Titin-related familial dilated cardiomyopathy: factors associated with disease onset

Renee Johnson^{1

2}, Robert A Fletcher^{3

4

5}, Stacey Peters⁶, Monique Ohanian¹, Magdalena Soka¹, Andrei Smolnikov⁷, Katherine E Abihider⁸, Michael J Ackerman^{9

10

11}, Flavie Ader¹², Mohammed M Akhtar^{13

14}, Ahmad S Amin^{15

16}, Euan A Ashley^{17

18

19}, John J Atherton^{20

21}, Rachel Austin^{22

23}, Annette F Baas^{16

24}, Richard D Bagnall^{25

26}, Samantha Barratt Ross²⁷, Jean-Louis Blouin²⁸, Emily E Brown²⁹, Henning Bundgaard^{16

30

31}, Douglas Cannie^{13

32}, Przemyslaw Chmielewski³³, Gemma Correnti³⁴, Maria Generosa Crespo-Leiro³⁵, Matteo Dal Ferro^{16

36

37}, Lisa M Dellefave-Castillo^{38

39}, Fernando Dominguez^{16

40}, Dennis Dooijes^{16

24}, Anne M Dybro^{16

41}, Youssef Ed Demri⁴², Mohamed El Hachmi^{43

44}, Luis Escobar-Lopez^{16

40}, Sarah Jajesnica Foye⁴⁵, Maria Franaszczyk^{46

47}, Marta Gigli^{16

36

37}, Esther Gonzalez Lopez^{16

40}, Adeline Goudal^{16

48}, Sharon Graw⁴⁹, Michel Guipponi²⁸, Eric Haan⁵⁰, Jan Haas^{51

52

53}, Daniel J Hammersley^{14

54}, Frederikke G Hansen⁵⁵, Christopher S Hayward^{2

56

57}, Thomas Morris Hey⁵⁵, Stephane Heymans^{16

58

59}, Carolyn Y Ho⁶⁰, Arjan C Houweling⁶¹, Jodie Ingles^{2

62}, Angela Ingrey⁶³, Andrew Jabbour^{2

56

57}, Paul A James^{64

65}, Joeri A Jansweijer^{66

67}, Jan D H Jongbloed⁶⁸, Anne M Keogh^{2

56

57}, Jose M Larrañaga-Moreira⁶⁹, Ronald H Lekanne Deprez^{16

61}, Ivan Macciocca^{70

71}, Peter S Macdonald^{2

56

57}, Nicolas Mansencal^{16

72}, Julia Mansour⁷³, Cristina Martinez-Veira⁷⁴, Barbara McDonough⁷⁵, Julie McGaughran^{22

76}, Kristen Medo⁴⁹, Marco Merlo^{16

36

37}, Ewa Michalak³³, Lorenzo Monserrat⁷⁷, Helen Mountain^{78

79}, Steven A Muller^{16

80}, Anne M Murphy⁸¹, Brittney Murray²⁹, Emily C Oates^{7

82}, Elizabeth Ormondroyd^{83

84}, Nicholas Pachter^{78

85

86}, Alessia Paldino^{16

36

37}, Aurélien Palmyre^{16

87}, Naveen L Pereira^{9

11}, Kermshlise C Picard⁶⁰, Nicola Poplawski^{34

88}, Sanjay Prasad⁵⁴, Julie Proukhnitzky^{16

89}, Jean-Francois Pruny^{16

90}, Patricia Reant^{16

91

92}, Pascale Richard¹², Anne Ronan^{93

94}, Farbod Sedaghat-Hamedani^{51

52

53}, Christopher Semsarian^{26

95

27}, Garrett Storm⁴⁹, Sophie Stroeks^{16

59

96}, Petros Syrris¹³, Matthew R G Taylor⁴⁹, Kate Thomson^{83

97}, Tina Thompson^{64

65}, J Peter van Tintelen^{16

24}, Christoffer Rasmus Vissing^{98

99}, Kathryn E Waddell-Smith³⁴, Mathew Wallis^{73

100}, Dominica Zentner^{6

64

65}; Australian Genomics Cardiac Flagship; Clare Arnott^{27

101}, Ali J Marian¹⁰², Jaewon Oh¹⁰³, Siv Fokstuen²⁸, Cynthia A James²⁹, Roberto Barriales-Villa¹⁰⁴, Benjamin Meder^{51

