TY - JOUR T1 - A novel GATA-binding protein 4 gene variation associated with familial atrial septal defect JF - bioRxiv DO - 10.1101/277780 SP - 277780 AU - Yongchao Yang AU - Yu Xia AU - Yueheng Wu AU - Shufang Huang AU - Yun Teng AU - Xiaobing Liu AU - Ping Li AU - Jimei Chen AU - Jian Zhuang Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/03/06/277780.abstract N2 - Atrial septal defect (ASD) is the most common congenital heart defect. Part of ASD exhibits familial predisposition, but the genetic mechanism remains largely unknown. In the current study, we use multiple methods to identify and confirm the gene associated with a familial ASD. Chromosomal microarray analyses, whole exome sequencing, Sanger sequencing, multiple bioinformatics programs, in silico protein structure modeling and molecular dynamics simulation were performed to predict the pathogenic of the variant gene. Dual-Luciferase reporter gene assay was performed to evaluate the influence of downstream target gene of the target variation. A novel, heterozygous, missense variant GATA-binding protein 4 (GATA4):c.958C>T, p.R320W was identified. An autosomal dominant inheritance pattern with incomplete penetrance was observed in the family. Multiple prediction indicate the variant in GATA4 to be deleterious. Molecular dynamics simulation further revealed that the variation of p.R320W could prevent the zinc finger of GATA4 from interacting with the DNA. Dual-Luciferase reporter assay demonstrated a significant decrease in transcriptional activity (0.90±0.099 vs 1.50±0.079, p = 0.001) of the variant GATA4 compared with the wild type. We believe the novel variation of GATA4 (c.958C>T, p.R320W) with a pattern of incomplete inheritance that may be highly associated with this familial ASD. The finding enriched our knowledge of variations that may associated with ASD. ER -