A Genetic Etiology for Interruption of the Aortic Arch Type B

Abstract

Interrupted aortic arch (IAA) type B is a congenital heart defect believed to be caused by an anomaly of branchial arch mesenchymal development. IAA type B has been associated with DiGeorge syndrome (DGS), which includes conotruncal heart defects, T-cell immunodeficiency, hypocalcemia, and facial abnormalities. The great majority of DGS cases are associated with hemizygous deletions at the chromosome 22q11 locus. The present study was designed to establish the involvement of the 22q11 locus in the etiology of IAA type B, independently from the typical DGS phenotype. An evaluation was performed on 73 patients with conotruncal heart defects using fluorescence in situ hybridization (FISH) analysis with probes from the 22q11 DGS locus. From this group, 7 patients were deleted (including 4 of the 11 patients with IAA type B). FISH analysis was extended to a total of 22 patients with IAA type B and 11 of these (50%) were deleted. FISH and Southern blot analyses using additional markers within the DiGeorge chromosomal region were performed on patients found not to be deleted in the initial FISH screening. No small deletions or rearrangements were detected. In our patient population, a single, specific genetic defect is the basis for one half of the IAA type B cases. These data suggest that IAA type B is one of the most etiologically homogeneous congenital heart defects. A 22q11 deletion in IAA type B may or may not be associated with the typical DGS phenotype. Therefore, IAA type B, per se, should be an indication for 22q11 deletion testing.