An Israeli study has identified TRIM63 as a significant genetic contributor to hypertrophic cardiomyopathy – the most common hereditary heart disease worldwide. The findings could transform genetic screening and treatment protocols for sufferers around the globe.
HCM is an incurable but often-undiagnosed type of heart disease that affects about one out of 500 people, some of whom will have a normal life expectancy but others who are at risk for complications including heart failure and sudden death.
The disease is an autosomal dominant condition, meaning it originates from one of the 22 non-sex chromosomes and needs transmission from only one parent, not both. People therefore have a 50% risk of inheriting it or passing on its predisposition to their children. HCM causes the heart muscle to become thickened, making it more difficult for the heart to pump blood.
It is a well-known cause of sudden death in athletes; almost half of deaths due to this condition happen during or just after some type of physical activity.
The symptoms include rapid, fluttering, or pounding heartbeats; chest pain; swelling of the legs, ankles, feet, stomach area, and neck veins; and shortness of breath or trouble breathing with activity or even at rest.
Ways to avoid complications, especially if one’s genes caused it, include not smoking, not taking diet pills or over-the-counter cold medications, avoiding saunas and hot tubs, and staying away from street drugs like cocaine and meth that are extremely dangerous for HCM patients.
Losing weight, light walking, reducing stress with relaxation techniques such as deep breathing, and treating hypertension (high blood pressure) can help ease symptoms.
There are also medications including beta-blockers and calcium channel blockers or other newer medicines prescribed to help the heart contract and relax properly. A defibrillator that identifies life-threatening heart rhythms and sends an electrical pulse to stop them is often inserted in significant cases, but when blood flow out of the heart is severely blocked, an open-heart operation called surgical myectomy may be done.
NOW, A PIONEERING study at the Clalit Research Institute and the Rabin Medical Center-Beilinson branch in Petah Tikva has revealed that the TRIM63 gene is a major genetic driver and risk factor for HCM. The team, led by Rabin’s Dr. Noa Ruhrman Shahar and Prof. Shay Ben-Shachar of the research institute, provides persuasive evidence for the gene’s role in both causing and increasing susceptibility to the heart condition.
The researchers urge its inclusion in global diagnostic panels for genetic diseases. Despite growing evidence, TRIM63 is missing from many commercial HCM gene panels, largely due to prolonged uncertainty about its involvement in the disease. This new research provides strong justification for its immediate inclusion in diagnostic protocols – particularly in high-risk or underrepresented populations, the team urged.
The study has just been published in the journal Circulation: Genomic and Precision Medicine under the title “Mono and biallelic variants in TRIM63 are frequently associated with a unique form of hypertrophic cardiomyopathy, could transform genetic screening and treatment protocols for HCM patients around the globe.”
“This is a life-saving discovery,” Ruhrman Shahar wrote. “Recognizing carriers of disease-causing TRIM63 mutations enables early monitoring and intervention, dramatically lowering the risk of severe, even fatal, cardiac events.”
Procedure of the study
The team followed 107 unrelated HCM patients using advanced exome-based gene panels, drawing from diverse populations including Ashkenazi Jews, North African and Middle Eastern Jewish communities, and Muslim Arabs. They found 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 were found 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 (277C>T) was identified as relatively common among Jews of Libyan descent, with an estimated disease frequency of one in 14,400. This highlights the importance of targeted screening in genetically isolated or consanguineous populations (people who marry first cousins).
These findings provide vital new insight,” Ben-Shachar said. “Beyond advancing our scientific understanding, they offer a real opportunity to prevent complications in thousands of high-risk patients through personalized care.”
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 Israel, making use of Clalit’s unique genomic database – one of the largest and most diverse in the country.
“Our findings represent a major step forward in cardiac genetics,” concluded 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.”