Association of Titin Variations With Late-Onset Dilated Cardiomyopathy

Abstract

ilated cardiomyopathy (DCM) is a nonischemic, nontoxic, noninfectious, or nonvalvular heart muscle disease characterized by left ventricular or biventricular systolic dysfunction. 1,2 Typical onset of the disease is in the fourth or fifth decade of life and it affects predominantly male individuals with a male-to-female ratio of 3:1. 2 Although a specific cause might be unknown in a non-negligible number of patients, to date, more than one-third of familial forms and approximately 25% of sporadic cases have positive genetic testing for pathogenic (P) or likely pathogenic (LP) variants. [3][4][5][6] Recent evidence highlights the importance of specific genotypes in determining the prognosis of patients with DCM, either alone or in combination with environmental factors. [7][8][9][10][11] Contemporary analyses highlight that DCM is increasingly diagnosed in older patients 12 and a late-onset (ie, age >60 years) form of DCM could differ from more typical-onset DCM presentations. 13 However, the genetic background and the prognostic impact of genetic characterization among patients with DCM presenting who are older than 60 years are largely unknown.The aim of the present study was to investigate the genetic background and the natural history of a large international cohort of individuals with DCM presenting in individuals older than 60 years to assess the importance of genetic testing in those patients. Methods Study PopulationFor the present study, we included all consecutive patients with DCM older than 60 years at the time of diagnosis (ie, lateonset DCM), with available genetic testing analysis, from 7 international tertiary centers worldwide: Cardiovascular IMPORTANCE Dilated cardiomyopathy (DCM) is frequently caused by genetic factors. Studies identifying deleterious rare variants have predominantly focused on early-onset cases, and little is known about the genetic underpinnings of the growing numbers of patients with DCM who are diagnosed when they are older than 60 years (ie, late-onset DCM).OBJECTIVE To investigate the prevalence, type, and prognostic impact of disease-associated rare variants in patients with late-onset DCM. DESIGN, SETTING, AND PARTICIPANTSA population of patients with late-onset DCM who had undergone genetic testing in 7 international tertiary referral centers worldwide were enrolled from March 1990 to August 2020. A positive genotype was defined as the presence of pathogenic or likely pathogenic (P/LP) variants. MAIN OUTCOMES AND MEASURESThe study outcome was all-cause mortality.RESULTS A total of 184 patients older than 60 years (103 female [56%]; mean [SD] age, 67 [6] years; mean [SD] left ventricular ejection fraction, 32% [10%]) were studied. Sixty-six patients (36%) were carriers of a P/LP variant. Titin-truncating variants were the most prevalent (present in 46 [25%] of the total population and accounting for 46 [69%] of all genotype-positive patients). During a median (interquartile range) follow-up of 42 (10-115) months, 23 patients (13%) died; 17 (25%) of these were carriers o...

Assessment of the Diagnostic Yield of Combined Cardiomyopathy and Arrhythmia Genetic Testing

“…Age should also not exclude patients from genetic testing because this testing can reveal pathogenic variants in patients older than 60 years. Moreover, cardiomyopathies and arrhythmias may have overlapping clinical presentations, and variants in the same gene may produce more than 1 phenotype. For example, patients with positive findings in the SCN5A gene had a mix of referral indications, including specific arrhythmia subtypes, specific cardiomyopathy subtypes, and unknown subtypes.…”

The crucial role of titin in fetal development: recurrent miscarriages and bone, heart, and muscle anomalies characterize the severe end of titinopathies spectrum

“…It must be emphasized that in subjects in whom a truncating variant in titin is found as an incidental finding the penetrance is far from being complete, and it is reasonably lower than the penetrance reported for patients with a positive family history for cardiac diseases. 27,28 Together with our knowledge of the titinopathies spectrum, the number of clinicians involved in the diagnosis and management of these not-so-rare diseases is constantly growing. 29,30 Ever since TMD was discovered 31 , it has been mainly the neurologists who dealt with titinopathies.…”

Use of animal models to understand titin physiology and pathology

“…[6][7][8] A secondary genetic or non-genetic hit is, however, usually required to develop the cardiac disease. 9 The pathomechanism underlying titin-related cardiomyopathies is still unclear: a reduced expression of wild-type protein and the stable expression of truncated titin protein have been recently reported analysing myocardial tissue samples from patients with titin-related DCM. 10,11 Biallelic mutations, mainly TTNtv with few non-truncating variants, cause skeletal muscle diseases with or without a cardiac involvement.…”