52

53}, Karim Wahbi^{42

105}, John R Giudicessi^{9

11}, Victoria N Parikh¹⁰⁶, James S Ware^{14

107}, Nicolas Piriou^{16

108}, Caroline Rooryck^{16

109

110}, Neal K Lakdawala^{60

111}, Luisa Mestroni⁴⁹, Gianfranco Sinagra^{16

36

37}, Perry M Elliott^{13

32}, Hugh Watkins⁸³, Elizabeth M McNally^{38

39}, Philippe Charron^{16

87

90}, Karin Y van Spaendonck-Zwarts^{22

61

68}, Pablo Garcia-Pavia^{16

40

112}, Maria Luisa Peña-Peña¹¹³, Jens Mogensen^{16

114}, Alex Hoerby Christensen⁹⁸, Zofia T Bilińska³³, Torsten B Rasmussen^{16

41}, Jonathan G Seidman⁷⁵, Christine E Seidman^{60

75}, Anneline S J M Te Riele^{16

80}, Job A J Verdonschot^{16

59

96}, Yigal M Pinto^{16

115}, Imke Christiaans⁶⁸, Diane Fatkin^{1

2

57}

Collaborators, Affiliations

Collaborators

Australian Genomics Cardiac Flagship:
Lesley Ades, Dimithu Alankarage, Morgan Almog, Mohammad Al-Shinnag, John J Atherton, Rachel Austin, Richard D Bagnall, Chris Barnett, Gillian M Blue, Simon Bodek, Kirsten Boggs, Michael Bogwitz, Tiffany Boughtwood, Alessandra Bray, Marie-Jo Brion, Jaye Brown, Rob Bryson-Richardson, Leslie Burnett, Charlotte Burns, Michelle Cao, Will Carr, Sarah Casauria, Heather Chalinor, Yuchen Chang, Gavin Chapman, Theodosia Charitou, Belinda Chong, Felicity Collins, Gemma Correnti, Kathy Cox, Fiona Cunningham, Debjani Das, Jason Davis, Andrew Davis, Paul De Fazio, Michelle de Silva, Nicola Den Elzen, Sophie Devery, Julia Dobbins, Sally L Dunwoodie, Nathan Dwyer, Stefanie Elbracht-Leong, David Elliott, Annabel Enriquez, Diane Fatkin, Vanessa Fear, Miriam Fine, Keri Finlay, Denisse Garza, Eleni Giannoulatou, Laura Gongolidis, Belinda Gray, Cassie Greer, Eric Haan, Mathilda Haas, Bernadette Hanna, Richard Harvey, Janette Hayward, Carmen Herrera, Adam Hill, Georgie Hollingsworth, Georgina Hollway, Ari E Horton, Denise Howting, Jodie Ingles, Joanne Isbister, Matilda Jackson, Paul James, Sarah Jane-Pantaleo, Renee Johnson, Andrew Kelly, Sarah King-Smith, Edwin Kirk, Sarah Kummerfeld, Timo Lassman, Jonathon Lipton, Sebastian Lunke, Ivan Macciocca, Paul MacIntyre, Evanthia O Madelli, Amali Mallawaarachchi, Julia Mansour, Ellenore Martin, Jacob Mathew, Tessa Mattiske, Julie McGaughran, Alison McLean, James McNamara, Caroline Medi, Alejandro Metke, Di Milnes, Michael Milward, Ansley Morrish, Jim Morwood, Helen Mountain, David Mowat, Chai-Ann Ng, Natalie Nowak, Noelia Nunez Martinez, Monique Ohanian, Sinead O'Sullivan, Angela Overkov, Nicholas Pachter, Chirag Patel, Mark Perrin, Matthew Perry, Andreas Pflaumer, Peta Phillips, Thuan Phuong, Rachel Pope-Couston, Nicola K Poplawski, Preeti Punni, Michael C J Quinn, Sulekha Rajagopalan, Hariharan Raju, Emma M Rath, Matthew Regan, Jonathan Rogers, Mark Ryan, Sarah Sandaradura, Nicole Schonrock, Paul Scuffham, Christopher Semsarian, Isabella Sherburn, Mary-Clare Sherlock, Emma Singer, Carla Smerdon, Janine Smith, Renee Smyth, Magdalena Soka, Zornitza Stark, Raymond Sy, Dotti Tang, Jessica Taylor, Shelby Taylor, Michel Tchan, Tina Thompson, Jordan Thorpe, Alison Trainer, Gunjan Trivedi, Giulia Valente, Karin van Spaendonck-Zwarts, Jamie Vandenberg, Kunal Verma, Miranda Vidgen, Jitendra Vohra, Kathryn Waddel-Smith, Mathew Wallis, Robert G Weintraub, Meredith Wilson, David Winlaw, Lisa Worgan, Linda Wornham, Kathy Wu, Laura Yeates, Dominica Zentner

