery at a single institution (BAV database, n  = 812) during a 20-year period (1995-2015). Cross-sectional follow-up revealed 63 (51%) patients who were still alive and willing to participate. Systematic follow-up visits were scheduled from March to December 2015 and included aortic imaging as well as peripheral blood sampling for genetic testing. Next-generation sequencing libraries were prepared using a custom-made HaloPlex HS gene panel and included 20 candidate genes known to be associated with aortopathy and BAV. The primary end-point was the prevalence of genetic defects in our study cohort. A total of 63 patients (mean age 46 ± 10 years, 92% men) with BAV root phenotype and mean post-aortic valve replacement follow-up of 10.3 ± 4.9 years were included. Our genetic analysis yielded a wide spectrum of rare, potentially or likely pathogenic variants in 19 (30%) patients, with NOTCH1 variants being the most common ( n  = 6). Moreover, deleterious variants were revealed in AXIN1 ( n  = 3), NOS3 ( n  = 3), ELN ( n  = 2), FBN1 ( n  = 2) , FN1 ( n  = 2) and rarely in other candidate genes. Our preliminary study demonstrates a high prevalence and a wide spectrum of rare genetic variants in patients with the BAV root phenotype, indicative of the potentially congenital origin of associated aortopathy in this specific BAV cohort. Show less

Myosin Binding Protein-C (MyBP-C) comprises a family of accessory proteins that includes the cardiac, slow skeletal, and fast skeletal isoforms. The three isoforms share structural and sequence homology, and localize at the C-zone of the sarcomeric A-band where they interact with thick and thin filaments to regulate the cycling of actomyosin crossbridges. The cardiac isoform, encoded by MYBPC3, has been extensively studied over the last several decades due to its high mutational rate in congenital hypertrophic and dilated cardiomyopathy. It is only recently, however, that the MYBPC1 gene encoding the slow skeletal isoform (sMyBP-C) has gained attention. Accordingly, during the last 5 years it has been shown that MYBPC1 undergoes extensive exon shuffling resulting in the generation of multiple slow variants, which are co-expressed in different combinations and amounts in both slow and fast skeletal muscles. The sMyBP-C variants are subjected to PKA- and PKC-mediated phosphorylation in constitutive and alternatively spliced sites. More importantly, missense, and nonsense mutations in MYBPC1 have been directly linked with the development of severe and lethal forms of distal arthrogryposis myopathy and muscle tremors. Currently, there is no mammalian animal model of sMyBP-C, but new technologies including CRISPR/Cas9 and xenografting of human biopsies into immunodeficient mice could provide unique ways to study the regulation and roles of sMyBP-C in health and disease. Show less