EP09.09: Significance of copy number variations and whole exome sequencing of different type of tetralogy of Fallot

To evaluate the performance of copy number variation sequencing (CNV-seq) and whole exome sequencing (WES) in identifying the genetic etiology of tetralogy of Fallot (TOF). A total of 232 fetuses diagnosed with TOF by fetal echocardiography in our centre were retrospectively analysed from December 2015 to January 2023.The cases were divided into 3 groups: TOF, pulmonary atresia with ventricular septal defect (PA-VSD) and absence of pulmonary valve syndrome type of TOF (APVS-TOF). CNV-seq was performed to screen aneuploidy (AUP) and copy number variations (CNVs), then WES was performed if the results were negative. Gene-level burden analysis and enrichment analysis were performed to identify candidate CHD/TOF genes and biological pathways, respectively. The total positive genetic abnormalities was 36.21% (84/232). WES increased the diagnostic yield for TOF by 13.51% (20/148). The diagnostic yield was the highest in APVS-TOF (75%,12/16), and the difference was statistically significant in 3 groups (Fisher = 17.325, P = 0.000). Extracardiac malformations were most common in PA-VSD, there was statistically significant difference between the syndromic and non-syndromic type of TOF and the diagnostic yield was higher in the former (χ2 = 13.68, P = 0.00022). The damaging variations (DDVs) were no statistical differences in 3 groups (χ2 = 0.063,P = 0.802). Burden analysis for rare DDVs identified a novel high confidence CHD risk gene at exome-wide significance (GNAI3; Poisson test, P = 2.728018e-07). Transforming growth factor beta stimulus (GO:0071560) and NURF complex (GO:0016589) were two novel pathways enriched significantly in the enrichment analysis. CNVs are the common genetic abnormalities in fetal TOF. WES could be performed to improve the identification of genetic etiology in the fetuses without chromosomal abnormalities and identify the candidate genes. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.