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

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.

Figure 1

Negative log p value of genotyped markers in the ERBB4 gene plotted by genomic position on chromosome 2. Exon (vertical bars) and intron structure of ERBB4 is indicated at the top of the figure. Single nucleotide polymorphism markers with a nominally significant result are labeled with their reference numbers. SNPs in Haplotype block 5 (position indicated by horizontal bar at top of plot) are represented by the ‘X’ symbol.