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A research team led by UCL has identified a new gene as the cause of inherited heart disease affecting one in 500 people. The results of the study were published in the “European Heart Journal”. The finding provides a new causal explanation for 1-2% of adults with hypertrophic cardiomyopathy. (In the UK, that’s about 1,250 to 2,500 people.)
As a result of the study, the new causal variants, known as the truncating ALPK3 (alpha-protein kinase) variants, are expected to be added to genetic testing / screenings, allowing doctors to identify more people at risk of developing the disease. and who would therefore benefit from regular monitoring. In hypertrophic cardiomyopathy, the heart muscles are thicker, which can make it more difficult for the heart to receive and pump blood.
Although in most cases the disease does not affect daily life, it can cause heart failure and is frequently cited as the most common cause of sudden unexpected death in young people. About half of cases already have known genetic causes, linked to eight to ten specific genes (only two of these unique genes have been found in the past decade). Lead author Dr Luis Lopes (UCL Institute of Cardiovascular Science), also a consultant cardiologist at the Barts Health NHS Trust, said: “Hypertrophic cardiomyopathy is an extremely common genetic disease. Previous small-scale studies have suggested that variants of the ALPK3 gene may be a cause of a rare pediatric form of cardiomyopathy, but only when two abnormal copies have been inherited. “” We have now proven that one abnormal copy is sufficient. to cause hypertrophic cardiomyopathy in adults, looking at a large number of patients and families. This form of inheritance (autosomal dominant) is much more common, since inheriting only one abnormal copy of a gene is more likely than inheriting two, ”added Dr Lopes.“ Identifying a new genetic cause is important because it opens up new possibilities for potential treatment. It also helps families who have been affected by the disease, but were unsure why, to know that a cause has been found for their specific case, “continued Dr Lopes.
In the new study, an international team of researchers analyzed the genomes of 2,817 people with hypertrophic cardiomyopathy referred from centers in Spain, the UK, Denmark, Russia, Latvia, Brazil and Argentina. They compared the prevalence of ALPK3 variants with that of the general population, finding it to be 16 times more common. The researchers also studied the presence of the variant within families, checking whether it was causal or not by examining whether the variant was associated with the disease, that is, whether family members who had the disease. variant also had the disease.
The research team looked at the distinct nature of the disease from when it was caused by defects in sarcomere genes, the primary mode of transmission of the disease. (They were named the sarcomere genes because their function relates to the sarcomeres, the basic contractile unit, or primary building block, of muscle fiber.) They found that in cases where the new gene is involved , the disease was diagnosed later (at an average age of 56) but had rates of heart failure and heart transplantation similar to those in cases linked to the sarcomere genes. Although little is known about the functional consequences of ALPK3 variants, they are thought to play a role in the regulation of protein function through a process of phosphorylation. Proteins are fundamental for the process of contraction and relaxation of heart muscle cells.
Dr Lopes said: “The ALPK3 variants represent a pathway to disease that is different from other major causes known in sarcomere genes. This discovery is exciting because it will set new targets for therapies. We must now explore the mechanisms that explain how the ALPK3 variants are related to the condition. In the UK, genetic testing is offered to anyone diagnosed with hypertrophic cardiomyopathy at referral centers such as the Barts Heart Center and, if there is a known genetic cause, to family members as well. Although there is currently no cure, people with the disease are monitored regularly, given medication and an important intervention is the installation of an implantable cardioverting defibrillator (ICD), a device similar to a pacemaker that can deliver a strong electric shock to the heart if it detects a dangerously abnormal heart rhythm. The study received funding from the Medical Research Council and the British Heart Foundation.
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