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

Kim L McBride1, Gloria A Zender, Sara M Fitzgerald-Butt

  • 1Center for Molecular and Human Genetics, Nationwide Children's Hospital, Department of Pediatrics, Ohio State University, Columbus, Ohio 43205, USA. Kim.McBride@NationwideChildrens.org

Birth Defects Research. Part A, Clinical and Molecular Teratology
|February 4, 2011
PubMed

Insights

Genetic analysis suggests ERBB4 is linked to left ventricular outflow tract (LVOT) defects, including aortic valve stenosis, coarctation of the aorta, and hypoplastic left heart syndrome. Further studies are needed to confirm this association in diverse populations.

Area of Science:

  • Genetics and Molecular Biology
  • Cardiovascular Research
  • Developmental Biology

Background:

  • Left ventricular outflow tract (LVOT) defects, such as aortic valve stenosis (AVS), coarctation of the aorta (COA), and hypoplastic left heart syndrome (HLHS), are common congenital cardiovascular malformations.
  • These conditions share embryological origins and lead to significant morbidity and mortality.
  • Previous research indicates a strong genetic influence on the development of LVOT defects.

Purpose of the Study:

  • To investigate the association between candidate genes in the epidermal growth factor receptor (EGFR) signaling pathway and LVOT defects.
  • To examine the roles of NRG1, ERBB3, and ERBB4 in the etiology of AVS, COA, and HLHS.
  • To explore the genetic basis of these related congenital heart conditions.

Main Methods:

  • Selection of NRG1, ERBB3, and ERBB4 as candidate genes due to their crucial role in cardiac development.
  • Single nucleotide polymorphism (SNP) genotyping was conducted on 343 affected case-parent trios of European ancestry.
  • Mutation screening and RT-PCR were performed to assess coding sequences, splice sites, and splice variant ratios.

Main Results:

  • A specific haplotype in intron 3 of ERBB4 was significantly associated with the combined LVOT defects phenotype (p=0.0005) and individual defects (AVS, COA, HLHS).
  • Mutation screening did not reveal coding or splice site alterations in ERBB4 among affected individuals.
  • RT-PCR analysis showed no altered splice variant ratios in subjects homozygous for the associated ERBB4 haplotype.

Conclusions:

  • The study suggests a significant association between ERBB4 and the development of LVOT defects.
  • The identified genetic association warrants further investigation.
  • Replication studies in independent cohorts are necessary to validate these findings and confirm the role of ERBB4.
Abstract

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