Genomics and Epigenomics of Congenital Heart Defects: Expert Review and Lessons Learned in Africa

Abstract

Congenital heart defects (CHD) are structural malformations found at birth with a prevalence of 1%. The clinical trajectory of CHD is highly variable and thus in need of robust diagnostics and therapeutics. Major surgical interventions are often required for most CHDs. In Africa, despite advances in life sciences infrastructure and improving education of medical scholars, the limited clinical data suggest that CHD detection and correction are still not at par with the rest of the world. But the toll and genetics of CHDs in Africa has seldom been systematically investigated. We present an expert review on CHD with lessons learned on Africa. We found variable CHD phenotype prevalence in Africa across countries and populations. There are important gaps and paucity in genomic studies of CHD in African populations. Among the available genomic studies, the key findings in Africa were variants in GATA4 (P193H), MTHFR 677TT, and MTHFR 1298CC that were associated with atrial septal defect, ventricular septal defect (VSD), Tetralogy of Fallot (TOF), and patent ductus arteriosus phenotypes and 22q.11 deletion, which is associated with TOF. There were no data on epigenomic association of CHD in Africa, however, other studies have shown an altered expression of miR-421 and miR-1233-3p to be associated with TOF and hypermethylation of CpG islands in the promoter of SCO2 gene also been associated with TOF and VSD in children with non-syndromic CHD. These findings signal the urgent need to develop and implement genetic and genomic research on CHD to identify the hereditary and genome-environment interactions contributing to CHD. These projected studies would also offer comparisons on CHD pathophysiology between African and other populations worldwide. Genomic research on CHD in Africa should be developed in parallel with next generation technology policy research and responsible innovation frameworks that examine the social and political factors that shape the emergence and societal embedding of new technologies.

Functional analysis of the congenital heart disease‑associated GATA4 H436Y mutation in�vitro

“…The same CHD phenotype can be caused by different mutations, and the same mutation may lead to different phenotypes in different patients (32). The occurrence of CHD is a complex process, involving genetic and environmental factors, epigenetic regulation and many other factors (33). In conclusion, the results of the present study may broaden the spectrum of known mutations in the GATA4 gene associated with congenital heart defects, and could provide novel insights into the mechanism underlying CHD.…”

Congenital heart disease in low‐and‐middle‐income countries: Focus on sub‐Saharan Africa

“…Data on the genetics of CHD specific to LMIC is nearly nonexistent. A comprehensive review by Thomford et al found that the vast majority of studies focused on phenotypes of CHD in Africa did not include genetic investigation (Thomford et al, 2018). There were a few African studies that showed that GATA4 (P193H), MTHFR 677TT, and MTHFR 1298CC were associated with atrial septal defect, ventricular septal defect, Tetralogy of Fallot, and patent ductus arteriosus F I G U R E 1 Global map showing percent of population living in multidimensional poverty (Alkire & Robles, 2015) (Al-Azzouny et al, 2016;Zidan, Rezk, & Mohammed, 2013).…”

The genetic workup for structural congenital heart disease

“…Next generation sequencing has become a powerful technology, both in the clinical and research setting, facilitating the interrogation of the entire exome or genome with massive parallel sequencing (Kruszka, Tanpaiboon, et al, 2017;Thomford et al, 2018). The major challenge of NGS is the growing amount of data generated that demands complex algorithms to analyze (Bien et al, 2019).…”