They clear up a mystery about two brothers with the same heart disease but different effects

2023-07-14 14:45:38

One of the maxims that experts in medical genetics follow is that it is not just a mutation that defines a disease of genetic origin: there are many other factors that intervene and that make each patient a different case.

A clear example is that of two brothers affected by hypertrophic cardiomyopathy, the most common inherited heart condition. Both carry the same disease-causing mutation, but one has much more severe cardiomyopathy than the other.

In order to explain these differences, a team from the Bellvitge Biomedical Research Institute (IDIBELL), located in Hospitalet de Llobregat and which is one of the CERCA institutions of the Generalitat of Catalonia, has generated a cellular model of the heart from stem cells from both brothers.

The work has been carried out in collaboration with researchers from the Familial Cardiopathies Unit of the University Hospital Complex of A Coruña, the Josep Trueta Hospital in Girona, and the National Center for Cardiovascular Research (CNIC), in Spain.

The study, which has been published in the academic journal Circulation Research, shows that the greater severity of heart disease in one of the brothers is due to a genetic variant, in addition to the original mutation, only present in him.

Members of the research team. (Photo: IDIBELL)

Thanks to the model, it has been possible to find the cause of the most severe pathology without the need to carry out a larger epidemiological study, with a much larger number of patients and investing much more time and money.

“Knowing the individual genetic variants responsible for each of the pathological manifestations is the first step in finding the most effective treatment for that specific patient,” explains Dr. Ángel Raya, project leader, who is an ICREA research professor at the IDIBELL, where he coordinates the Regenerative Medicine Program, and director of the Clinical Translation Program of Regenerative Medicine of Catalonia (P-CMR[C]).

“We can modify the genes of the heart model with stem cells and see the effects, to decipher which variant is responsible for the most severe pathology in one of the siblings,” adds Dr. Rubén Escribá, co-author of the study.

Brother hearts in the laboratory

To generate the protagonist model of this work, a skin biopsy was performed on each of the siblings. The obtained cells were transformed into stem cells that later differentiated into cardiomyocytes, heart cells. In culture, these cells are even capable of beating spontaneously.

The IDIBELL team took advantage of the latest CRISPR gene editing tools to identify the genetic variants of each sibling and try to add or remove them in the heart model to resolve which ones were responsible for each pathological manifestation.

The researchers found that the most severely affected sibling was the only one with an additional genetic variant to the original mutation that caused their cells to not contract correctly. The different functional tests with the heart model showed that this variant was responsible for the fact that he presented much more serious clinical manifestations than his sister. “This type of model allows us to get closer to personalized medicine every day, analyzing each case in depth and offering a more effective individualized treatment with fewer unwanted side effects”, highlights Dr. Raya, who is also a member of the Center for Biomedical Network Research in Biomaterials and Nanomedicine (CIBERBBN) in Spain. (Source: IDIBELL)