Key Gene Identified in Common Heart Disease Unlocks Life-Saving Diagnostic Potential

Hypertrophic cardiomyopathy (HCM) is the most prevalent hereditary heart disease globally, affecting approximately 1 in 200 individuals, and remains a leading cause of heart transplantation. Many people with HCM are unaware they have the condition until symptoms manifest, often when the disease has already progressed to a more severe stage. Now, a groundbreaking study has identified TRIM63 as a significant genetic factor contributing to HCM. The findings, published in Circulation: Genomic and Precision Medicine, have the potential to revolutionize genetic screening and treatment protocols for HCM patients worldwide.

The study, conducted by researchers at Clalit Research Institute (Ramat-Gan, Israel), provides compelling evidence of the gene’s role in both the causation and increased susceptibility to HCM. The researchers analyzed 107 unrelated HCM patients using advanced exome-based gene panels, focusing on diverse populations such as Ashkenazi Jews, Muslim Arabs, and North African and Middle Eastern Jewish communities. The study found biallelic (two-copy) pathogenic TRIM63 variants in 4.7% of the patients, accounting for 18.5% of all genetic diagnoses in the cohort. These patients displayed early-onset, severe heart muscle thickening, frequent arrhythmias, and recurrent fainting episodes, with some requiring implantable defibrillators (ICDs) before receiving their genetic diagnosis. Additionally, monoallelic (single-copy) pathogenic variants were identified in 7.5% of patients. Compared to a non-cardiac control group, these variants were found to be 8.2 times more common in HCM patients, strongly suggesting that even one faulty copy of TRIM63 significantly increases the risk of developing HCM.

The study also uncovered a previously undocumented mutation (c.277C>T), which was notably common among individuals of Libyan Jewish descent, with an estimated disease frequency of 1 in 14,400. This highlights the importance of targeted screening in genetically isolated or consanguineous populations. Despite accumulating evidence, TRIM63 is still absent from many commercial HCM gene panels, primarily due to historical uncertainty surrounding its role in the disease. This new research provides compelling evidence to include TRIM63 in diagnostic protocols, especially in high-risk or underrepresented populations. The study also emphasizes the benefits of exome-based genetic testing, which allows for continuous reanalysis and the easy inclusion of newly validated genes, offering far more flexibility than traditional static, gene-specific panels.

“This is a life-saving discovery. Recognizing carriers of disease-causing TRIM63 mutations enables early monitoring and intervention, dramatically lowering the risk of severe, even fatal, cardiac events,” said Dr. Ruhrman Shahar who led the study. “Our findings represent a major step forward in cardiac genetics. This mutation causes severe cardiomyopathy and should be recognized as a key risk factor for heart dysfunction. We believe these insights will impact millions worldwide, both in diagnosis and in care.”

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