Affiliations

¹ Molecular Cardiology Division, Victor Chang Cardiac Research Institute, 405 Liverpool St, Darlinghurst, NSW 2010, Australia.
² School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Kensington, NSW 2052, Australia.
³ The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia.
⁴ Department of Public Health and Primary Care, British Heart Foundation Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, UK.
⁵ Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.
⁶ Department of Cardiology, Royal Melbourne Hospital, Melbourne, VIC, Australia.
⁷ School of Biotechnology and Biomolecular Sciences, Faculty of Science, UNSW Sydney, Sydney, NSW, Australia.
⁸ Division of Clinical Genetics, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁹ Department of Cardiovascular Medicine, Division of Heart Rhythm Services, Windland Smith Rice Genetic Heart Rhythm Clinic, Mayo Clinic, Rochester, MN, USA.
¹⁰ Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN, USA.
¹¹ Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN, USA.
¹² Department of Cardiogenetic and Myogenetic Molecular and Cellular, Metabolic Biochemistry, AP-HP Sorbonne Université, Pitié Salpêtrière Hospital, Paris, France.
¹³ Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK.
¹⁴ Cardiology Department, Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
¹⁵ Department of Clinical Cardiology, Heart Center, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.
¹⁶ European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), Amsterdam, The Netherlands.
¹⁷ Department of Medicine, Stanford University, Stanford, CA, USA.
¹⁸ Department of Genetics, Stanford University, Stanford, CA, USA.
¹⁹ Department of Biomedical Data Science, Stanford University, Stanford, CA, USA.
²⁰ Department of Cardiology, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
²¹ Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
²² Genetic Health Queensland Service, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
²³ Australian Genomics, Melbourne, VIC, Australia.
²⁴ Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
²⁵ Bioinformatics and Molecular Genetics Group, Centenary Institute, University of Sydney, Sydney, NSW, Australia.
²⁶ Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
²⁷ Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
²⁸ Department of Diagnostics, Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland.
²⁹ Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
³⁰ Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
³¹ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
³² Department of Inherited Cardiovascular Diseases, Barts Heart Centre, St Bartholomew's Hospital, London, UK.
³³ Unit for Screening Studies in Inherited Cardiovascular Diseases, National Institute of Cardiology, Warsaw, Poland.
³⁴ Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA, Australia.
³⁵ Heart Failure and Heart Transplant Unit, Complexo Hospitalario Universitario a Coruña, Centro de Investigación Biomédica en Red (CIBERCV), Instituto de Investigación Biomédica de A Coruña (INIBIC), Universidade da Coruña, La Coruña, Spain.
³⁶ Department of Cardiothoracovascular, Azienda Sanitaria Universitaria Integrata, Trieste, Italy.
³⁷ Department of Medicine, University of Trieste, Trieste, Italy.
³⁸ Center for Genetic Medicine, Northwestern University, Evanston, IL, USA.
³⁹ Center for Genetic Medicine, Bluhm Cardiovascular Institute, Chicago, IL, USA.
⁴⁰ Department of Cardiology, Hospital Universitario Puerta de Hierro, Instituto Investigación Sanitaria Puerta de Hierro-Segovia de Arana, CIBERCV, Madrid, Spain.
⁴¹ Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.
⁴² Cardiology Department, AP-HP, Cochin Hospital, Paris, France.
⁴³ Département de Génétique, AP-HP, Hôpital Européen Georges Pompidou, Service de Médecine Génomique des Maladies Rares, Paris, France.
⁴⁴ Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
⁴⁵ Team Titin, Inc . Pine Brook, NJ, USA.
⁴⁶ Department of Medical Biology, National Institute of Cardiology, Warsaw, Poland.
⁴⁷ Department of Medical Genetics, Warsaw Medical University, Warsaw, Poland.
⁴⁸ Service de Genetique Medicale, Centre Hospitalier Universitaire de Nantes, Nantes, France.
⁴⁹ Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado, Cardiovascular Institute, Aurora, CO, USA.
⁵⁰ Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia.
⁵¹ Department of Cardiology, Pneumology and Angiology, Heidelberg University Hospital, Heidelberg, Germany.
⁵² Informatics for Life, Heidelberg, Germany.
⁵³ DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
⁵⁴ National Heart and Lung Institute, Imperial College, London, UK.
⁵⁵ Department of Cardiology, Odense University Hospital, Odense, Denmark.
⁵⁶ Heart Transplantation Division, Victor Chang Cardiac Research Institute, Sydney, NSW, Australia.
⁵⁷ Cardiology Department, St Vincent's Hospital Sydney, 390 Victoria St, Darlinghurst, NSW 2010, Australia.
