Discovering Pathogenic Variants Associated with Tricuspid Atresia through Whole Exome Sequencing



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Congenital heart disease (CHD) is the most common birth defect, present in 1/110 live births, and those considered critical (CCHD) require surgical intervention within the first year of life. A rare form of CCHD, tricuspid atresia, is present in 1/10,000 live births in the United States and accounts for approximately 1-3% of all CHD. It is characterized by the absence of the tricuspid, or right atrioventricular, valve and presents with additional phenotypes that are required to survive to birth. At this point, very few genetic studies have been conducted on this condition and the results have been very sparse. Currently 22q11 deletion (DiGeorge syndrome), 8p23 (GATA4 region), 4q31 (NFB), and 3p (TGFBR2) have been found associated with the few tricuspid atresia patients that have been characterized through limited genetic testing. In this study, a retrospective chart review was undertaken on the largest cohort of tricuspid atresia patients (n=234) and includes the first genetic testing outcome results for any tricuspid atresia retrospective review study. Following this, a family with various cardiac phenotypes including tricuspid atresia and bicuspid aortic valve was assessed via whole exome sequencing (WES) to discover pathogenic variants. Following the compilation of all genetic testing data from the literature, the retrospective review, and the family WES, a common pathway was identified that is disrupted in all subjects without a syndromic diagnosis. The pathway, beginning with TGF-beta and RANKL signaling, involves the expression of NFATC1 via NFkappaB activity and NFATC1 transcription factor function regulation by a complex including TAB2. WES in 342 patients with congenital cardiac left-sided lesions revealed extensive genetic heterogeneity. This is the only other study to screen a large cohort of patients with WES and reported 28 candidate variants in 27 genes. Of these, 17 genes were not previously associated with CHD. Our study is the first to begin identifying a potential genetic etiology for tricuspid atresia which is a right-sided lesion.



Congenital heart disease, Tricuspid atresia, Whole exome sequencing, NFATC1, TAB2, Polygenic disease, Pathogenic variants, Mutations