Abstract P1121: Transposition Of Great Arteries - Genetics And Beyond

Abstract

Background: Transposition of great arteries (TGA) is one of the most common severe congenital heart defects and neonatal cyanotic heart diseases. Given contribution of several molecular pathways involved in cardiac differentiation (Fig.1), the etiology governing morphogenesis of TGA remains largely unknown. There is greater insight into interactions and molecular variations culminating in aortic-pulmonary transposition. Clinical evidence and genetic sequencing has led to several polymorphic mutations demonstrating phylogenetic conservation of regulatory domains. Defects in transcription factors involved in nodal signaling, in addition to ZIC3 & PROSIT 240, are strongly implicated in arterial transposition. We reviewed current literature on the genetics determining TGA development and associated lateral syndromes Methods: We searched PubMed, Scopus, Web of Science, and Google Scholar to identify listed keywords Body: TGA is now postulated as part of a spectrum of genetic disorders with familial recurrence, rather than sporadic defect. Evidence exists for TGA's correlation with genes involving lateralization defects, heterotaxy and asplenia. Evidence, albeit scarce, has surfaced depicting association of TGA with genetic syndromes like Trisomy 8, 18, VACTERL and CHARGE syndrome, Tuberous sclerosis, Deletion 11q, 18p, and other genetic syndromes like Digeorge, Turner’s, Noonan’s, Williams, and Marfan. Additional gene mutations causing TGA might include CFC-1, TRAP2, FOXH1, LEFTY2, PITX2, GDF1. The interrelation between mutations in ciliary genes contributing to both TGA and neurodevelopment disorder, prompts consideration of common ciliopathic pathogenies explaining association between TGA and neurodevelopmental disorders. Conclusion: The occurrence of mutations in a single gene, though a cause for TGA, does not correlate with 5-7% occurrence rate for TGA. Major research has focused on a single gene approach, neglecting the simultaneous screening for other susceptible targets. The multiple-hit model suggested by De Luca et al. (2010) is a promising approach for further understanding the contribution of multi-gene sequences. Minor genetic variations in several genes may have a cumulative effect that increases disease susceptibility in TGA and other congenital heart defects