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Down's syndrome (DS), resulting from an additional copy of chromosome 21 (trisomy 21), is frequently associated with congenital heart defects (CHDs). Although the increased dosage of chromosome 21 sequences is likely to be part of the etiology of cardiac defects, only a proportion of DS patients exhibit a congenital heart defect (birth prevalence 40-60%). Through a large-candidate gene-sequencing screen in patients with atrioventricular septal defects, substitutions were identified in bone morphogenetic protein (BMP) type I receptor ALK2 and two other genes in a patient with DS and a primum-type atrial septal defect. Structural modeling of the cytoplasmic domain of the ALK2 receptor suggests that H286 is in close proximity to the nucleotide-binding site of the kinase domain. We investigated whether this p.His286Asp substitution altered ALK2 function by using both in vitro as well as in vivo assays. The p.His286Asp variant demonstrated impaired functional activity as measured by BMP-specific transcriptional response assays. Furthermore, mild dominant-interfering activity was observed in vivo compared with wild-type ALK2 as determined by RNA injection into zebrafish embryos. These data indicate that in the context of a DS background, ALK2-mediated reduction of BMP signaling may contribute to CHDs.

Through the use of animal studies, many candidate genes (mainly encoding transcriptional factors and receptors) have been implicated in the development of congenital heart disease. Thus far, only a minority of these genes have been shown to carry mutations associated with congenital disease in humans, e.g., GATA 4, TBX-5, NOTCH1 and NKX2-5. Mutations in these genes can cause a variety of cardiac defects even within the same family. Conversely, similar phenotypes are observed for different gene mutations suggesting a common pathway. Multiple genes and genetic pathways have been related to atrioventricular valve formation, although most of these genes have not yet been demonstrated as causative in human atrioventricular valve defects. Key pathways include the epidermal growth factor receptor pathway and related interacting pathways, most importantly the pathway of UDP-glucose dehydrogenase, resulting ultimately in activation of Ras. Other examples of interacting pathways include that of Nodal/Cited2/Pitx2, Wnt, Notch and ECE. Further studies are needed to investigate the pathways which are crucial for atrioventricular valve formation in humans. Understanding the underlying molecular process of abnormal atrioventricular valve formation in patients with congenital heart disease may provide important insight, in the etiology and possibly into preventive or treatment regimes.