Hereditary cardiomyopathies (CMPs) are diseases related to impaired structure and function of the heart muscles and cavities, which greatly contribute to cardiovascular mortality. These conditions can be grouped into three main categories: arrhythmogenic cardiomyopathy (ACM), dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Whilst these diseases differ in which part of the heart they affect and how they reduce life expectancy in the patients that are diagnosed with them, all three of them usually stem from genetic causes.
Currently, a list of genes has been found to cause CMPs, and scientific literature shows definitive evidence of their link to the three types. This is why they are generally targeted by diagnostic tests for patients. However, recent advances in Next-Generation Sequencing (NGS) have allowed us to focus on more minor gene variants in order to analyse their importance in the rise of CMPs. The suggested read for this month presents the analysis of several databases, including ClinGen, ClinVar and GeneReviews, that summarise genetic variants, their clinical significance, and related health conditions, as well as recent scientific literature[1]. In the end, several new genes were classified according to their link with the presence of CMPs in patients, in several categories: moderate, limited, not associated, and not curated. Most importantly, this study highlights the importance of genetic testing to identify pathogenic mutations causing CMPs, which enables early diagnosis in asymptomatic and at-risk relatives.
Ultimately, 41 genes were identified based on evidence linking them to the prevalence of CMPs. The majority were autosomal dominant, indicating that a genetic variation in one copy of the gene resulted in an altered phenotype associated with ACM, DCM, or HCM. The analysis was conducted separately for each of the three diseases, and by referencing the three previously mentioned databases, a consensus could be reached for certain genes. However, for most genes, discrepancies between the databases prevented a definitive consensus. Additionally, the genes having definite evidence for being linked with CMPs were confirmed as such.
In addition to the classification step on the 41 genes of interest, the review paper focuses on the proportion of Pathogenic/Likely-Pathogenic variants (P/LP) and Variants of Uncertain Significance (VUS) for certain genes. Amongst these genes, examples which usually contain VUS are CTNNA3, ABCC9, MYH6 and MYOM1; in general, these genes contain the most variants.
In general, it is clear that cardiomyopathies are genetically diverse diseases that can result from mutations in multiple genes, some with minor or additive effects. Whilst major genes are primary drivers, minor genes may influence disease severity when combined with other variants. Understanding these minor genes is essential for improving prognosis assessment and exploring new therapies, as well as tailoring these treatments for patients and their families. For instance, the implementation of defibrillators for certain patients can be decided upon the identification of a gene responsible for the increased risk of sudden cardiac arrest. It is worth mentioning the 2024 American Heart Association (AHA) guidelines that summarise how to manage hypertrophic cardiomyopathy, and which highlight the importance of determining several aspects such as a patient’s risk for cardiac death or family history.
We at 4bases introduced the CARDIO pro kit designed for the characterisation of familial cardiovascular diseases, powered by NGS technologies. The panel contains genes related to inherited cardiomyopathies and allows the identification of SNVs and CNVs in both somatic and germline samples.
[1] Micolonghi, C.; Perrone, F.; Fabiani, M.; Caroselli, S.; Savio, C.; Pizzuti, A.; Germani, A.; Visco, V.; Petrucci, S.; Rubattu, S.; et al. Unveiling the Spectrum of Minor Genes in Cardiomyopathies: A Narrative Review. Int. J. Mol. Sci.2024, 25, 9787. https://doi.org/10.3390/ijms25189787
Ommen, S. R., Ho, C. Y., Asif, I. M., Balaji, S., Burke, M. A., Day, S. M., Dearani, J. A., Epps, K. C., Evanovich, L., Ferrari, V. A., Joglar, J. A., Khan, S. S., Kim, J. J., Kittleson, M. M., Krittanawong, C., Martinez, M. W., Mital, S., Naidu, S. S., Saberi, S., . . . Waldman, C. B. (2024). 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation, 149(23). https://doi.org/10.1161/cir.0000000000001250