Abstract 17979: A Subset of Patients with Isolated Transposition of the Great Arteries and Double Outlet Right Ventricle Fall Within the Spectrum of Heterotaxy Syndrome

Abstract

Background: Heterotaxy is a rare disorder of laterality. ZIC3 was the first gene in which human disease-causing mutations were identified. Mutations typically result in males with situs ambiguus and complex congenital heart disease; however affected females and one male with isolated transposition of the great arteries (TGA) have been reported. We hypothesized that a subset of patients with heart defects common to heterotaxy but without laterality defects would have ZIC3 mutations. We also sought to estimate the prevalence of ZIC3 mutations in sporadic heterotaxy. Methods and Results: Patients with TGA (n=169), double outlet right ventricle (DORV) (n=90), complete atrioventricular canal (n= 41) and heterotaxy (n=53) underwent sequencing of the ZIC3 open reading frame. We tested 90 patients with tetralogy of Fallot (TOF) to correlate genotype with phenotype. Three mutations were detected: 1 female with isolated DORV [c.49G>T (Gly17Cys)], 1 male with isolated TGA [c.98C>T (Ala33Val)], and 1 female with sporadic heterotaxy [841C>T (His280Tyr)] that were absent in 100 Caucasian and 100 African American control patients. We also identified a novel insertional mutation (CPFP333ins) in a family with heterotaxy. No mutations were found in cases with TOF. Transcriptional activation studies demonstrated significantly reduced transcription of the ZIC3 His280Tyr mutant construct. Conclusions: Isolated TGA and DORV, like heterotaxy, can arise from mutations in ZIC3, confirming a spectrum of disease that includes isolated cardiac malformations. ZIC3 mutations were found in 2% of patients with sporadic heterotaxy, therefore routine testing should be considered in patients with heterotaxy.