03 February 2023
A new mutation makes a heavy heart
Published online 14 September 2021
The discovery of a genetic mutation points to novel mechanisms behind a congenital heart condition.
A novel genetic variant has been linked with abnormal thickening of heart muscles, a condition known as hypertrophic cardiomyopathy (HCM). HCM is one of the most common inherited cardiac conditions, and the new findings could be used to improve screening and diagnosis.
The research was carried out by an international, interdisciplinary team of geneticists, cardiovascular clinicians, molecular biologists and data scientists, which included researchers at Cairo University and the Aswan Heart Centre in Egypt. The researchers sequenced data from about 500 Egyptian HCM patients at the Aswan Heart Center and identified a genetic variant linked with the condition. The change, a single base deletion in a gene already known to be linked with HCM, was present in 3.3% of the patients but not in control samples, in two genome databases, or in more than 6,000 White HCM patients.
Analysis of published data from non-Middle Eastern HCM studies found that the variant was only reported once outside the Middle East, though many non-European populations have not been sufficiently studied. “It is important to state here that the Egyptian population is ethnically and genetically heterogeneous,” says lead author Yasmine Aguib. More future in depth analysis will help us understand the ethnic specificity of the variant.” Aguib also points out that “studying different populations with different ethnicities reflected in their genetic background can boost the global understanding of disease etiologies and mechanisms, which benefits not only patients of a specific ethic background but also the global patient community.”
The team next carried out a detailed study of the extended family of a hypertrophic cardiomyopathy patient. Cardiologists diagnosed family members without knowing their genotype and reported HCM in six of the sixteen they examined. The presence of the variant was subsequently confirmed in all six, none of whom had mutations in other HCM-related genes.
Known HCM-linked variants in this gene produce proteins with a change in their structure and function. This specific variant produces a truncated version of the protein, making it a new class of pathogenic HCM variants. This means that, in addition to being useful for screening and diagnosis, it also reveals a previously unknown mechanism behind HCM. “Future studies will dissect this possible mechanism in order to understand how it contributes to the disease phenotype and how the development of the disease can be reversed,” says Aguib.
Aguib, Y. et al. New variant with a previously unrecognized mechanism of pathogenicity in hypertrophic cardiomyopathy. Circulation 144, 754-757 (2021).