Genetics of congenital heart disease

Abstract

Purpose of review: The goal of this review is to highlight recent discoveries in the field of genetics as it relates to congenital heart disease (CHD). Recent advancements in next generation sequencing technology and tools to interpret this growing body of data have allowed us to refine our understanding of the molecular mechanisms that result in CHD.

Recent findings: From multiple different study designs, the genetic lesions that cause CHD are increasingly being elucidated. Of the more novel findings, a forward genetic screen in mice has implicated recessive inheritance and the ciliome broadly in CHD pathogenesis. The developmental delays frequently observed in patients with CHD appear to result from mutations affecting genes that overlap heart and brain developmental regulation. A meta-analysis has provided clarity, discriminating pathologic from incidental copy number variations and defining a critical region or gene.

Summary: Recent technological advances have rapidly expanded our understanding of CHD genetics, and support the applicability to the clinical domain in both sporadic and inherited disease. Though significant gaps remain, genetic lesions remain the primary explanation for CHD pathogenesis, although the precise mechanism is likely multifactorial.

FIGURE 1

Ultrasound diagnoses of CHD and cilia defects in CHD mutants. (a and b) Vevo 2100 color flow imaging showed crisscrossing of blood flow indicating normal aorta (Ao) and pulmonary artery alignment, confirmed by histopathology (b). Cd, caudal; Cr, cranial; L, left; LV, left ventricle; R, right; RV, right ventricle. (c and d) Embryonic day (e) 16.5 mutant mouse (line b2b327) exhibited a blood flow pattern indicating single great artery (pulmonary artery) and ventricular septal defect (VSD) (c), suggesting aortic atresia with ventricular septal defect, confirmed by histopathology (d). (e–h) Color flow imaging of E15.5 mutant mouse (line b2b2025) with heterotaxy (stomach on right) showed side by side aorta and pulmonary artery, with the aorta emerging from the right ventricle, indicating DORV/ventricular septal defect (e and f) and the presence of AVSD (g and h). AVSD, atrioventricular septal defect; DORV, double outlet right ventricle; LA, left atrium; RA, right atrium. (i–k) Histopathology also showed a bicuspid aortic valve (BAV) (i), interrupted aortic arch (IAA) (j), and common atrioventricular valve (k). Reproduced with permission from [9^▪▪].

FIGURE 2

Reciprocal ovarian transplants between young and old mothers localize the basis of the maternal-age-associated risk to the mother. The incidence of ventricular septal defects for the offspring of old mothers with young ovaries is significantly greater than that of young mothers with old ovaries. The observed incidence in the offspring of recipient mothers matches that expected for a maternal but not an oocyte basis of the age effect. The observed and expected incidences were compared in a chi-squared goodness-of-fit test. The number of recipient mothers and the number of pups in each age group are shown. Reproduced with permission from [19^▪▪]. VSD, ventricular septal defect.