Titin, genome-first: disease spectrum and modifiers of heritable cardiomyopathy

The National Heart, Lung, and Blood Institute awarded Geisinger Clinic $823,655 on August 17, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to assemble and harmonize genomic and phenotypic data across three large biobanks—MyCode at Geisinger, BioVU, and the UK Biobank—approaching one million individuals to understand the disease spectrum and clinical modifiers of titin gene protein-truncating variants (TTNTV) in heritable cardiomyopathy.

TTNTV account for roughly 20 percent of familial and idiopathic dilated cardiomyopathy cases but are present in approximately 1 percent of the general population, creating uncertainty about disease risk in otherwise healthy carriers. The research tests how TTNTV variant type and location modulate penetrance of arrhythmias and cardiomyopathy to identify variants warranting close clinical management. The project investigates three hypotheses: differences in variant pathogenicity across the TTN gene, the spectrum of cardiac structure and function that remains clinically undetected, and the "two-hit" phenomenon where secondary factors such as chemotherapy and pregnancy influence disease development in TTNTV carriers. All three biobanks include cardiac imaging data—echocardiogram and cardiac MRI—for many participants.

Work is performed in Danville, Pennsylvania, with a period of performance from August 17, 2026, through May 31, 2031. The assistance type is a Project Grant.

Abstract

Protein-truncating variants in the titin gene TTN (ttntv) are the most common cause of familial and idiopathic dilated cardiomyopathy (DCM), accounting for roughly 20% of cases. Ttntv are also implicated in other cardiomyopathies, arrhythmias, and even sudden cardiac death. Because of these risks, IT is recommended to report "secondary" ttntv findings ascertained through genomic screening. However, ttntv are much more common (~1% prevalence in the general population) than familial DCM (~0.1% prevalence). Therefore, if an otherwise healthy individual is identified with a ttntv, the risk of developing heart disease is poorly understood. The observed variability in outcomes for individuals with ttntv may be due to: 1) differences in variant pathogenicity across the TTN gene, 2) a resultant spectrum of cardiac structure and function that remains clinically undetected, and 3) the 'two-HIT' hypothesis, where DCM and associated comorbidities in ttntv are influenced by secondary factors such as chemotherapy and pregnancy. Understanding the impact of each of these phenomena and their links to disease will advance precision therapies and inform clinical management of genomic screening identification of ttntv. This proposal leverages three large biobanks approaching one million individuals to address these hypotheses in the following ways: in aim 1, we will assemble and harmonize genomic and phenotypic data across three of the largest biobanks with genome-wide sequencing data linked to extensive phenotypic (i.e. health record) information: mycode at geisinger, biovu, and the UK biobank. We will then test how ttntv variant type and location modulates penetrance of arrhythmias and cardiomyopathy to identify variants that may warrant close clinical management. All three biobanks include cardiac imaging data for many participants, including echocardiogram and cardiac MRI data. In aim 2, these data will be used to make group-wise comparisons of both clinical and sub-clinical cardiac structure (muscle mass, chamber volumes, tissue composition) and function (ejection fraction, filling ratio, strains, and strain rates). Further, mycode supports targeted participant recontact for prospective study. To determine if ttntv causes subclinical cardiac damage, we will recruit and compare mycode participants with ttntv but no history of diagnosed heart disease to matched controls using advanced cardiac MRI to assess diastolic dysfunction, myocardial strain, torsion, and dyssynchrony. In aim 3, we will test how candidate second "hits", such as hypertension or coronary artery disease, interact with ttntv to heighten disease risk. The unique resources amalgamated through this project will enable US to comprehensively investigate for the first time this two-HIT hypothesis from a genome-first perspective and conduct a comprehensive investigation to identify yet unknown secondary triggers that will launch future clinical trials. Upon completion, these aims will improve risk stratification by characterizing the spectrum of ttntv-associated disease and its triggers, directly informing management recommendations for genomic screening initiatives.