title: Congenital heart diseases and their association with the variant distribution features on susceptibility genes.
abstract: Congenital heart disease (CHD), one of the causes of childhood morbidity and mortality, is mainly triggered by a combination of environmental and genetic factors. Several susceptible genes, such as NKX2-5, GATA4 and TBX5, have been reported as closely related to heart and vessel development. CHD subtypes are classified into diverse clinical phenotypes, such as atrial septal defects (ASD), ventricular septal defects (VSD), tetralogy of Fallot (TOF), and Holt-Oram syndrome (HOS). Here, we summarize the associations of the genetic variants in these three genes with CHD subtypes. CHD-associated variants of NKX2-5 locate mainly in the tinman domain and the homeodomain. Mutations in the homeodomain are correlated with ASD and atrioventricular (AV) block subtypes. VSD-associated variants of GATA4 are mainly at its terminal ends. Variants of TBX5 gene are primarily in exons 3, 4, 5 and 7 and highly associated with HOS subtype. Hence, the variant distribution of NKX2-5, GATA4 and TBX5 are tightly associated with particular CHD subtypes. Further structure-modelling analysis revealed that these mutated amino acid residuals maintain their DNA-binding ability and structural stability. Therefore structural features of these genes may be used to predict the high risk of CHD subtypes in infants.
authors.affiliation: Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: W
authors.initials: W
authors.lastname: Su
authors.affiliation: Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: P
authors.initials: P
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: R
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: M
authors.initials: M
authors.lastname: Wang
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: L
authors.initials: L
authors.lastname: Mei
authors.affiliation: Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: J
authors.initials: J
authors.lastname: Tang
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: M
authors.initials: M
authors.lastname: Kumar
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: L
authors.initials: L
authors.lastname: Su
authors.affiliation: Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: N
authors.initials: N
authors.lastname: Dong
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology; D050991:GATA4 Transcription Factor / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006330:Heart Defects, Congenital / Q000145:classification / Q000235:genetics* / Q000473:pathology; D006344:Heart Septal Defects, Atrial / Q000235:genetics / Q000473:pathology; D006345:Heart Septal Defects, Ventricular / Q000235:genetics / Q000473:pathology; D000072576:Homeobox Protein Nkx-2.5 / Q000235:genetics*; D006801:Humans; D038061:Lower Extremity Deformities, Congenital / Q000235:genetics / Q000473:pathology; D009154:Mutation; D010641:Phenotype; D020825:T-Box Domain Proteins / Q000235:genetics*; D013771:Tetralogy of Fallot / Q000235:genetics / Q000473:pathology; D038062:Upper Extremity Deformities, Congenital / Q000235:genetics / Q000473:pathology
chemical_list: D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D000072576:Homeobox Protein Nkx-2.5; C095552:NKX2-5 protein, human; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5
keywords: GATA4; NKX2-5; TBX5; congenital heart disease; gene variant; mutation