Prevalence of Congenital Cardiovascular Malformations among Relatives of Infants with Hypoplastic Left Heart, Coarctation of the Aorta, and d-Transposition of the Great Arteries

Cardiovascular malformations (CVM) are the most common birth defects and carry significant and lifelong personal and societal costs. Research into genetic and environmental risk factors is therefore critical in identifying clues to causation and prevention. The purpose of this study was to investigate patterns of familial aggregation in CVM, specifically among infants with left-sided obstructive heart defects. We ascertained families of probands with hypoplastic left heart (HLH: N = 38), coarctation of the aorta (CoA: N = 46), and d-transposition of the great arteries (dTGA: N = 22). First degree relatives had clinical examinations and echocardiograms; all other relatives had detailed reviews of medical records. A total of 2,694 relatives were included in the study: 379 1st degree, 986 2nd degree, and 1,329 3rd degree. Mean nuclear family size and sibship size were similar among the groups. CVM were detected more frequently in 1st degree relatives of probands with HLH (19.3%) or CoA (9.4%) than among dTGA families (2.7%). The proportions of affected 2nd degree relatives were similar across groups (≤1%). In 3rd degree relatives, CVM was detected in 1.8% of the HLH families compared to 1.2% in CoA and 0.4% in dTGA families. The predominant types of CVM among relatives of HLH and CoA probands were left-sided obstructive lesions, in 72% (21 of 29) and 67% (25 of 37) of the affected relatives, respectively. Familial aggregation of these types of CVM is therefore confirmed in this study, potentially facilitating the search for specific genetic and other risk factors in recurrent CVM.