Research identifies new cause of inherited heart condition

A research team led by the University of London has discovered a novel gene that may be responsible for an inherited cardiac ailment that affects one in every 500 people.

European Heart Journal reported the study’s findings, which were published in full in the journal.

The study provides a novel causal explanation for the 1-2 percent of individuals who have hypertrophic cardiomyopathy that previously had no explanation. (In the United Kingdom, this translates to around 1,250-2,500 persons.)

Consequently, doctors should include the new causal variants, known as truncating ALPK3 (alpha-protein kinase) variants, in genetic testing and screening, allowing them to identify an increased number of people who are at risk for developing the condition and who would benefit from regular monitoring.

Hypertrophic cardiomyopathy is characterized by thicker heart muscles, which can make it more difficult for the heart to receive and pump blood.

While the illness will not interfere with daily activities in the vast majority of instances, it can induce heart failure and is usually listed as the most prevalent cause of sudden unexpected death in adolescents and young adults.

Approximately half of all instances have already been identified as having genetic origins, which have been connected to eight to ten particular genes (only two of these single genes were found in the last decade).

Dr Luis Lopes (UCL Institute of Cardiovascular Science), who is also a Consultant Cardiologist at Barts Health NHS Trust, remarked, “Hypertrophic cardiomyopathy is a genetic disorder that affects a large number of people.” The ALPK3 gene has been linked to an uncommon juvenile cardiomyopathy in small-scale investigations in the past, but only when two defective copies of the gene were passed down.

“By studying a large number of patients and their families, we have now demonstrated that only one defective copy is sufficient to develop hypertrophic cardiomyopathy in adults. “This type of inheritance (autosomal dominant) is significantly more common than the other types of inheritance since inheriting just one abnormal copy of a gene is more likely than getting two faulty copies,” Dr Lopes explained.

A new genetic cause is crucial because it opens the door to new approaches for future treatment,” says the researcher. Additionally, it provides comfort to families who have been impacted by the ailment but did not understand why, by letting them know that a reason has been identified for their individual case,” Dr Lopes stated.

In the current study, an international team of researchers examined the genomes of 2,817 persons with hypertrophic cardiomyopathy who were referred to the study from centers in Spain, the United Kingdom, Denmark, Russia, Latvia, Brazil, and Argentina, among other countries, for analysis.

When the researchers compared the prevalence of ALPK3 variations with that of the general population, they discovered that they were 16 times more prevalent.

The presence of the variant within families was also investigated, with the goal of determining whether or not the variant was causal by examining whether or not the variant tracked with the disease — that is, whether or not family members who had the variant also had the condition.

The research team contrasted the distinct character of the disease when it was caused by flaws in the sarcomere genes — which is the primary way the disease is inherited — to when it was caused by other causes. (“Sarcomere genes,” because their activity is related to sarcomeres, which are the fundamental contractile unit, or primary building component, of muscle fiber,” explains the research team.)

Interestingly, they discovered that, in cases where the novel gene was implicated, the condition was identified later (on average at the age of 56), but that the rates of heart failure and heart transplantation were comparable to those in cases associated to sarcomere genes.

It is hypothesized that ALPK3 variations have a role in the control of protein function through the process of phosphorylation, despite the fact that little is known about the functional ramifications of the ALPK3 variants.

In the process of cardiac muscle cells contracting and relaxing, proteins play a critical role.

In his words, “ALPK3 mutations represent a distinct pathway to the disease than the other main known causes in the sarcomere genes,” Dr Lopes explained. This discovery is interesting because it will lead to the identification of novel therapeutic targets. This means that we must now investigate the processes that explain how the ALPK3 mutations are associated with the disease.”

In the United Kingdom, genetic testing is available to all persons who have been diagnosed with hypertrophic cardiomyopathy at referral centers such as Barts Heart Centre, as well as to their family members if there is a known hereditary etiology for the condition.

At the moment, there is no cure for the condition; however, people who have it are monitored on a regular basis and medicated; one important intervention is the placement of an implantable cardioverter-defibrillator (ICD), which is a device that is similar to a pacemaker and is capable of delivering a powerful electric shock to the heart if it detects a dangerously abnormal heartbeat.

A grant from the Medical Research Council as well as a grant from the British Heart Foundation supported the research.