title: Cardiovascular malformations caused by NOTCH1 mutations do not keep left: data on 428 probands with left-sided CHD and their families.
abstract: We aimed to determine the prevalence and phenotypic spectrum of NOTCH1 mutations in left-sided congenital heart disease (LS-CHD). LS-CHD includes aortic valve stenosis, a bicuspid aortic valve, coarctation of the aorta, and hypoplastic left heart syndrome.
  
  
  
  NOTCH1 was screened for mutations in 428 nonsyndromic probands with LS-CHD, and family histories were obtained for all. When a mutation was detected, relatives were also tested.
  
  
  
  In 148/428 patients (35%), LS-CHD was familial. Fourteen mutations (3%; 5 RNA splicing mutations, 8 truncating mutations, 1 whole-gene deletion) were detected, 11 in familial disease (11/148 (7%)) and 3 in sporadic disease (3/280 (1%)). Forty-nine additional mutation carriers were identified among the 14 families, of whom 12 (25%) were asymptomatic. Most of these mutation carriers had LS-CHD, but 9 (18%) had right-sided congenital heart disease (RS-CHD) or conotruncal heart disease (CTD). Thoracic aortic aneurysms (TAAs) occurred in 6 mutation carriers (probands included 6/63 (10%)).
  
  
  
  Pathogenic mutations in NOTCH1 were identified in 7% of familial LS-CHD and in 1% of sporadic LS-CHD. The penetrance is high; a cardiovascular malformation was found in 75% of NOTCH1 mutation carriers. The phenotypic spectrum includes LS-CHD, RS-CHD, CTD, and TAA. Testing NOTCH1 for an early diagnosis in LS-CHD/RS-CHD/CTD/TAA is warranted.Genet Med 18 9, 914-923.
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Wilhelmina S
authors.identifier: 0000-0003-2528-2203
authors.initials: WS
authors.lastname: Kerstjens-Frederikse
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Ingrid M B H
authors.initials: IM
authors.lastname: van de Laar
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Yvonne J
authors.initials: YJ
authors.lastname: Vos
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Judith M A
authors.initials: JM
authors.lastname: Verhagen
authors.affiliation: Center for Congenital Heart Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Rolf M F
authors.initials: RM
authors.lastname: Berger
authors.affiliation: Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Klaske D
authors.initials: KD
authors.lastname: Lichtenbelt
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Jolien S
authors.initials: JS
authors.lastname: Klein Wassink-Ruiter
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Paul A
authors.initials: PA
authors.lastname: van der Zwaag
authors.affiliation: Center for Congenital Heart Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Gideon J
authors.initials: GJ
authors.lastname: du Marchie Sarvaas
authors.affiliation: Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Klasien A
authors.initials: KA
authors.lastname: Bergman
authors.affiliation: Department of Obstetrics and Gynaecology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Catia M
authors.initials: CM
authors.lastname: Bilardo
authors.affiliation: Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Jolien W
authors.initials: JW
authors.lastname: Roos-Hesselink
authors.affiliation: Department of Cardiology, Saint Anna Hospital, Geldrop, The Netherlands.
authors.forename: Johan H P
authors.initials: JH
authors.lastname: Janssen
authors.affiliation: Department of Pediatric Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Frohn-Mulder
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Karin Y
authors.initials: KY
authors.lastname: van Spaendonck-Zwarts
authors.affiliation: Center for Congenital Heart Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Joost P
authors.initials: JP
authors.lastname: van Melle
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.|Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.|Neural Development and Gastroenterology Units, University College London Institute of Child Health, London, UK.
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: M W
authors.initials: MW
authors.lastname: Wessels
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001011:Aorta / Q000503:physiopathology; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000503:physiopathology; D006333:Heart Failure / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D018636:Hypoplastic Left Heart Syndrome / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D051881:Receptor, Notch1 / Q000235:genetics*
chemical_list: C497761:NOTCH1 protein, human; D051881:Receptor, Notch1
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