⁵⁸ Department of Cardiovascular Sciences, Centre for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium.
⁵⁹ Department of Cardiology, Maastricht University, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands.
⁶⁰ Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁶¹ Department of Human Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
⁶² Genomics and Inherited Disease Program, Garvan Institute of Medical Research, Sydney, NSW, Australia.
⁶³ Hunter Genetics, Hunter New England Local Health District, Newcastle, NSW, Australia.
⁶⁴ Genomic Medicine, Royal Melbourne Hospital, Melbourne, VIC, Australia.
⁶⁵ Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia.
⁶⁶ Department of Clinical and Experimental Cardiology, Amsterdam University Medical Centre, Amsterdam, The Netherlands.
⁶⁷ Department of Cardiology, Haga Teaching Hospital, The Hague, The Netherlands.
⁶⁸ Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands.
⁶⁹ Unidad de Cardiopatías Familiares, INIBIC, Complexo Hospitalario Universitario de A Coruña, Servizo Galego de Saúde, Universidade da Coruña, A Coruña, Spain.
⁷⁰ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
⁷¹ Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
⁷² Department of Emergency Medicine, AP-HP, Hôpital Ambroise Paré, Boulogne-Billancourt, France.
⁷³ Tasmanian Clinical Genetics Service and Tasmanian Health Service, Hobart, TAS, Australia.
⁷⁴ Unidad de Cardiopatías Familiares, CIBERCV, Madrid, Spain.
⁷⁵ Department of Genetics, Harvard Medical School, Boston, MA, USA.
⁷⁶ School of Medicine, The University of Queensland, Brisbane, QLD, Australia.
⁷⁷ Department of Cardiology, Health in Code, A Coruña, Spain.
⁷⁸ Genetic Services of Western Australia, Perth, WA, Australia.
⁷⁹ Genetic Counselling Department, Graduate School of Health, University of Technology Sydney, Sydney, NSW, Australia.
⁸⁰ Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
⁸¹ Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸² Department of Neurology, Sydney Children's Hospital, Sydney, NSW, Australia.
⁸³ Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
⁸⁴ NIHR Oxford Biomedical Research Centre, Oxford, UK.
⁸⁵ Genetic Services Department, King Edward Memorial Hospital, Perth, WA, Australia.
⁸⁶ School of Medicine, University of Western Australia, Perth, WA, Australia.
⁸⁷ Department of Genetics and Referral Center for Hereditary Cardiac Diseases, AP-HP, Hôpital Ambroise Paré, Boulogne-Billancourt, France.
⁸⁸ Discipline of Paediatrics, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
⁸⁹ Genetics and Cardiology Department, Sorbonne Université, AP-HP, INSERM UMRS_1166, IHU-ICAN, Hôpital Pitié-Salpêtrière, Paris, France.
⁹⁰ Sorbonne Université, Centre de Référence pour les Maladies Cardiaques Héréditaires ou rares, AP-HP, INSERM UMRS_1166, IHU-ICAN, Hôpital Pitié-Salpêtrière, Paris, France.
⁹¹ Service de Cardiologie, Centre Hospitalier Universitaire de Bordeaux, Université de Bordeaux, CIC 1401, Bordeaux, France.
⁹² French Reference Center in Inherited Cardiomyopathies, ERN GUARD-Heart, Bordeaux, France.
⁹³ Genetics Unit, Newcastle Medical Genetics, Newcastle, NSW, Australia.
⁹⁴ School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, NSW, Australia.
⁹⁵ Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, University of Sydney, Sydney, NSW, Australia.
⁹⁶ Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
⁹⁷ Oxford Regional Genetics Laboratories, Churchill Hospital, Oxford, UK.
⁹⁸ Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
⁹⁹ Cardiology Department, Hvidovre Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
¹⁰⁰ School of Medicine and Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
¹⁰¹ Cardiovascular Program, The George Institute for Global Health, UNSW Sydney, Sydney, NSW, Australia.
¹⁰² Center for Cardiovascular Genetic Research, Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX, USA.
¹⁰³ Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Korea.
¹⁰⁴ Inherited Cardiovascular Disease Unit, Complexo Hospitalario Universitario A Coruña, A Coruña, Galicia, Spain.
¹⁰⁵ Faculté de Médecine, Université Paris-Cité, Paris, France.
¹⁰⁶ Department of Medicine, Stanford Center for Inherited Cardiovascular Disease, Stanford, CA, USA.
¹⁰⁷ Cardiovascular and Genomic Medicine, National Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK.
¹⁰⁸ Centre de Référence Cardiomyopathies, L'institut du Thorax, Nantes Université, Nantes, France.
¹⁰⁹ Service de Génétique Médicale, CHU Bordeaux, Bordeaux, France.
¹¹⁰ Maladies Rares: Génétique et Métabolisme, Université de Bordeaux, INSERMU1211, Bordeaux, France.
¹¹¹ Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹¹² Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
¹¹³ Department of Cardiology, Virgen del Rocio University Hospital, Seville, Spain.
¹¹⁴ Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark.
¹¹⁵ Department of Clinical Cardiology and Experimental Cardiology, University of Amsterdam, Amsterdam University Medical Centers, Amsterdam, The Netherlands.

