6q25.1 (TAB2) microdeletion is a risk factor for hypoplastic left heart: a case report that expands the phenotype

Abstract

Introduction: Hypoplastic left heart syndrome (HLHS) is a rare but devastating congenital heart defect (CHD) accounting for 25% of all infant deaths due to a CHD. The etiology of HLHS remains elusive, but there is increasing evidence to support a genetic cause for HLHS; in particular, this syndrome is associated with abnormalities in genes involved in cardiac development. Consistent with the involvement of heritable genes in structural heart abnormalities, family members of HLHS patients have a higher incidence of both left- and right-sided valve abnormalities, including bicuspid aortic valve (BAV).

Case presentation: We previously described (Am J Med Genet A 173:1848-1857, 2017) a 4-generation family with a 6q25.1 microdeletion encompassing TAB2, a gene known to play an important role in outflow tract and cardiac valve formation during embryonic development. Affected adult family members have short stature, dysmorphic facial features, and multiple valve dysplasia, including BAV. This follow-up report includes previously unpublished details of the cardiac phenotype of affected family members. It also describes a baby recently born into this family who was diagnosed prenatally with short long bones, intrauterine growth restriction (IUGR), and HLHS. He was the second family member to have HLHS; the first died several decades ago. Postnatal genetic testing confirmed the baby had inherited the familial TAB2 deletion.

Conclusions: Our findings suggest TAB2 haploinsufficiency is a risk factor for HLHS and expands the phenotypic spectrum of this microdeletion syndrome. Chromosomal single nucleotide polymorphism (SNP) microarray analysis and molecular testing for a TAB2 loss of function variant should be considered for individuals with HLHS, particularly in those with additional non-cardiac findings such as IUGR, short stature, and/or dysmorphic facial features.

Keywords: Bicuspid aortic valve; Hypoplastic left heart syndrome; TAB2 gene deletion.

Fig. 1

Hypoplastic left heart syndrome and its surgical repair. Legend: HLHS involves a hypoplastic aorta and left ventricle, a large patent ductus arteriosus (PDA), and an atrial septal defect (ASD). This results in a mixture of oxygenated (from PDA flow) and deoxygenated blood flow to the body. A 3-stage surgical repair involves ligation of the PDA, construction of a neo-Aorta, and a baffle in the right atrium that guides deoxygenated blood into the pulmonary circulation. (Reproduced with permission from Benson DW, Martin LJ, Lo CW. [1])

Fig. 2

Pedigree of the four-generation family showing segregation of the 6q25.1 deletion with congenital heart defects

Fig. 3

Echocardiogram findings for previously reported family members. Legend: II.3 A: Anterior and posterior aortic leaflets (orange arrows) of a bicuspid aortic valve. II.3B: Calcified aortic valve (red arrow) with a dilated ascending aorta. II.3C: Cardiac MR image showing the ascending aortic aneurysm dilated at 5.8 cm. III.3A: Two leaflets of the bicuspid aortic valve (orange arrows). III.3B: Doming of the aortic valve (blue arrow), consistent with a bicuspid aortic valve, and mitral valve prolapse (red arrow). III.4A: Anterior and posterior leaflets (orange arrows) of a bicuspid aortic valve. III.4B: Thickened mitral valve (red arrow). III.5A: Tri-leaflet aortic valve. III.5B: Thickened mitral valve leaflets (red arrow). IV.1A: Bicuspid aortic valve leaflets (orange arrows). IV.1B-C: Septal defect between the left and right atrium

Fig. 4

Echocardiogram findings for IV.3. Legend: a Large atrial septal defect (ASD) with a diminutive/hypoplastic left ventricle (LV); RV-right ventricle. b Orange arrows point to bicuspid aortic valve leaflets. c Hypoplastic aorta (Ao) with a discrete coarctation. d and e Two views of the patent ductus arteriosus (PDA); PA -pulmonary artery; RPA - right pulmonary artery; LPA - left pulmonary artery. f-g-h Color and spectral Doppler of the to-and-fro PDA flow from the PA and Ao