Abstract
Conotruncal defects with normally related great vessels (CTD-NRGVs) occur in both patients with and without 22q11.2 deletion syndrome (22q11.2DS), but it is unclear to what extent the genetically complex etiologies of these heart defects may overlap across these two groups, potentially involving variation within and/or outside of the 22q11.2 region. To explore this potential overlap, we conducted genome-wide SNP-level, gene-level, and gene set analyses using common variants, separately in each of five cohorts, including two with 22q11.2DS (N = 1472 total cases) and three without 22q11.2DS (N = 935 total cases). Results from the SNP-level analyses were combined in meta-analyses, and summary statistics from these analyses were also used in gene and gene set analyses. Across all these analyses, no association was significant after correction for multiple comparisons. However, several SNPs, genes, and gene sets with suggestive evidence of association were identified. For common inherited variants, we did not identify strong evidence for shared genomic mechanisms for CTD-NRGVs across individuals with and without 22q11.2 deletions. Nevertheless, several of our top gene-level and gene set results have been linked to cardiogenesis and may represent candidates for future work.
Highlights
Congenital heart defects comprise some of the most common, serious, and clinically important groups/types of birth defects [1,2,3]. These defects consist of a heterogenous group of structural heart malformations that are thought to have at least some shared genetic basis [4,5,6,7]
Some conotruncal heart defects involve a deviation from the normal position of the origin of the aorta and pulmonary trunk, in which case the great vessels are said to be transposed
Conotruncal heart defects with normally related great vessels (CTD-NRGVs) frequently occur in individuals with a hemizygous 22q11.2 deletion, whereas those with transposed great vessels very rarely occur in the context of a 22q11.2 deletion
Summary
Congenital heart defects comprise some of the most common, serious, and clinically important groups/types of birth defects [1,2,3] These defects consist of a heterogenous group of structural heart malformations (i.e., conotruncal heart defects that affect the cardiac outflow tract) that are thought to have at least some shared genetic basis [4,5,6,7]. Conotruncal heart defects with normally related great vessels (CTD-NRGVs) frequently occur in individuals with a hemizygous 22q11.2 deletion, whereas those with transposed great vessels very rarely occur in the context of a 22q11.2 deletion. This suggests that the genetic basis of CTD-NRGV may differ from CTDs with transposed vessels. This potential overlap in genetic etiology could include genetic variation within as well as outside of the 22q11.2 region, though this hypothesis has not been extensively studied
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