PMID: 40796136
DOI: 10.1093/eurheartj/ehaf380

Titin-related familial dilated cardiomyopathy: factors associated with disease onset

Renee Johnson et al. Eur Heart J. 2025.

. 2025 Aug 11:ehaf380.

doi: 10.1093/eurheartj/ehaf380. Online ahead of print.

Authors

Collaborators

Australian Genomics Cardiac Flagship:
Lesley Ades, Dimithu Alankarage, Morgan Almog, Mohammad Al-Shinnag, John J Atherton, Rachel Austin, Richard D Bagnall, Chris Barnett, Gillian M Blue, Simon Bodek, Kirsten Boggs, Michael Bogwitz, Tiffany Boughtwood, Alessandra Bray, Marie-Jo Brion, Jaye Brown, Rob Bryson-Richardson, Leslie Burnett, Charlotte Burns, Michelle Cao, Will Carr, Sarah Casauria, Heather Chalinor, Yuchen Chang, Gavin Chapman, Theodosia Charitou, Belinda Chong, Felicity Collins, Gemma Correnti, Kathy Cox, Fiona Cunningham, Debjani Das, Jason Davis, Andrew Davis, Paul De Fazio, Michelle de Silva, Nicola Den Elzen, Sophie Devery, Julia Dobbins, Sally L Dunwoodie, Nathan Dwyer, Stefanie Elbracht-Leong, David Elliott, Annabel Enriquez, Diane Fatkin, Vanessa Fear, Miriam Fine, Keri Finlay, Denisse Garza, Eleni Giannoulatou, Laura Gongolidis, Belinda Gray, Cassie Greer, Eric Haan, Mathilda Haas, Bernadette Hanna, Richard Harvey, Janette Hayward, Carmen Herrera, Adam Hill, Georgie Hollingsworth, Georgina Hollway, Ari E Horton, Denise Howting, Jodie Ingles, Joanne Isbister, Matilda Jackson, Paul James, Sarah Jane-Pantaleo, Renee Johnson, Andrew Kelly, Sarah King-Smith, Edwin Kirk, Sarah Kummerfeld, Timo Lassman, Jonathon Lipton, Sebastian Lunke, Ivan Macciocca, Paul MacIntyre, Evanthia O Madelli, Amali Mallawaarachchi, Julia Mansour, Ellenore Martin, Jacob Mathew, Tessa Mattiske, Julie McGaughran, Alison McLean, James McNamara, Caroline Medi, Alejandro Metke, Di Milnes, Michael Milward, Ansley Morrish, Jim Morwood, Helen Mountain, David Mowat, Chai-Ann Ng, Natalie Nowak, Noelia Nunez Martinez, Monique Ohanian, Sinead O'Sullivan, Angela Overkov, Nicholas Pachter, Chirag Patel, Mark Perrin, Matthew Perry, Andreas Pflaumer, Peta Phillips, Thuan Phuong, Rachel Pope-Couston, Nicola K Poplawski, Preeti Punni, Michael C J Quinn, Sulekha Rajagopalan, Hariharan Raju, Emma M Rath, Matthew Regan, Jonathan Rogers, Mark Ryan, Sarah Sandaradura, Nicole Schonrock, Paul Scuffham, Christopher Semsarian, Isabella Sherburn, Mary-Clare Sherlock, Emma Singer, Carla Smerdon, Janine Smith, Renee Smyth, Magdalena Soka, Zornitza Stark, Raymond Sy, Dotti Tang, Jessica Taylor, Shelby Taylor, Michel Tchan, Tina Thompson, Jordan Thorpe, Alison Trainer, Gunjan Trivedi, Giulia Valente, Karin van Spaendonck-Zwarts, Jamie Vandenberg, Kunal Verma, Miranda Vidgen, Jitendra Vohra, Kathryn Waddel-Smith, Mathew Wallis, Robert G Weintraub, Meredith Wilson, David Winlaw, Lisa Worgan, Linda Wornham, Kathy Wu, Laura Yeates, Dominica Zentner

