University of Pittsburgh School of Medicine researchers have identified two genes responsible for the congenital heart defect hypoplastic left heart syndrome (HLHS).
HLHS is a rare structural abnormality in the heart that is present from birth, affecting between 2 and 3 live births in every 10,000 in the United States. With HLHS, the left side of the heart is not well developed, hampering the pumping of blood around the body. The defect is severe and will result in death if the condition is not treated.
HLHS can be treated with surgery, although multiple surgeries are required during childhood and the procedures are complex. Some patients however do not respond well to surgery and will go on to suffer heart failure if a heart transplant is not provided.
While the condition was known to result from genetic mutations, the gene or genes responsible for the condition were unknown. The University of Pittsburgh researchers discovered genetic mutations that caused the condition in mice.
The researchers said their study was made possible by leveraging the results of a large-scale analysis in mice to recover genetic mutations causing congenital heart defects. That analysis allowed the researchers to recover mice models of HLHS.
Cecilia Lo, Ph.D., professor at Pitt’s School of Medicine, said “Analysis of these mice with HLHS allowed us to identify for the first time two genes interacting in combination to cause HLHS.”
The team identified eight mice with experimentally induced HLHS using ultrasound imaging. The team then compared the genomes of those mice with normal healthy mice to identify genetic mutations. The team identified hundreds of mutations in the HLHS mice, although the mutations were concentrated in two chromosomal regions. Those regions matched the findings from studies on humans with the condition.
The team found that only when mutations were present in two genes – Sap130 and Pcdha9 – did the mice develop HLHS. The team was able to confirm that the two genes caused HLHS by editing the genes using the CRISPR-Cas9 tool. If mice only had one mutation in gene Pcdha9 the effect was a defect in the aorta rather than the left ventricle. The gene pair was also found to cause mitochondrial defects, suggesting both genes played a role in regulating metabolic function in cardiac muscle.
While surgery can correct the left ventricle, Lo explained that it would do nothing to correct cellular defects. Now that the genes responsible for causing the condition have been identified, along with the cellular defects involved, it is hoped that new therapies can be developed to improve the prognosis for patients with the condition.
The study – The complex genetics of hypoplastic left heart syndrome – has recently been published in the journal Nature Genetics.