title: Genotype-phenotype correlation in patients with bicuspid aortic valve and aneurysm.
abstract: OBJECTIVE
  Bicuspid aortic valve is the most common congenital cardiac abnormality, occurring in 1% to 2% of the population, and often associates with ascending aortic aneurysm. Based on familial studies, bicuspid aortic valve with aneurysm segregates in an autosomal dominant manner with incomplete penetrance. NOTCH1 mutations have been reported in 6 families with prominent valve calcification and dysfunction and low penetrance of aneurysm. We sought to determine the contribution of NOTCH1 mutations to the more common phenotype of highly penetrant aneurysms with low penetrance of bicuspid aortic valve and with rare valve calcification or dysfunction.
  
  
  METHODS
  All exons and splice junctions of NOTCH1 were sequenced in probands from 13 affected families presenting with bicuspid aortic valve with ascending aortic aneurysm in the absence of valve calcification. In addition, mutation analysis was performed on a single individual with aneurysm and calcified tricuspid aortic valve. Sequences were aligned and compared with the reference genomic sequence.
  
  
  RESULTS
  Corroborating previous studies, analysis of the single sporadic patient with calcified aortic valve in the presence of ascending aortic aneurysm revealed a novel heterozygous missense mutation in NOTCH1 resulting in a nonsynonymous amino acid substitution (p.T1090S, c.C3269G) of an evolutionarily conserved residue. This change was not observed in controls. In contrast, we did not identify any pathologic NOTCH1 mutations in the 13 families segregating noncalcified bicuspid aortic valve with highly penetrant aortic aneurysm.
  
  
  CONCLUSIONS
  These data suggest that there are phenotypic differences that distinguish families with and without NOTCH1 mutations, indicating a genotype-phenotype correlation with potential implications for patient diagnosis, counseling, and management.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Kent
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Crenshaw
authors.forename: Denise L M
authors.initials: DL
authors.lastname: Goh
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
mesh_terms: D000293:Adolescent; D000328:Adult; D001014:Aortic Aneurysm / Q000150:complications* / Q000235:genetics*; D001021:Aortic Valve / Q000002:abnormalities; D000082882:Bicuspid Aortic Valve Disease; D002648:Child; D005260:Female; D056726:Genetic Association Studies; D006349:Heart Valve Diseases; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D051881:Receptor, Notch1 / Q000235:genetics*; D055815:Young Adult
chemical_list: D051881:Receptor, Notch1