Affiliations

¹ Molecular Cardiology Division, Victor Chang Cardiac Research Institute, 405 Liverpool St, Darlinghurst, NSW 2010, Australia.
² School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Kensington, NSW 2052, Australia.
³ The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia.
⁴ Department of Public Health and Primary Care, British Heart Foundation Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, UK.
⁵ Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.
⁶ Department of Cardiology, Royal Melbourne Hospital, Melbourne, VIC, Australia.
⁷ School of Biotechnology and Biomolecular Sciences, Faculty of Science, UNSW Sydney, Sydney, NSW, Australia.
⁸ Division of Clinical Genetics, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁹ Department of Cardiovascular Medicine, Division of Heart Rhythm Services, Windland Smith Rice Genetic Heart Rhythm Clinic, Mayo Clinic, Rochester, MN, USA.
¹⁰ Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN, USA.
¹¹ Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN, USA.
¹² Department of Cardiogenetic and Myogenetic Molecular and Cellular, Metabolic Biochemistry, AP-HP Sorbonne Université, Pitié Salpêtrière Hospital, Paris, France.
¹³ Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK.
¹⁴ Cardiology Department, Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
¹⁵ Department of Clinical Cardiology, Heart Center, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.
¹⁶ European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart), Amsterdam, The Netherlands.
¹⁷ Department of Medicine, Stanford University, Stanford, CA, USA.
¹⁸ Department of Genetics, Stanford University, Stanford, CA, USA.
¹⁹ Department of Biomedical Data Science, Stanford University, Stanford, CA, USA.
²⁰ Department of Cardiology, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
²¹ Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
²² Genetic Health Queensland Service, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
²³ Australian Genomics, Melbourne, VIC, Australia.
²⁴ Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
²⁵ Bioinformatics and Molecular Genetics Group, Centenary Institute, University of Sydney, Sydney, NSW, Australia.
²⁶ Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
²⁷ Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
²⁸ Department of Diagnostics, Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland.
²⁹ Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
³⁰ Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
³¹ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
³² Department of Inherited Cardiovascular Diseases, Barts Heart Centre, St Bartholomew's Hospital, London, UK.
³³ Unit for Screening Studies in Inherited Cardiovascular Diseases, National Institute of Cardiology, Warsaw, Poland.
³⁴ Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA, Australia.
³⁵ Heart Failure and Heart Transplant Unit, Complexo Hospitalario Universitario a Coruña, Centro de Investigación Biomédica en Red (CIBERCV), Instituto de Investigación Biomédica de A Coruña (INIBIC), Universidade da Coruña, La Coruña, Spain.
³⁶ Department of Cardiothoracovascular, Azienda Sanitaria Universitaria Integrata, Trieste, Italy.
³⁷ Department of Medicine, University of Trieste, Trieste, Italy.
³⁸ Center for Genetic Medicine, Northwestern University, Evanston, IL, USA.
³⁹ Center for Genetic Medicine, Bluhm Cardiovascular Institute, Chicago, IL, USA.
⁴⁰ Department of Cardiology, Hospital Universitario Puerta de Hierro, Instituto Investigación Sanitaria Puerta de Hierro-Segovia de Arana, CIBERCV, Madrid, Spain.
⁴¹ Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.
