BACKGROUND: The left ventricular outflow tract (LVOT) defects aortic valve stenosis (AVS), coarctation of the aorta (COA), and hypoplastic left heart syndrome (HLHS) represent an embryologically related group of congenital cardiovascular malformations. They are common and cause substantial morbidity and mortality. Prior evidence suggests a strong genetic component in their causation. METHODS: We selected NRG1, ERBB3, and ERBB4 of the epidermal growth factor receptor (EGFR) signaling pathway as candidate genes for investigation of association with LVOT defects based on the importance of this pathway in cardiac development and the phenotypes in knockout mouse models. Single nucleotide polymorphism (SNP) genotyping was performed on 343 affected case-parent trios of European ancestry. RESULTS: We identified a specific haplotype in intron 3 of ERBB4 that was positively associated with the combined LVOT defects phenotype (p=0.0005) and in each anatomic defect AVS, COA, and HLHS separately. Mutation screening of individuals with an LVOT defect failed to identify a coding sequence or splice site change in ERBB4. RT-PCR on lymphoblastoid cells from LVOT subjects did not show altered splice variant ratios among those homozygous for the associated haplotype. CONCLUSION: These results suggest ERBB4 is associated with LVOT defects. Further replication will be required in separate cohorts to confirm the consistency of the observed association.
BACKGROUND: The left ventricular outflow tract (LVOT) defects aortic valve stenosis (AVS), coarctation of the aorta (COA), and hypoplastic left heart syndrome (HLHS) represent an embryologically related group of congenital cardiovascular malformations. They are common and cause substantial morbidity and mortality. Prior evidence suggests a strong genetic component in their causation. METHODS: We selected NRG1, ERBB3, and ERBB4 of the epidermal growth factor receptor (EGFR) signaling pathway as candidate genes for investigation of association with LVOT defects based on the importance of this pathway in cardiac development and the phenotypes in knockout mouse models. Single nucleotide polymorphism (SNP) genotyping was performed on 343 affected case-parent trios of European ancestry. RESULTS: We identified a specific haplotype in intron 3 of ERBB4 that was positively associated with the combined LVOT defects phenotype (p=0.0005) and in each anatomic defect AVS, COA, and HLHS separately. Mutation screening of individuals with an LVOT defect failed to identify a coding sequence or splice site change in ERBB4. RT-PCR on lymphoblastoid cells from LVOT subjects did not show altered splice variant ratios among those homozygous for the associated haplotype. CONCLUSION: These results suggest ERBB4 is associated with LVOT defects. Further replication will be required in separate cohorts to confirm the consistency of the observed association.
Authors: Paul Hardenbol; Johan Banér; Maneesh Jain; Mats Nilsson; Eugeni A Namsaraev; George A Karlin-Neumann; Hossein Fakhrai-Rad; Mostafa Ronaghi; Thomas D Willis; Ulf Landegren; Ronald W Davis Journal: Nat Biotechnol Date: 2003-05-05 Impact factor: 54.908
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Authors: Kim L McBride; Maurisa F Riley; Gloria A Zender; Sara M Fitzgerald-Butt; Jeffrey A Towbin; John W Belmont; Susan E Cole Journal: Hum Mol Genet Date: 2008-06-30 Impact factor: 6.150
Authors: Laura E Mitchell; A J Agopian; Angela Bhalla; Joseph T Glessner; Cecilia E Kim; Michael D Swartz; Hakon Hakonarson; Elizabeth Goldmuntz Journal: Hum Mol Genet Date: 2014-08-18 Impact factor: 6.150
Authors: Cammon B Arrington; Steven B Bleyl; Norisada Matsunami; Gabriel D Bonnell; Brith E M Otterud; Douglas C Nielsen; Jeffrey Stevens; Shawn Levy; Mark F Leppert; Neil E Bowles Journal: Circ Cardiovasc Genet Date: 2012-02-15
Authors: Neil A Hanchard; Shanker Swaminathan; Kristine Bucasas; Dieter Furthner; Susan Fernbach; Mahshid S Azamian; Xueqing Wang; Mark Lewin; Jeffrey A Towbin; Lisa C A D'Alessandro; Shaine A Morris; William Dreyer; Susan Denfield; Nancy A Ayres; Wayne J Franklin; Henri Justino; M Regina Lantin-Hermoso; Elena C Ocampo; Alexia B Santos; Dhaval Parekh; Douglas Moodie; Aamir Jeewa; Emily Lawrence; Hugh D Allen; Daniel J Penny; Charles D Fraser; James R Lupski; Mojisola Popoola; Lalita Wadhwa; J David Brook; Frances A Bu'Lock; Shoumo Bhattacharya; Seema R Lalani; Gloria A Zender; Sara M Fitzgerald-Butt; Jessica Bowman; Don Corsmeier; Peter White; Kelsey Lecerf; Gladys Zapata; Patricia Hernandez; Judith A Goodship; Vidu Garg; Bernard D Keavney; Suzanne M Leal; Heather J Cordell; John W Belmont; Kim L McBride Journal: Hum Mol Genet Date: 2016-03-09 Impact factor: 6.150