title: Genetic abnormalities in bicuspid aortic valve root phenotype: preliminary results.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany.
authors.forename: Evaldas
authors.initials: E
authors.lastname: Girdauskas
authors.affiliation: Institute of Human Genetics, Friedrich-Schiller University Hospital Jena, Jena, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Geist
authors.affiliation: Department of Cardiac Surgery, Central Hospital Bad Berka, Bad Berka, Germany.
authors.forename: Kushtrim
authors.initials: K
authors.lastname: Disha
authors.affiliation: Department of Cardiac Surgery, Central Hospital Bad Berka, Bad Berka, Germany.
authors.forename: Iliaz
authors.initials: I
authors.lastname: Kazakbaev
authors.affiliation: Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Groß
authors.affiliation: Institute of Human Genetics, Friedrich-Schiller University Hospital Jena, Jena, Germany.
authors.forename: Solveig
authors.initials: S
authors.lastname: Schulz
authors.affiliation: Institute of Human Genetics, Friedrich-Schiller University Hospital Jena, Jena, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Ungelenk
authors.affiliation: Department of Cardiac Surgery, Central Hospital Bad Berka, Bad Berka, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kuntze
authors.affiliation: Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Reichenspurner
authors.affiliation: Institute of Human Genetics, Friedrich-Schiller University Hospital Jena, Jena, Germany.|Institute of Human Genetics, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Kurth
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001021:Aortic Valve / Q000002:abnormalities* / Q000601:surgery; D000082882:Bicuspid Aortic Valve Disease; D003430:Cross-Sectional Studies; D004247:DNA / Q000235:genetics*; D004452:Echocardiography; D005260:Female; D005500:Follow-Up Studies; D005544:Forecasting; D015723:Gene Library; D005820:Genetic Testing; D006349:Heart Valve Diseases / Q000175:diagnosis / Q000235:genetics* / Q000601:surgery; D019918:Heart Valve Prosthesis Implantation; D006801:Humans; D019028:Magnetic Resonance Imaging, Cine; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D004247:DNA
keywords: Aortopathy; Bicuspid aortic valve; Root phenotype