Some people carry a genetic change in a heart gene called TTN. This change is surprisingly common, and most people who have it feel completely healthy. But for some, it can increase the risk of developing heart disease later in life. We want to understand why some of these people get heart disease, while others don't.

One potential explanation is the “two‑hit” hypothesis:

• First hit: A person is born with a genetic variant (like a change in TTN) that makes the heart more vulnerable.

• Second hit: Additional stressors over time—such as high blood pressure, pregnancy, certain medications, alcohol, or other health conditions—place extra strain on the heart.

On their own, either factor may not cause disease. But together, they can push the heart past a tipping point, leading to problems like weakened heart muscle or heart failure.

What makes our approach different is that we work “genome‑first.” Instead of starting with patients who already have heart disease, we begin by identifying people with TTN variants through genetic data and then carefully study their health over time. This lets us detect early changes in heart function, identify which “second hits” matter most, and learn why some people stay healthy while others develop disease.

Ultimately, our goal is to predict risk earlier and prevent disease before it starts, by combining genetic information with real‑world health factors.

In some people, problems with the heart’s electrical system—such as abnormal rhythms or pacing—can reduce the heart's pump function. This condition, called abnormal conduction–induced cardiomyopathy (ACCM), is often overlooked but can lead to serious complications like heart failure if not recognized early.

The good news is that this form of heart disease is usually reversible. When the underlying electrical problem is treated, heart function improves.

However, not everyone who has electrical problems develops ACCM. We are studying whether genetic changes are a culprit. By identifying patterns that link genetic variation with specific rhythm-related heart problems, we seek to improve early detection, clarify the true cause of heart dysfunction, and help guide the most effective, personalized treatments.

This work will help clinicians recognize and treat this condition earlier, preventing long-term damage and improving patient outcomes.

In collaboration with researchers at multiple institutions with access to large biobanks, we are conducting studies to investigate novel genes and variants associated with dilated (DCM) and hypertrophic (HCM) cardiomyopathies. DCM and HCM are common and often inherited causes of heart failure and sudden cardiac death. However, in many patients, the underlying genetic cause is still unknown, and genetic test results are often difficult to interpret.

These projects use large-scale biobank data (over 1 million participants) to better understand how genetic variation contributes to heart disease. By combining DNA sequencing, clinical data, and patterns of shared ancestry across populations, we aim to identify which genes truly cause disease, clarify uncertain genetic findings (variants of uncertain significance), discover new genes and pathways involved in cardiomyopathy, and define how specific genetic variants affect disease risk, presentation, and outcomes.

A key innovation is leveraging shared genetic segments across distant relatives to identify additional carriers of rare variants—even in individuals without full sequencing data—dramatically increasing the power to detect meaningful associations.

Together, this work will improve the accuracy and clinical usefulness of genetic testing, enabling more precise diagnosis, risk prediction, and treatment for patients and families affected by cardiomyopathy.