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The combination of three genetic mutations could generate congenital heart disease

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Wednesday, July 17, 2019

Researchers at the Gladstone Institutes and the University of California, San Francisco, USA, recently published an article in the journal Science showing that a combination of three different genetic variants can cause congenital heart disease.

To check the initial assumption that several genes would be involved in the development of the condition, a family with different cases of severe congenital heart disease was studied, in which an inadequate maturation of the heart was resulting in poor blood pumping. Several cases, both symptomatic and asymptomatic, were detected and the complete exome was sequenced. As a result, it was seen that the father had transmitted to his three descendants two harmful mutations of the genes MKL2 and MYH7. The MYH7 gene encodes for a myosin protein chain and MKL2 encodes for a member of the myocardin family, regulators of two protein elements essential for the formation of the heart.

Subsequently, the researchers searched for variants shared by the three children and the mother that could play a role in the functioning of the heart and effectively found a third mutation in the NKX2 gene. To demonstrate that, the combination of the three mutations or variants of the gene was responsible for the heart defects observed in the three children, the CRISPR genome-editing tool was used and mice carrying the three variants were created. The model mice that had only one of the three identified variants showed no signs of heart disease but those animals carrying the three mutations simultaneously showed the same defects as the children. To corroborate that this was also true in humans, the research team used cells from affected family members to generate induced pluripotent stem cells (iPS) and differentiate them into heart cells. After a few days, the same changes in gene expression that had been observed in the mice were observed. 

This finding paves the way for the identification of genetic disease modifiers and their use as targets for developing new therapies in the future.

Access to the original article: Oligogenic inheritance of a human heart disease involving a genetic modifier. Science.

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