Israeli breakthrough identifies key gene in common heart disease, unlocking life-saving diagnostic potential

A pioneering Israeli study has identified TRIM63 as a significant genetic contributor to hypertrophic cardiomyopathy (HCM)—the most common hereditary heart disease worldwide. The findings, published in Circulation: Genomic and Precision Medicine, could transform genetic screening and treatment protocols for HCM patients around the globe.

Led by Dr. Noa Ruhrman Shahar of Rabin Medical Center (Beilinson Hospital) and Professor Shay Ben-Shachar of the Clalit Research Institute, the study provides compelling evidence for the gene’s role in both causing and increasing susceptibility to HCM.

“This is a life-saving discovery,” said Dr. Ruhrman Shahar. “Recognizing carriers of disease-causing TRIM63 mutations enables early monitoring and intervention, dramatically lowering the risk of severe, even fatal, cardiac events.”

Key Findings

The study analyzed 107 unrelated HCM patients using advanced exome-based gene panels, drawing from diverse populations including Ashkenazi Jews, Muslim Arabs, and North African and Middle Eastern Jewish communities. The study uncovered:

• Biallelic (two-copy) pathogenic TRIM63 variants in 4.7% of patients—accounting for 18.5% of all genetic diagnoses in the cohort. These individuals exhibited early-onset, severe heart muscle thickening, frequent arrhythmias, and recurrent fainting episodes, with some requiring implantable defibrillators (ICDs) prior to their genetic diagnosis.
• Monoallelic (single-copy) pathogenic variants in an additional 7.5% of patients. Compared to a non-cardiac control group, these variants were found to be 8.2 times more common among HCM patients—strongly suggesting that even one faulty copy of TRIM63 significantly increases HCM risk.
• A previously undocumented mutation (c.277C>T) was identified as relatively common among individuals of Libyan Jewish descent, with an estimated disease frequency of 1 in 14,400—highlighting the importance of targeted screening in genetically isolated or consanguineous populations.

“These findings provide vital new insight,” said Prof. Ben-Shachar. “Beyond advancing our scientific understanding, they offer a real opportunity to prevent complications in thousands of high-risk patients through personalized care.”

Rewriting the Genetic Playbook

Despite growing evidence, TRIM63 is currently absent from many commercial HCM gene panels, largely due to historic uncertainty surrounding its role. This new research provides strong justification for its immediate inclusion in diagnostic protocols—particularly in high-risk or underrepresented populations.

The study also highlights the advantages of exome-based genetic testing, which allows for ongoing reanalysis and the seamless addition of newly validated genes—offering far greater flexibility than static, gene-specific panels.

Global Implications

Incorporating TRIM63 into standard HCM testing could lead to:

• Earlier and more accurate diagnoses
• Targeted surveillance for patients and at-risk family members
• Personalized treatment plans tailored to genetic risk
• Improved clinical outcomes and quality of life

This landmark research was made possible through a national collaboration between the Clalit Research Institute and Rabin Medical Center, as well as other leading institutes in Israe, leveraging Clalit’s unique genomic database—one of the largest and most diverse in Israel.

Clalit is Israel’s largest healthcare organization, serving over half the population and operating 14 innovation hubs across hospitals and community settings.

The research reflects the growing impact of the Berkowitz Family Living Laboratory, a partnership between Clalit and Harvard Medical School’s Department of Biomedical Informatics. This collaboration advances the use of AI and data science to improve patient care worldwide.

“Our findings represent a major step forward in cardiac genetics” concluded Dr. Ruhrman Shahar. “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.”

Link to the Publication: https://www.ahajournals.org/doi/10.1161/CIRCGEN.124.004864