Whole Exome Sequencing of Congenital Heart Disease Patients in Sub-Saharan Africa

My research is on the genetics of congenital heart disease (CHD), and although it is one of the most common birth defects, the genetic causes of most cases are unknown. So I’m always interested to read new papers on the topic to see how different groups are addressing the problem and to find new candidate disease genes to look into.

A group at the NIH led by Dr. Paul Kruszka recently published a paper in Circulation: Genomic and Precision Medicine titled “Exome Sequencing and Congenital Heart Disease in Sub-Saharan Africa”. The authors begin by pointing out that while there are many studies using whole-exome sequencing to identify genes associated with CHD, these cohorts are primarily made up of patients of European descent. However, CHD and the pathogenic variants that cause it do not discriminate based on ethnicity. This group sought to help fill the gap in research on non-syndromic CHD cases in sub-Saharan Africa.

Using data from 98 trios of patients and their parents, they identified de novo variants (found in a patient but not their parents) or singleton variants (found only in one patient) in 9 genes known to cause CHD. They also identified several very rare protein-truncating variants in 5 known CHD genes and 3 novel candidate genes that are predicted to be intolerant to loss-of-function. They functionally tested high-interest candidate genes in knockout Drosophila models, as they have similar cardiac developmental networks to humans. These experiments identified 4 genes that resulted in elevated fly mortality which were not previously associated with CHD (UBB, EIF4G3, SREBF1, and METTLE23).

For me, the main takeaway from this paper is tied to its limitations of small sample size and lack of a control population for testing variant burden. We need to focus on creating diverse and representative patient and control cohorts in sequencing studies to identify novel disease-causing genes and pathways and prevent misclassification of variants. In accomplishing that, our research can be as meaningful as possible to as many patients as possible.


Ekure EN, et al. Exome Sequencing and Congenital Heart Disease in Sub-Saharan Africa. Circulation: Genomic and Precision


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