Genetically alike Syrian hamsters display both bifoliate and trifoliate aortic valves

Abstract

The bifoliate, or bicuspid, aortic valve (BAV) is the most frequent congenital cardiac anomaly in man. It is a heritable defect, but its mode of inheritance remains unclear. Previous studies in Syrian hamsters showed that BAVs with fusion of the right and left coronary leaflets are expressions of a trait, the variation of which takes the form of a phenotypic continuum. It ranges from a trifoliate valve with no fusion of the coronary leaflets to a bifoliate root devoid of any raphe. The intermediate stages are represented by trifoliate valves with fusion of the coronary aortic leaflets, and bifoliate valves with raphes. The aim of this study was to elucidate whether the distinct morphological variants rely on a common genotype, or on different genotypes. We examined the aortic valves from 1 849 Syrian hamsters belonging to a family subjected to systematic inbreeding by full-sib mating. The incidence of the different trifoliate aortic valve (TAV) and bifoliate aortic valve (BAV) morphological variants widely varied in the successive inbred generations. TAVs with extensive fusion of the leaflets, and BAVs, accounted for five-sixths of the patterns found in Syrian hamsters considered to be genetically alike or virtually isogenic, with the probability of homozygosity being 0.999 or higher. The remaining one-sixth hamsters had aortic valves with a tricuspid design, but in most cases the right and left coronary leaflets were slightly fused. Results of crosses between genetically alike hamsters, with the probability of homozygosity being 0.989 or higher, revealed no significant association between the valvar phenotypes in the parents and their offspring. Our findings are consistent with the notion that the BAVs of the Syrian hamster are expressions of a quantitative trait subject to polygenic inheritance. They suggest that the genotype of the virtually isogenic animals produced by systematic inbreeding greatly predisposes to the development of anomalous valves, be they bifoliate, or trifoliate with extensive fusion of the leaflets. We infer that the same underlying genotype may account for the whole range of valvar morphological variants, suggesting that factors other than genetic ones are acting during embryonic life, creating the so-called intangible variation or developmental noise, and playing an important role in the definitive anatomic configuration of the valve. The clinical implication from our study is that congenital aortic valves with a trifoliate design, but with fusion of coronary aortic leaflets, may harbour the same inherent risks as those already recognised for BAVs with fusion of right and left coronary leaflets.

Genetic Basis of Familial Valvular Heart Disease

“…This suggests that a single underlying genotype may predispose to BAV and account for the whole range of valve morphology, and implies that nongenetic factors are acting during embryonic life, creating "developmental noise," to influence the definitive anatomic configuration of the valve. 87 This finding supports a complex inheritance pattern, as seen in human BAV, and may explain the relatively low recurrence rate of BAV in first-degree relatives, despite its common prevalence within the general population. 87 The findings also provide a potential explanation regarding aortic valve anatomy in monozygotic twins where BAV was present in 1 twin, but tricuspid aortic valve in the other.…”

“…87 This finding supports a complex inheritance pattern, as seen in human BAV, and may explain the relatively low recurrence rate of BAV in first-degree relatives, despite its common prevalence within the general population. 87 The findings also provide a potential explanation regarding aortic valve anatomy in monozygotic twins where BAV was present in 1 twin, but tricuspid aortic valve in the other. 88 Although specific gene mutations can cause BAV in mice and humans, the variability in BAV morphology and its disease manifestations cannot be entirely explained.…”

“…62 This anomalous behavior of the cardiac neural crest is believed to explain the association of the right and left coronary leaflet fusion BAV morphology with coarctation of the aorta and the more pronounced aortic wall degeneration, compared with BAV with fusion of the right and noncoronary leaflets. 62 It is interesting that Sans-Coma et al 87 recently demonstrated that BAV in Syrian hamsters express a quantitative trait, subject to polygenic inheritance, with reduced penetrance and variable expressivity. Furthermore, examination of aortic valve morphology in virtually isogenic Syrian hamsters produced by systematic inbreeding through fullsib mating, with the probability of homozygosity being 0.999 or higher, demonstrated the presence of BAV in up to five sixths of the hamsters studied, whereas the remaining one sixth had a trileaflet aortic valve.…”

Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract

“…Further research using genetic sequencing in humans has also suggested this because human BAV patients harboring rare GATA5 mutations have a higher incidence of right–left and right–noncoronary BAVs 36. Nevertheless, a study of 1849 inbred Syrian hamsters with a high probability of homozygosity found variable aortic valve morphology and suggested that environmental factors, rather than genetics, account for BAV morphology 37, 38. Gene–environment interactions may also play a role in the development of BAV because mutations in the Notch signaling pathway combined with environmental effectors have been demonstrated to increase the penetrance of disease states 39.…”

A Roadmap to Investigate the Genetic Basis of Bicuspid Aortic Valve and its Complications

“…It develops spontaneously in an inbred strain of Syrian hamsters but without valve or aortic complications typical of human BAV, and the underlying genetic defect is unknown (32,33). Targeted deletions of fibroblast growth factor, bone morphogenetic protein, and Notch pathway genes in mice produced BAV with incomplete penetrance, as well as various malformations of the LVOT and aorta (Table 2).…”