A precision medicine approach to interpret a GATA4 genetic variant in a paediatric patient with congenital heart disease [RNA-seq]

Background. Patients with congenital heart disease are identified in 1% of live births, and with improved surgical intervention many patients now survive to adulthood, the corollary of which is increased mortality in the over-65-year-old CHD population. In the clinic, genetic sequencing increasingly identifies novel genetic variants in genes related to congenital heart disease (CHD). Traditional assays for interpreting novel genetic variants are often limited by gene-specificity, whereas animal models are cumbersome and may not accurately reflect human disease. This study investigates CRISPR gene editing in induced pluripotent stem cells and cardiomyocyte-directed differentiation as a human disease model to investigate novel genetic variants identified in association with CHD. Methods and Results. The GATA4 p.Arg284His genetic variant was introduced into iPSCs using high efficiency CRISPR gene editing with homology-directed repair. GATA4 genetic variant and isogenic control cell pairs were selected and differentiated into cardiomyocytes. Expression of the GATA4 p.Arg284His variant resulted in altered calcium transient’s indicative of CHD and consistent with the patient’s clinical phenotype. Transcriptomics revealed molecular and cellular pathway changes in cardiac development, calcium handling, and energy metabolism that contribute to disease aetiology and mechanism, and identified potential treatments that could restore normal cell function. Conclusion. Directed differentiation of iPSCs harbouring the GATA4 p.Arg284His genetic variant recapitulated the CHD phenotype, indicated disease mechanisms, and pointed to potential treatments. The study highlights the utility of transcriptomics for the functional interpretation of cardiac genetic variants and is an exemplar for precision medicine approaches for the investigation of CHD.