title: Variants in the NOTCH1 gene in patients with aortic coarctation.
abstract: OBJECTIVE
  Malformations of the left ventricular outflow tract are one of the most common forms of congenital heart disorders. Recently, it has been shown that mutations in the NOTCH1 gene can lead to bicuspid aortic valve, aortic aneurysm, and hypoplastic left heart syndrome. The aim of our study was to estimate the frequency of NOTCH1 gene mutations/substitutions in patients with aortic coarctation, isolated or combined with bicuspid aortic valve.
  
  
  METHODS
  The study included 51 children with coarctation. Detailed family history was obtained for every study subject, and echocardiographic data were obtained for the relatives when available. We applied a strategy of targeted mutation screening for 10 out of 34 exons of the NOTCH1 gene by direct sequencing. Control DNA was obtained from 200 healthy donors.
  
  
  RESULTS
  In more than half of the cases, coarctation was combined with bicuspid aortic valve, and in approximately half of the cases, it was combined with hypoplasia of the aortic arch or descending aorta. Familial history of congenital heart disease was observed in 34.3% of the cases. In total, 29 variants of the NOTCH1 gene were identified in the patient group and in the control subjects. Four of those variants led to amino acid exchange, of which only one, R1279H, was identified in both the patient group and in the controls. This variant was significantly overrepresented in the patients with aortic coarctation compared with those in the control group (P < .05). We conclude that the R1279H substitution in the NOTCH1 gene is significantly overrepresented in patients with aortic coarctation and, therefore, may represent a disease-susceptibility allele.
authors.affiliation: Almazov Federal Heart, Blood and Endocrinology Center, St. Petersburg, Russia.
authors.forename: Olga
authors.initials: O
authors.lastname: Freylikhman
authors.forename: Tatyana
authors.initials: T
authors.lastname: Tatarinova
authors.forename: Natalia
authors.initials: N
authors.lastname: Smolina
authors.forename: Sergey
authors.initials: S
authors.lastname: Zhuk
authors.forename: Alexandra
authors.initials: A
authors.lastname: Klyushina
authors.forename: Artem
authors.initials: A
authors.lastname: Kiselev
authors.forename: Olga
authors.initials: O
authors.lastname: Moiseeva
authors.forename: Gunnar
authors.initials: G
authors.lastname: Sjoberg
authors.forename: Anna
authors.initials: A
authors.lastname: Malashicheva
authors.forename: Anna
authors.initials: A
authors.lastname: Kostareva
mesh_terms: D000015:Abnormalities, Multiple; D000293:Adolescent; D001017:Aortic Coarctation / Q000175:diagnosis / Q000235:genetics*; D001021:Aortic Valve / Q000002:abnormalities; D000082882:Bicuspid Aortic Valve Disease; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006349:Heart Valve Diseases / Q000175:diagnosis / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010641:Phenotype; D051881:Receptor, Notch1 / Q000235:genetics*
chemical_list: C497761:NOTCH1 protein, human; D051881:Receptor, Notch1
keywords: Aortic Coarctation; Bicuspid Aortic Valve; Genetic Variant; NOTCH1