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Congenital heart disease is the leading cause of birth defects, affecting 9 out of 1000 newborns each year. A particularly severe form of congenital heart disease is heterotaxy, a disorder of left-right development. Despite aggressive surgical management, patients with heterotaxy have poor survival rates and severe morbidity due to their complex congenital heart disease. Recent genetic analysis of affected patients has found novel candidate genes for heterotaxy although their underlying mechanisms remain unknown. In this review, we discuss the importance and challenges of birth defects research including high locus heterogeneity and few second alleles that make defining disease causality difficult. A powerful strategy moving forward is to analyze these candidate genes in a high-throughput human disease model. Xenopus is ideal for these studies. We present multiple examples demonstrating the power of Xenopus in discovering new biology from the analysis of candidate heterotaxy genes such as GALNT11, NEK2 and BCOR. These genes have diverse roles in embryos and have led to a greater understanding of complex signaling pathways and basic developmental biology. It is our hope that the mechanistic analysis of these candidate genes in Xenopus enabled by next generation sequencing of patients will provide clinicians with a greater understanding of patient pathophysiology allowing more precise and personalized medicine, to help patients more effectively in the future.
Fig. 1. Ciliary flow and signaling in the gastrocel roof plate (GRP) of the frog.
-The black dashed line outlines the GRP. The red lines represent the inner motile cilia, and the green and purple represent the outer immotile cili The blue arrows show the leftward fluid flow across the GRP that is produced by the motile cilia and sensed by the immotile cili.
-coco is initially expressed bilaterally. Ciliary flow reduces the expression of coco on the left side. Coco inactivates Nodal on the left, which leads to pitx2c expression on the left side of the embryo and ultimately plays a role in organ situs and asymmetric development.
Fig. 2. Model for patient centered gene discovery, analysis and ultimately personalized medicine.
This model highlights how DNA can be taken from a patient with congenital heart disease. His or her genome can then be sequeneced, and geneticists can analyze it for likely causative mutations. Embyologists can then use Xenopus as a model system to understand gene function. This knowledge can then be taken back to the patient in order to personalize medicine.
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