Association of common variants in ERBB4 with congenital left ventricular outflow tract obstruction defects

Kim L. Mcbride, Gloria A. Zender, Sara M. Fitzgerald-Butt, Nikki J. Seagraves, Susan D. Fernbach, Gladys Zapata, Mark Lewin, Jeffrey Towbin, John W. Belmont

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)162-168
Number of pages7
JournalBirth Defects Research Part A - Clinical and Molecular Teratology
Volume91
Issue number3
DOIs
StatePublished - Mar 1 2011
Externally publishedYes

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Hypoplastic Left Heart Syndrome
Ventricular Outflow Obstruction
Aortic Coarctation
Aortic Valve Stenosis
Haplotypes
Phenotype
Epidermal Growth Factor Receptor
Knockout Mice
Causality
Introns
Single Nucleotide Polymorphism
Morbidity
Polymerase Chain Reaction
Mutation
Mortality
Genes

All Science Journal Classification (ASJC) codes

  • Pediatrics, Perinatology, and Child Health
  • Embryology
  • Developmental Biology

Cite this

Mcbride, K. L., Zender, G. A., Fitzgerald-Butt, S. M., Seagraves, N. J., Fernbach, S. D., Zapata, G., ... Belmont, J. W. (2011). Association of common variants in ERBB4 with congenital left ventricular outflow tract obstruction defects. Birth Defects Research Part A - Clinical and Molecular Teratology, 91(3), 162-168. https://doi.org/10.1002/bdra.20764

Association of common variants in ERBB4 with congenital left ventricular outflow tract obstruction defects. / Mcbride, Kim L.; Zender, Gloria A.; Fitzgerald-Butt, Sara M.; Seagraves, Nikki J.; Fernbach, Susan D.; Zapata, Gladys; Lewin, Mark; Towbin, Jeffrey; Belmont, John W.

In: Birth Defects Research Part A - Clinical and Molecular Teratology, Vol. 91, No. 3, 01.03.2011, p. 162-168.

Research output: Contribution to journalArticle

Mcbride, KL, Zender, GA, Fitzgerald-Butt, SM, Seagraves, NJ, Fernbach, SD, Zapata, G, Lewin, M, Towbin, J & Belmont, JW 2011, 'Association of common variants in ERBB4 with congenital left ventricular outflow tract obstruction defects', Birth Defects Research Part A - Clinical and Molecular Teratology, vol. 91, no. 3, pp. 162-168. https://doi.org/10.1002/bdra.20764
Mcbride, Kim L. ; Zender, Gloria A. ; Fitzgerald-Butt, Sara M. ; Seagraves, Nikki J. ; Fernbach, Susan D. ; Zapata, Gladys ; Lewin, Mark ; Towbin, Jeffrey ; Belmont, John W. / Association of common variants in ERBB4 with congenital left ventricular outflow tract obstruction defects. In: Birth Defects Research Part A - Clinical and Molecular Teratology. 2011 ; Vol. 91, No. 3. pp. 162-168.
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