PURPOSE: 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. METHODS: 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. RESULTS: 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%)). CONCLUSION: 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.
PURPOSE: 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. METHODS: 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. RESULTS: 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%)). CONCLUSION: 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: Luika A Timmerman; Joaquín Grego-Bessa; Angel Raya; Esther Bertrán; José María Pérez-Pomares; Juan Díez; Sergi Aranda; Sergio Palomo; Frank McCormick; Juan Carlos Izpisúa-Belmonte; José Luis de la Pompa Journal: Genes Dev Date: 2003-12-30 Impact factor: 11.361
Authors: Frances A High; Maozhen Zhang; Aaron Proweller; Lili Tu; Michael S Parmacek; Warren S Pear; Jonathan A Epstein Journal: J Clin Invest Date: 2007-02 Impact factor: 14.808
Authors: Jennifer C Hirsch; Glenn Copeland; Janet E Donohue; Russell S Kirby; Violanda Grigorescu; James G Gurney Journal: J Pediatr Date: 2011-02-24 Impact factor: 4.406
Authors: Hector I Michelena; Amber D Khanna; Douglas Mahoney; Edit Margaryan; Yan Topilsky; Rakesh M Suri; Ben Eidem; William D Edwards; Thoralf M Sundt; Maurice Enriquez-Sarano Journal: JAMA Date: 2011-09-14 Impact factor: 56.272
Authors: Kim L McBride; Ricardo Pignatelli; Mark Lewin; Trang Ho; Susan Fernbach; Andres Menesses; Wilbur Lam; Suzanne M Leal; Norman Kaplan; Paul Schliekelman; Jeffrey A Towbin; John W Belmont Journal: Am J Med Genet A Date: 2005-04-15 Impact factor: 2.802
Authors: Constance Th R M Schrander-Stumpel; Liesbeth Spruyt; Leopold M G Curfs; Truus Defloor; Jaap J P Schrander Journal: Am J Med Genet A Date: 2005-01-30 Impact factor: 2.802
Authors: Mary Ella Pierpont; Craig T Basson; D Woodrow Benson; Bruce D Gelb; Therese M Giglia; Elizabeth Goldmuntz; Glenn McGee; Craig A Sable; Deepak Srivastava; Catherine L Webb Journal: Circulation Date: 2007-05-22 Impact factor: 29.690
Authors: M Iascone; R Ciccone; L Galletti; D Marchetti; F Seddio; A R Lincesso; L Pezzoli; A Vetro; D Barachetti; L Boni; D Federici; A M Soto; J V Comas; P Ferrazzi; O Zuffardi Journal: Clin Genet Date: 2011-04-25 Impact factor: 4.438
Authors: Emmi Helle; Aldo Córdova-Palomera; Tiina Ojala; Priyanka Saha; Praneetha Potiny; Stefan Gustafsson; Erik Ingelsson; Michael Bamshad; Deborah Nickerson; Jessica X Chong; Euan Ashley; James R Priest Journal: Genet Epidemiol Date: 2018-12-04 Impact factor: 2.135
Authors: Mary Ella Pierpont; Martina Brueckner; Wendy K Chung; Vidu Garg; Ronald V Lacro; Amy L McGuire; Seema Mital; James R Priest; William T Pu; Amy Roberts; Stephanie M Ware; Bruce D Gelb; Mark W Russell Journal: Circulation Date: 2018-11-20 Impact factor: 29.690
Authors: Christina V Theodoris; Foteini Mourkioti; Yu Huang; Sanjeev S Ranade; Lei Liu; Helen M Blau; Deepak Srivastava Journal: J Clin Invest Date: 2017-03-27 Impact factor: 14.808
Authors: Patrick Y Jay; Ehiole Akhirome; Rachel A Magnan; M Rebecca Zhang; Lillian Kang; Yidan Qin; Nelson Ugwu; Suk Dev Regmi; Julie M Nogee; James M Cheverud Journal: Mol Cell Endocrinol Date: 2016-08-20 Impact factor: 4.102
Authors: Gavin Chapman; Julie L M Moreau; Eddie I P; Justin O Szot; Kavitha R Iyer; Hongjun Shi; Michelle X Yam; Victoria C O'Reilly; Annabelle Enriquez; Joelene A Greasby; Dimuthu Alankarage; Ella M M A Martin; Bernadette C Hanna; Matthew Edwards; Steven Monger; Gillian M Blue; David S Winlaw; Helen E Ritchie; Stuart M Grieve; Eleni Giannoulatou; Duncan B Sparrow; Sally L Dunwoodie Journal: Hum Mol Genet Date: 2020-03-13 Impact factor: 6.150