Ventricular Septal Defect 3

A number sign (#) is used with this entry because of evidence that ventricular septal defect-3 (VSD3) is caused by heterozygous mutation in the NKX2-5 gene (600584) on chromosome 5q35.

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 NKX2-5 gene include atrial septal defect with or without atrioventricular conduction defects (ASD7; 108900), tetralogy of Fallot (see TOF, 187500), conotruncal malformations (see 217095), and hypoplastic left heart syndrome (HLHS2; 614435).

For a discussion of genetic heterogeneity of ventricular septal defect, see VSD1 (614429).

Molecular Genetics

Peng et al. (2010) analyzed the NKX2-5 gene in 135 Chinese pediatric patients with nonfamilial congenital cardiac defects and identified a heterozygous missense mutation (P283Q; 600584.0021) in 1 of 82 patients with ventricular septal defect. In addition to VSD, the patient had patent ductus arteriosus and aortic isthmus stenosis.

Chen et al. (2010) analyzed the NKX2-5 gene in 30 patients with nonsyndromic congenital heart defects, including 10 with VSD, 10 with ASD, 8 with VSD combined with ASD, and 2 with atrioventricular septal defects (AVSD). They identified a missense NKX2-5 variant in 1 patient with VSD (600584.0023).

Wang et al. (2011) screened 136 Chinese probands with VSD for mutations in NKX2-5 and identified heterozygosity for a missense mutation (P59A; 600584.0022) in 1 (0.74%) of 136 probands that was not found in 200 ethnically matched controls. The mutation was present in the 6-year-old male proband and his affected 4-year-old sister and 32-year-old affected father; all 3 had isolated VSD without atrioventricular conduction defects. The deceased paternal grandfather and paternal great-aunt both had VSD and atrioventricular block, associated with pulmonary artery stenosis in the former and with atrial septal defect in the latter.