Association of Titin Variations with Late-Onset Dilated Cardiomyopathy

Antonio Cannatà*, Marco Merlo, Matteo Dal Ferro, Giulia Barbati, Paolo Manca, Alessia Paldino, Sharon Graw, Marta Gigli, Davide Stolfo, Renee Johnson, Darius Roy, Kevin Tharratt, Daniel I. Bromage, Jean Jirikowic, Antonio Abbate, Allison Goodwin, Krishnasree Rao, Amr Marawan, Gerry Carr-White, Leema RobertVictoria Parikh, Euan Ashley, Theresa McDonagh, Neal K. Lakdawala, Diane Fatkin, Matthew R.G. Taylor, Luisa Mestroni, Gianfranco Sinagra

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)


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 Participants: A 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 Measures: The 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 of P/LP variants, while 6 patients (5.1%) were genotype-negative. Conclusions and Relevance: Late-onset DCM might represent a distinct subgroup characterized by and a high genetic variation burden, largely due to titin-truncating variants. Patients with a positive genetic test had higher mortality than genotype-negative patients. These findings support the extended use of genetic testing also in older patients.

Original languageEnglish
Pages (from-to)371-377
Number of pages7
JournalJAMA Cardiology
Issue number4
Publication statusPublished - Apr 2022


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