Abstract
Human beings are characterized by a left–right asymmetric arrangement of their internal organs, and the heart is the first organ to break symmetry in the developing embryo. Aberrations in normal left–right axis determination during embryogenesis lead to a wide spectrum of abnormal internal laterality phenotypes, including situs inversus and heterotaxy. In more than 90% of instances, the latter condition is accompanied by complex and severe cardiovascular malformations. Atrioventricular canal defect and transposition of the great arteries—which are particularly frequent in the setting of heterotaxy—are commonly found in situs solitus with or without genetic syndromes. Here, we review current data on morphogenesis of the heart in human beings and animal models, familial recurrence, and upstream genetic pathways of left–right determination in order to highlight how some isolated congenital heart diseases, very common in heterotaxy, even in the setting of situs solitus, may actually be considered in the pathogenetic field of laterality defects.
Highlights
Human beings, like other vertebrates, are characterized by a left–right asymmetric arrangement of their internal organs
Clinical observations made in human beings and studies in animal models of laterality disease suggest that all these stages of cardiac development are influenced by the embryonic left–right body axis
Because isolated the great arteries (TGA) in situs solitus has been found in transgenic mice as well as in human beings harboring mutations in laterality genes, this suggests that TGA may be the only phenotype of a left–right patterning defect
Summary
Like other vertebrates, are characterized by a left–right asymmetric arrangement of their internal organs. In 1998, Brett Casey, one of the pioneers in the field of genetics of heterotaxy, asked: “Are some complex, isolated heart malformations unrecognized manifestations of aberrant left–right asymmetry development?” [7]. This question was based on clinical and genetic observations, which suggested that familial heterotaxy occurred with autosomal dominant (usually with incomplete penetrance), recessive, and X-linked inheritance [8,9], and that some isolated CHDs appearing in relatives of individuals with heterotaxy would be linked to laterality defects. The aim of this review, based upon morphology, familial recurrence, experiments on animal models, and genetic data, is to highlight how some isolated heterotaxy-like CHDs, even in the setting of situs solitus, can be related to laterality defects
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