⁴² Cardiology Department, AP-HP, Cochin Hospital, Paris, France.
⁴³ Département de Génétique, AP-HP, Hôpital Européen Georges Pompidou, Service de Médecine Génomique des Maladies Rares, Paris, France.
⁴⁴ Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
⁴⁵ Team Titin, Inc . Pine Brook, NJ, USA.
⁴⁶ Department of Medical Biology, National Institute of Cardiology, Warsaw, Poland.
⁴⁷ Department of Medical Genetics, Warsaw Medical University, Warsaw, Poland.
⁴⁸ Service de Genetique Medicale, Centre Hospitalier Universitaire de Nantes, Nantes, France.
⁴⁹ Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado, Cardiovascular Institute, Aurora, CO, USA.
⁵⁰ Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia.
⁵¹ Department of Cardiology, Pneumology and Angiology, Heidelberg University Hospital, Heidelberg, Germany.
⁵² Informatics for Life, Heidelberg, Germany.
⁵³ DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
⁵⁴ National Heart and Lung Institute, Imperial College, London, UK.
⁵⁵ Department of Cardiology, Odense University Hospital, Odense, Denmark.
⁵⁶ Heart Transplantation Division, Victor Chang Cardiac Research Institute, Sydney, NSW, Australia.
⁵⁷ Cardiology Department, St Vincent's Hospital Sydney, 390 Victoria St, Darlinghurst, NSW 2010, Australia.
⁵⁸ Department of Cardiovascular Sciences, Centre for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium.
⁵⁹ Department of Cardiology, Maastricht University, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands.
⁶⁰ Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁶¹ Department of Human Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
⁶² Genomics and Inherited Disease Program, Garvan Institute of Medical Research, Sydney, NSW, Australia.
⁶³ Hunter Genetics, Hunter New England Local Health District, Newcastle, NSW, Australia.
⁶⁴ Genomic Medicine, Royal Melbourne Hospital, Melbourne, VIC, Australia.
⁶⁵ Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia.
⁶⁶ Department of Clinical and Experimental Cardiology, Amsterdam University Medical Centre, Amsterdam, The Netherlands.
⁶⁷ Department of Cardiology, Haga Teaching Hospital, The Hague, The Netherlands.
⁶⁸ Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands.
⁶⁹ Unidad de Cardiopatías Familiares, INIBIC, Complexo Hospitalario Universitario de A Coruña, Servizo Galego de Saúde, Universidade da Coruña, A Coruña, Spain.
⁷⁰ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
⁷¹ Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
⁷² Department of Emergency Medicine, AP-HP, Hôpital Ambroise Paré, Boulogne-Billancourt, France.
⁷³ Tasmanian Clinical Genetics Service and Tasmanian Health Service, Hobart, TAS, Australia.
⁷⁴ Unidad de Cardiopatías Familiares, CIBERCV, Madrid, Spain.
⁷⁵ Department of Genetics, Harvard Medical School, Boston, MA, USA.
⁷⁶ School of Medicine, The University of Queensland, Brisbane, QLD, Australia.
⁷⁷ Department of Cardiology, Health in Code, A Coruña, Spain.
⁷⁸ Genetic Services of Western Australia, Perth, WA, Australia.
⁷⁹ Genetic Counselling Department, Graduate School of Health, University of Technology Sydney, Sydney, NSW, Australia.
⁸⁰ Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
⁸¹ Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸² Department of Neurology, Sydney Children's Hospital, Sydney, NSW, Australia.
⁸³ Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
⁸⁴ NIHR Oxford Biomedical Research Centre, Oxford, UK.
⁸⁵ Genetic Services Department, King Edward Memorial Hospital, Perth, WA, Australia.
⁸⁶ School of Medicine, University of Western Australia, Perth, WA, Australia.
