Congenital Heart Defects, Multiple Types, 2

A number sign (#) is used with this entry because of evidence that multiple types of congenital heart defects (CHTD2) are caused by heterozygous mutation in the TAB2 gene (605101) on chromosome 6q25.

For a discussion of genetic heterogeneity of multiple types of congenital heart defects, see 306955.

Clinical Features

Thienpont et al. (2010) described 2 patients with multiple types of congenital heart defects who were found to have a mutation in the TAB2 gene. One patient was a woman with left ventricular outflow tract obstruction, subaortic stenosis due to a fibromuscular shelf, residual aortic regurgitation, and atrial fibrillation; she died from heart failure at 61 years of age. The other patient was a man with a bicuspid aortic valve and aortic dilation.

Weiss et al. (2015) reported a 3-generation family in which 4 individuals had congenital heart defects. The proband was a female infant who was noted at birth to have tetralogy of Fallot, short-segment pulmonary atresia, large malalignment ventricular septal defect, and small atrial septal defect. The mitral and tricuspid valves were both prolapsed, with thickened and myxomatous leaflets. The proband's 32-year-old mother was diagnosed at age 2 years with bicuspid aortic valve and ventricular septal defect. Echocardiogram in adulthood also showed mild aortic valve stenosis and mildly prolapsing myxomatous mitral and tricuspid valves. The 66-year-old maternal grandmother was diagnosed at age 13 years with mitral regurgitation due to a myxomatous and prolapsed valve, for which she underwent valve replacement at age 22. Echocardiography later showed a myxomatous and prolapsed tricuspid valve, and she also had atrial fibrillation. Family history revealed that the grandmother's first pregnancy resulted in a male stillbirth; autopsy showed bicuspid aortic valve and aortic stenosis, as well as hydrops fetalis.

Mapping

Thienpont et al. (2010) reviewed the genotype and phenotype data from 12 patients with a chromosomal deletion on 6q (see 612863) and delineated an 850-kb critical region for congenital heart disease on chromosome 6q25.1.

Molecular Genetics

Thienpont et al. (2010) analyzed the TAB2 gene in 402 patients with cardiac outflow tract defects and identified heterozygosity for missense mutations in 2 patients with multiple types of congenital heart defects (605101.0001 and 605101.0002); neither mutation was found in 658 ethnically matched control chromosomes.

In the proband from a 3-generation family with congenital heart defects, Weiss et al. (2015) performed SNP microarray and identified a 281-kb deletion at chromosome 6q25.1. The minimum deleted segment was mapped at genomic location chr6:149,580,983-149,861,981 (GRCh37) and included 4 genes: TAB2, SUMO4 (608829), ZC3H12D (611106), and PPIL4 (607609). FISH analysis confirmed deletion at 6q25.1 in the affected mother and maternal grandmother, whereas the unaffected father and maternal aunt had normal hybridization signals. Weiss et al. (2015) stated that this was the smallest reported deletion involving TAB2 that segregated with congenital heart defects.