In the US and Europe, birth defects are the leading cause of infant mortality. Among birth defects, Congenital Heart Disease (CHD) occurs in approximately 8 out of 1000 live births, affects 1.3 million newborns per year worldwide, and has the highest mortality rate. While there is evidence to indicate that CHD does have a genetic basis, most of the CHD burden remains unexplained genetically. Fortunately, new genomics technologies are enabling genetic analyses of CHD patients. Whole exome sequencing of trios as well as copy number variations assayed by high-density SNP arrays can now be obtained at high efficiency and relatively low cost. These efforts are identifying a number of sequence variations in patients with CHD, but only a small percentage have second unrelated alleles to validate them as disease causing. Importantly, most of these candidate genes do not have an identified molecular mechanism implicating them in cardiac development. Therefore, there is a pressing need to develop rapid functional assays to evaluate candidate genes for a role in cardiac development, and then to investigate the underlying developmental mechanisms. Most recently, the advent of CRISPR/Cas9 genome editing technology has greatly enhanced the ability to manipulate and observe the function of the genome in model systems and cell culture. Incorporating the power of a developmental system such as Xenopus tropicalis with the CRISPR/Cas9 system and the microscale imaging modality optical coherence tomography (OCT), the analysis of thousands of different genes in cardiac development becomes possible.
Keywords: CRISPR/Cas9; Congenital heart disease (CHD); Human disease modeling; Microinjection; Optical coherence tomography (OCT).