Characterization of a Novel GATA4 Missense Variant p.Gly303Trp in a Family with Septal Heart Defects and Pulmonary Stenosis

Abstract

Congenital heart disease (CHD) represents a prevalent group of structural cardiac anomalies often associated with alterations in key transcription factors including NKX2-5, TBX5, and, particularly, GATA4. GATA4 is a zinc finger transcription factor essential for regulating genes involved in cardiogenesis. Here, we report the identification of a novel heterozygous missense variant in GATA4 (NM_002052.5:c.907G>T, p.Gly303Trp) in a family with a history of CHD. The proband, exhibiting ventricular septal defect (VSD) and pulmonary stenosis, was referred for genetic evaluation after recurrent spontaneous abortions occurred in their partner. In addition, the mother of the proband has a history of atrial septal defect (ASD) with pulmonary stenosis, which suggests a familial inheritance pattern.

Keywords: GATA4; atrial septal defects; congenital heart disease ventricular septal defect; pulmonary stenosis; whole exome sequencing.

Figure 1

Comprehensive transthoracic echocardiographic assessment in a patient with a history of perimembranous ventricular septal defect (VSD) repair, patent foramen ovale (PFO) closure, and pulmonary artery plasty. (A) Apical two-chamber view showing a left ventricular (LV) end-diastolic volume of 42 mL, end-systolic volume of 46 mL, and preserved systolic function with ejection fraction (EF) of 62%. (B) Parasternal long axis view measuring interventricular septum (IVSd: 1.2 cm), LV internal diameter (LVIDd: 5.1 cm), posterior wall (LVPWd: 1.0 cm), and LV mass (214 g; indexed LV mass: 112.63 g/m²). (C) Right ventricular outflow tract (RVOT) view, with diameter of 2.1 cm, cross-sectional area of 3.46 cm², and stroke volume of 93 mL. (D) Apical view of right chambers showing mild right atrial dilation (TD area: 30 cm²). (E) Four-chamber view demonstrating mild left atrial enlargement (area: 15.2 cm²) and eccentric tricuspid regurgitation directed toward the atrial septum. (F) Left atrial volume estimation (21.6 cm³). (G) Pulsed-wave Doppler of mitral inflow showing an E/A ratio of 2.1, suggestive of normal LV filling pressures. (H) LVOT Doppler showing VTI of 23.3 cm, stroke volume of 73 mL, and Qp/Qs ratio of 1.3, indicating a small residual left-to-right shunt. (I) Continuous-wave Doppler showing a pulmonary peak velocity of 140 cm/s and a pressure gradient of 8 mmHg, consistent with mild residual pulmonary valve insufficiency. Overall, systolic function is preserved, and there are no signs of pericardial effusion. Right-sided sections are mildly dilated with preserved contractility (TAPSE 25 mm, FAC 47%). The inferior vena cava is not dilated and shows normal collapsibility.

Figure 2

Familial segregation and molecular characterization of the GATA4 c.907G>T variant. (A) Pedigree of the family showing autosomal dominant inheritance. Genotypes for the GATA4 c.907G>T variant are shown under each tested individual: heterozygous carriers (+/−) are present among affected and unaffected subjects, while homozygous wild-type (−/−) individuals are unaffected. (B) Electropherogram showing Sanger sequencing validation of the GATA4 c.907G>T (p.Gly303Trp) variant. The upper panel represents the proband’s heterozygous mutation (arrow), while the lower panel shows a control subject with a wild-type sequence at the same position.

Figure 3

Structural and genomic characterization of the GATA4 c.907G>T (p.Gly303Trp) variant. (A) In silico protein modeling of the GATA4 zinc finger domain highlights the structural impact of the Gly303Trp substitution. The wild-type structure (left) shows Glycine at position 303, while the mutated structure (right) illustrates the steric hindrance of tryptophan residue, potentially affecting the spatial conformation and DNA-binding capacity. (B) Schematic representation of the GATA4 gene and protein domains. The c.907G>T variant is located within exon 4, corresponding to the nuclear localization signal (NLS) domain. The positions of the transcriptional activation domain (TAD), the two zinc finger domains (ZN I and ZN II), and the NLS are indicated. (C) UCSC Genome Browser Snapshot showing the position of the GATA4 variant (highlighted in yellow) in a highly conserved region across multiple vertebrate species. The alignment demonstrates evolutionary conservation of the mutated residue, supporting its functional relevance.