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. 2022 Apr 1;7(4):371-377.
doi: 10.1001/jamacardio.2021.5890.

Association of Titin Variations With Late-Onset Dilated Cardiomyopathy

Antonio Cannatà  1   2   3 , Marco Merlo  1 , Matteo Dal Ferro  1 , Giulia Barbati  4 , Paolo Manca  1 , Alessia Paldino  1 , Sharon Graw  5 , Marta Gigli  1 , Davide Stolfo  1 , Renee Johnson  6   7   8 , Darius Roy  9 , Kevin Tharratt  10 , Daniel I Bromage  2   3 , Jean Jirikowic  5 , Antonio Abbate  11 , Allison Goodwin  12 , Krishnasree Rao  11 , Amr Marawan  11 , Gerry Carr-White  13 , Leema Robert  14 , Victoria Parikh  10 , Euan Ashley  10 , Theresa McDonagh  2   3 , Neal K Lakdawala  9 , Diane Fatkin  6   7   8 , Matthew R G Taylor  5 , Luisa Mestroni  5 , Gianfranco Sinagra  1
Affiliations

Association of Titin Variations With Late-Onset Dilated Cardiomyopathy

Antonio Cannatà et al. JAMA Cardiol. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Abbate reported grants from Novartis, Serpin Pharma, Olatec Pharma, R-Pharm, and Kiniksa and personal fees from Janssen, Merck, Novo Nordisk, Serpin Pharma, Olatec Pharma, Cromos Pharma, Kiniksa, Implicit Biosciences, Applied Biomed, and AstraZeneca outside the submitted work. Dr Parkih reports personal fees from BioMarin, Inc during the conduct of the study. Dr Ashley reported being founder of Personalis, DeepCell, and Silicon Valley Exercise Analytics; being founding adviser of Nuevocor; nonexecutive director of AstraZeneca; adviser for Apple, Cathay, Third Rock, Medical Excellence, Foresite, Novartis, SequenceBio, Genome, and Disney; grants from Bristol Myers Squibb, Takeda, Google, and Verily; and in-kind support from Samsung, Analog Devices, Illumina, PacBio, and Nanopore outside the submitted work. Dr McDonagh reported personal fees from AstraZeneca, Boehringer Ingleheim, Corpus, and Vifor Pharma outside the submitted work. Dr Lakdawala reported personal fees from Pfizer, Bristol Myers Squibb, Tenaya, Cytokinetics, and Sarepta outside the submitted work. Dr Mestroni reported grants from the National Institutes of Health and Fondation Leducq during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Diagnostic Yield and Genetic Landscape in the Late-Onset Dilated Cardiomyopathy Population
FLNC indicates filamin C; LMNA, lamin A/C; TTNtv, titin-truncating variants.
Figure 2.
Figure 2.. Sex Prevalence in the Total, Titin-Truncating Variants (TTNtv), and Other Genetic Variant Cohorts
Figure 3.
Figure 3.. Long-term Prognosis of Late-Onset Dilated Cardiomyopathy (DCM) According to Genetic Testing Results and Sex Distribution of Adverse Events
TTNtv indicates titin-truncating variants. aSignificant after Bonferroni correction.
See this image and copyright information in PMC

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