# A precision medicine approach to interpret a GATA4 genetic variant in a paediatric patient with congenital heart disease

## TL;DR

This study uses CRISPR-edited stem cells to investigate a GATA4 genetic variant linked to congenital heart disease in a pediatric patient, revealing disease mechanisms and potential treatments.

## Contribution

A novel precision medicine approach using CRISPR-edited iPSCs to model and interpret a specific CHD-related genetic variant.

## Key findings

- The GATA4 p.Arg284His variant caused altered calcium transients in cardiomyocytes, consistent with the patient's CHD phenotype.
- Transcriptomics identified disrupted pathways in cardiac development and energy metabolism linked to the variant.
- The study demonstrated the utility of iPSC-based models for functional interpretation of CHD genetic variants.

## Abstract

Patients with congenital heart disease are identified in 1% of live births. Improved surgical intervention means many patients now survive to adulthood, the corollary of which is increased mortality in the over-65-year-old congenital heart disease (CHD) population. In the clinic, genetic sequencing increasingly identifies novel genetic variants in genes related to 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.

We identified a GATA4 p.Arg284His genetic variant in a paediatric patient. This genetic variant was introduced into induced pluripotent stem cells (iPSCs) using CRISPR gene editing with homology-directed-repair. GATA4 genetic variant and isogenic control iPSCs were selected and differentiated into cardiomyocytes. Expression of the GATA4 p.Arg284His variant resulted in altered calcium transients, indicative of CHD and consistent with the patient’s clinical phenotype. Transcriptomics revealed cellular pathway changes in cardiac development, calcium handling, and energy metabolism that contribute to disease aetiology, mechanism and identification of potential treatments.

Directed differentiation of iPSCs harbouring the GATA4 p.Arg284His genetic variant recapitulated the CHD phenotype, indicated disease mechanisms, and pointed to potential sites for targeting with therapy. 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.

The online version contains supplementary material available at 10.1186/s40246-025-00907-6.