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 Robert; Victoria Parikh; Euan Ashley; Theresa McDonagh; Neal K. Lakdawala; Diane Fatkin; Matthew R.G. Taylor; Luisa Mestroni; Gianfranco Sinagra

doi:10.1001/jamacardio.2021.5890

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

Cardiovascular Sciences

Research output: Contribution to journal › Article › peer-review

27 Citations (Scopus)

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.

Original language	English
Pages (from-to)	371-377
Number of pages	7
Journal	JAMA Cardiology
Volume	7
Issue number	4
DOIs	https://doi.org/10.1001/jamacardio.2021.5890
Publication status	Published - Apr 2022

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10.1001/jamacardio.2021.5890

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Cannatà, A., Merlo, M., Dal Ferro, M., Barbati, G., Manca, P., Paldino, A., Graw, S., Gigli, M., Stolfo, D., Johnson, R., Roy, D., Tharratt, K., Bromage, D. I., Jirikowic, J., Abbate, A., Goodwin, A., Rao, K., Marawan, A., Carr-White, G., ... Sinagra, G. (2022). Association of Titin Variations with Late-Onset Dilated Cardiomyopathy. JAMA Cardiology, 7(4), 371-377. https://doi.org/10.1001/jamacardio.2021.5890

@article{5f7b0c2e3ba64c97a91f63cbda317904,

title = "Association of Titin Variations with Late-Onset Dilated Cardiomyopathy",

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.",

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

note = "Funding Information: 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. Funding Information: 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 Publisher Copyright: {\textcopyright} 2022 American Medical Association. All rights reserved.",

year = "2022",

month = apr,

doi = "10.1001/jamacardio.2021.5890",

language = "English",

volume = "7",

pages = "371--377",

journal = "JAMA Cardiology",

issn = "2380-6583",

publisher = "American Medical Association",

number = "4",

}

Cannatà, A, Merlo, M, Dal Ferro, M, Barbati, G, Manca, P, Paldino, A, Graw, S, Gigli, M, Stolfo, D, Johnson, R, Roy, D, Tharratt, K, Bromage, DI, Jirikowic, J, Abbate, A, Goodwin, A, Rao, K, Marawan, A, Carr-White, G, Robert, L, Parikh, V, Ashley, E, McDonagh, T, Lakdawala, NK, Fatkin, D, Taylor, MRG, Mestroni, L & Sinagra, G 2022, 'Association of Titin Variations with Late-Onset Dilated Cardiomyopathy', JAMA Cardiology, vol. 7, no. 4, pp. 371-377. https://doi.org/10.1001/jamacardio.2021.5890

TY - JOUR

T1 - Association of Titin Variations with Late-Onset Dilated Cardiomyopathy

AU - Cannatà, Antonio

AU - Merlo, Marco

AU - Dal Ferro, Matteo

AU - Barbati, Giulia

AU - Manca, Paolo

AU - Paldino, Alessia

AU - Graw, Sharon

AU - Gigli, Marta

AU - Stolfo, Davide

AU - Johnson, Renee

AU - Roy, Darius

AU - Tharratt, Kevin

AU - Bromage, Daniel I.

AU - Jirikowic, Jean

AU - Abbate, Antonio

AU - Goodwin, Allison

AU - Rao, Krishnasree

AU - Marawan, Amr

AU - Carr-White, Gerry

AU - Robert, Leema

AU - Parikh, Victoria

AU - Ashley, Euan

AU - McDonagh, Theresa

AU - Lakdawala, Neal K.

AU - Fatkin, Diane

AU - Taylor, Matthew R.G.

AU - Mestroni, Luisa

AU - Sinagra, Gianfranco

N1 - Funding Information: 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. Funding Information: 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 Publisher Copyright: © 2022 American Medical Association. All rights reserved.

PY - 2022/4

Y1 - 2022/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85125075486&partnerID=8YFLogxK

U2 - 10.1001/jamacardio.2021.5890

DO - 10.1001/jamacardio.2021.5890

M3 - Article

C2 - 35138330

AN - SCOPUS:85125075486

SN - 2380-6583

VL - 7

SP - 371

EP - 377

JO - JAMA Cardiology

JF - JAMA Cardiology

IS - 4

ER -

Association of Titin Variations with Late-Onset Dilated Cardiomyopathy

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