Genetic Mutation May Not Predict Heart Disease


A recent study from Penn Medicine found that just 5% of patients with a mutation of the TTN gene have dilated cardiomyopathy.

heart disease

A recent study has found that a cardiac genetic mutation may not be as reliable in predicting heart disease as once thought.

Investigators from Penn Medicine examined more than 70,000 participants and found that 95% of patients with a mutation in the titin (TTN) gene did not have idiopathic dilated cardiomyopathy (DCM) or signs of cardiac decline.

“It’s clear that these gene mutations have a real effect on one’s heart, and yet, there are a lot of people carrying the deleterious mutations right now who are fine,” said the study author Zoltan Arany, MD, PhD, a professor of cardiovascular medicine at the Perelman School of Medicine at the University of Pennsylvania.

Investigators sought to determine the impact of truncating variants of the TTN (TTNtvs), which impact about 1% of the worldwide population, with cardiomyopathy. Investigators used data from the Geinsinger MyCode Community Health Initiative and the Penn Medicine BioBank (PMBB) to identify a total of 71,413 individuals with the gene mutations.

Data available included diagnoses, test results, and imaging results. Through the use of electronic health records, investigators were able to evaluate associations of TTNtvs with diagnoses and quantitative echocardiographic measures.

Investigators’ analyses were adjusted for age, sex, and principal components of ancestry. Additionally, investigators used results from the Jackson Heart Study to validate specific analyses for individuals of African ancestry.

Of the 61,040 individuals identified through he Geisinger, 0.6% were identified with a TTNtv in a highly expressed exon (hiPSI). Of the 10,273 individuals identified through the PMBB, 1.2% were identified with a hiPSI TTNtv.

Investigators found that the presence of hiPSI TTNtv was associated with increased odds of DCM in individuals of European ancestry (95% CI 18.7 [9.1—39.4] (PMBB) and 10.8 [7.0–16.0] (Geisinger)). Conversely, investigators noted that hiPSI TTNtvs were not associated with DCM in individuals of African ancestry, even with a high DCM prevalence.

Investigators found that, among the 244 individuals of European ancestry with DCM in the PMBB cohort, hiPSI TTNtv carriers had lower left ventricular ejection fraction, and increased left ventricular diameter. Additionally, in the Geisinger cohort, hiPSI TTNtv carriers without a cardiomyopathy diagnosis had more atrial fibrillation (OR: 2.4 [1.6—3.6]), heart failure (OR: 3.8 [2.4– 6.0]), and lower left ventricular ejection fraction.

Within their conclusion, authors noted the study’s findings indicate that clinical identification of hiPSI TTNtv carriers could alter management strategies.

“If we were to find that the combination of a TTN gene mutation and a mutation in another gene causes people to get the disease, then we’d recommend genetic testing for both of the variants. But right now we still don’t know enough,” Arany said.

This study, titled “Genomics-first evaluation of heart disease associated with Titin-truncating variants,” is published in Circulation.

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