⁸⁷ Department of Genetics and Referral Center for Hereditary Cardiac Diseases, AP-HP, Hôpital Ambroise Paré, Boulogne-Billancourt, France.
⁸⁸ Discipline of Paediatrics, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
⁸⁹ Genetics and Cardiology Department, Sorbonne Université, AP-HP, INSERM UMRS_1166, IHU-ICAN, Hôpital Pitié-Salpêtrière, Paris, France.
⁹⁰ Sorbonne Université, Centre de Référence pour les Maladies Cardiaques Héréditaires ou rares, AP-HP, INSERM UMRS_1166, IHU-ICAN, Hôpital Pitié-Salpêtrière, Paris, France.
⁹¹ Service de Cardiologie, Centre Hospitalier Universitaire de Bordeaux, Université de Bordeaux, CIC 1401, Bordeaux, France.
⁹² French Reference Center in Inherited Cardiomyopathies, ERN GUARD-Heart, Bordeaux, France.
⁹³ Genetics Unit, Newcastle Medical Genetics, Newcastle, NSW, Australia.
⁹⁴ School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, NSW, Australia.
⁹⁵ Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, University of Sydney, Sydney, NSW, Australia.
⁹⁶ Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
⁹⁷ Oxford Regional Genetics Laboratories, Churchill Hospital, Oxford, UK.
⁹⁸ Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
⁹⁹ Cardiology Department, Hvidovre Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
¹⁰⁰ School of Medicine and Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
¹⁰¹ Cardiovascular Program, The George Institute for Global Health, UNSW Sydney, Sydney, NSW, Australia.
¹⁰² Center for Cardiovascular Genetic Research, Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX, USA.
¹⁰³ Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Korea.
¹⁰⁴ Inherited Cardiovascular Disease Unit, Complexo Hospitalario Universitario A Coruña, A Coruña, Galicia, Spain.
¹⁰⁵ Faculté de Médecine, Université Paris-Cité, Paris, France.
¹⁰⁶ Department of Medicine, Stanford Center for Inherited Cardiovascular Disease, Stanford, CA, USA.
¹⁰⁷ Cardiovascular and Genomic Medicine, National Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK.
¹⁰⁸ Centre de Référence Cardiomyopathies, L'institut du Thorax, Nantes Université, Nantes, France.
¹⁰⁹ Service de Génétique Médicale, CHU Bordeaux, Bordeaux, France.
¹¹⁰ Maladies Rares: Génétique et Métabolisme, Université de Bordeaux, INSERMU1211, Bordeaux, France.
¹¹¹ Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹¹² Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
¹¹³ Department of Cardiology, Virgen del Rocio University Hospital, Seville, Spain.
¹¹⁴ Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark.
¹¹⁵ Department of Clinical Cardiology and Experimental Cardiology, University of Amsterdam, Amsterdam University Medical Centers, Amsterdam, The Netherlands.

PMID: 40796136
DOI: 10.1093/eurheartj/ehaf380

Abstract

Background and aims: Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv.

Methods: An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM.

Results: A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80-30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06-5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27-3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR, 4.75; 95% CI, 2.35-9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08-.23).

Conclusions: Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.

Keywords: Dilated cardiomyopathy; Genetics; Prevention; Risk factors; Titin.

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Titin-related familial dilated cardiomyopathy: factors associated with disease onset

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Titin-related familial dilated cardiomyopathy: factors associated with disease onset

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