Ventricular Septal Defect 1

A number sign (#) is used with this entry because of evidence that ventricular septal defect-1 (VSD1) is caused by heterozygous mutation in the GATA4 gene (600576) on chromosome 8p23.

Description

Ventricular septal defect (VSD) is the most common form of congenital cardiovascular anomaly, occurring in nearly 50% of all infants with a congenital heart defect and accounting for 14 to 16% of cardiac defects that require invasive treatment within the first year of life. Congenital VSDs may occur alone or in combination with other cardiac malformations. Large VSDs that go unrepaired may give rise to cardiac enlargement, congestive heart failure, pulmonary hypertension, Eisenmenger's syndrome, delayed fetal brain development, arrhythmias, and even sudden cardiac death (summary by Wang et al. (2011, 2011)).

Other congenital cardiac defects caused by mutation in the GATA4 gene include atrial septal defect (ASD2; 607941), tetralogy of Fallot (see TOF, 187500), and endocardial cushion defects (AVSD4; 614430).

Genetic Heterogeneity of Ventricular Septal Defect

VSD2 (614431) is caused by mutation in the CITED2 gene (602937) on chromosome 6q24; VSD3 (614432) is caused by mutation in the NKX2-5 gene (600584) on chromosome 5q34.

Somatic mutations in the HAND1 gene (602406) have been identified in tissue samples from patients with VSD.

Molecular Genetics

Zhang et al. (2008) analyzed the GATA4 gene (600576) in 486 Chinese patients with nonsyndromic congenital heart defects and identified 9 heterozygous mutations in 12 patients, including 9 (2.8%) of 319 patients with VSD (see, e.g., 600576.0007 and 600576.0009-600576.0010).

Peng et al. (2010) screened 135 Chinese pediatric patients with nonfamilial congenital heart defects for mutations in GATA4 and identified a heterozygous missense mutation in 1 of 82 patients with VSD (600576.0013).

Wang et al. (2011) scanned the GATA4 gene in 210 unrelated Chinese patients with VSD, 45 of whom had additional cardiac anomalies, and identified a missense mutation (600576.0014) in 1 proband (estimated population prevalence of GATA4 mutations, 0.48%). The proband was a 5-year-old girl, whose affected father and paternal aunt also carried the mutation; none of the 3 had atrioventricular conduction defects. Her father had atrial septal defect (ASD) in addition to VSD, and her deceased paternal grandfather had ASD, pulmonary stenosis, and atrioventricular block.

Yang et al. (2012) identified a heterozygous missense mutation in GATA4 (R43W; 600576.0015) in 1 (0.63%) of 160 unrelated Han Chinese individuals with VSD. The proband was a 1-year-old girl from a 4-generation family in which 6 additional affected members over 3 generations were found to be heterozygous for the mutation. All affected individuals had perimembranous VSD; additional cardiac structural defects were present in 3 of the mutation-positive patients, including ASD in the proband's father and paternal grandfather and patent ductus arteriosus in her paternal aunt. A deceased paternal great uncle had VSD, ASD, and pulmonary artery stenosis.

Associations Pending Confirmation

Cheng et al. (2011) analyzed the coding region of the IRX4 gene (606199) in 698 Chinese individuals with nonsyndromic congenital cardiac malformations and identified 2 potentially disease-causing missense mutations in 2 patients with VSD who were not found in 250 controls. Both mutations were located in highly conserved regions of IRX4, and transfection studies demonstrated weakened protein-protein interactions compared to wildtype. Cheng et al. (2011) suggested that protein alterations of IRX4 may have an impact on the development of the interventricular septum.

For discussion of a possible relationship between variation in the NTRK3 gene and ventricular septal defect, see 191316.