The burden of TTN variants in the genomic era: Analysis of 18,462 individuals from the Solve-RD consortium and general recommendations
Year: 2025
Type: article
Study design: Observational Study
Abstract: PURPOSE: Titin, the largest protein in the human body, has been associated with several disease phenotypes caused by variants in the TTN gene. With around 20% of the population carrying a rare TTN variant and over 60 million genomes expected to have been sequenced worldwide by 2025, interpreting these findings presents major challenges. This study analyzed TTN variants in the Solve-RD cohort, the European network for unsolved rare disease cases. METHODS: We collected data from 11,072 individuals with suspected rare diseases and 7390 healthy relatives from the Solve-RD consortium, checking and manually reviewing TTN variants. We then used a filtering approach focused on clinical relevance, and we provided updated recommendations based on recent literature. RESULTS: Among the cohort, 240 individuals (1.3%) carried at least one heterozygous TTN truncating variant (TTNtv), with a 3.8% prevalence in the neuromuscular subgroup, primarily composed of unsolved cases. Four individuals received a titinopathy diagnosis. Additionally, 99 participants (0.5%) had a TTNtv in a high cardiac percent spliced in exon (>80%), and 4 had an overt cardiomyopathy. CONCLUSION: This study highlights the need for standardized approach to TTN variants, and investigation of missing heritability in individuals with skeletal myopathy with het TTNtv. Establishing consensus on percent spliced in-based thresholds will be essential for assessing cardiac risk and guiding the management of asymptomatic individuals.
Source: Genetics in Medicine
Authors: Maria Francesca Di Feo, Ida Paramonov, Leslie Matalonga Borrel, Ana Töpf, Alexander Hoischen, Sergi Beltran, Holm Graessner, Lisenka Vissers, Richarda de Voer, Marielle van Gijn, Simona Balestrini, Holger Lerche, Gaëtan Lesca, Swethaa Natraj Gayathri, Kornelia Ellwanger, Mireille Cossee, Aurelien Perrin, Anna Sarkozy, Gisele Bonne, Job A.J. Verdonschot, German Demidov, Steven Laurie, Mridul Johari, Adam Jackson, Alain Verloes, Alberto Corvo, Alessandra Ferlini, Alessia Costa, Alexander Hoischen, Alexandra Durr, Alice Krebsová, Alison Metcalfe, Ana Rath, Ana Töpf, Anastasios Papakonstantinou, Andreas Traschütz, Ange-Line Bruel, Anna Esteve Codina, Anna Heinzmann, Anna Katharina Sommer, Anna Sarkozy, Annalaura Torella, Anne-Sophie Denommé-Pichon, Anthony J. Brookes, Antonio Atalaia, Antonio Vitobello, Baptist Resch, Bart van de Warrenburg, Bart van der Sanden, Birte Zurek, Boris Keren, Bruno Eymard, Burcu Yaldiz, Carla Oliveira, Carles Hernández, Carlo Wilke, Caterina Lucano, Celina São José, Charissa Millevert, Chiara Marini Bettolo, Christel Thauvin, Christian Boßelmann, Christian Gilissen, Claire-Sophie Davoine, Coline Thomas, Corinne Metay, Cyril Mignot, Dana Thomasová, Daniel Danis, Daniel Picó, Danique Beijer, David Lagorce, David Ruvolo, Davide Piscia, Deepthi Sukumaran, Delphine Heron, Dieuwke Roelofs-Prins, Dylan Spalding, Elisa Cali, Elizabeth Alexander, Elke de Boer, Emanuele Raineri, Emeline Lebreton, Enzo Cohen, Erik Janssen, Erik-Jan Kamsteeg, Eveline Zonneveld-Huijssoon, Fátima Carneiro, Francesca Gualandi, Francesca Magrinelli, Francesco Muntoni, Geert de Vries, Gemma Bullich, Gerben van der Vries, German Demidov, Giovanni Stevanin, Gisèle Bonne, Giulia Coarelli, Giulio Piluso, Glenn Robert, Greg Warren, Gulcin Gumus, Han Brunner, Hannah Stamberger, Hans Scheffer, Heba Morsy, Helen Parkinson, Henry Houlden, Holger Hengel, Holger Lerche, Holm Graessner, Ida Paramonov, Ingrid Kolen, Irene Gullo, Irina Zaharieva, Iris te Paske, Isabel Spier, Isabelle Nelson, Ivo Glynne Gut, Jana Vandrovcova, Jean-Madeleine de Sainte Agathe, Jill Clayton-Smith, Jishu Xu, Joeri K. van der Velde, Jonathan Baets, Jonathan De Winter, Jonathan Rohrer, Joohyun Park, Jordi Diaz Manera, Jose Garcia-Pelaez, Josua Kegele, Julia M. Schulze-Hentrich, Juliane Müller, Karin Engelhardt, Karolis Sablauskas, Kornelia Ellwanger, Kornelia Neveling, Kristin M. Abbott, Laurence Faivre, Léna Guillot-Noel, Lennart Johansson, Leon Schütz, Leslie Matalonga, Liedewei Van de Vondel, Lisenka E.L.M. Vissers, Ludger Schöls, Lukáš Ryba, Luke Perry, Luzia Garrido, Lydia Sagath, Mallory Freeberg, Manuela Morleo, Marc Dabad, Marc Hanauer, Marc Sturm, Marcella Neri, Marcos Fernandez-Callejo, Marek Turnovec, Mariateresa Zanobio, Marielle van Gijn, Markéta Havlovicová, Marloes Steehouwer, Maroua Chahdil, Marta Ferreira, Marta Gut, Mary Reilly, Matthis Synofzik, Melanie Kellner, Michele Pinelli, Mike Hanna, Milan Macek, Morris A. Swertz, Nicoline Hoogerbrugge, Nienke van Os, Noor Smal, Olaf Riess, Oscar Hongnat, Patrick Moloney, Pavla Doležalová, Pedro Ferreira, Peter A.C. ’t Hoen, Peter de Jonghe, Peter Heutink, Peter Robinson, Petra Lišková, Pieter B. Neerincx, Rabah Ben Yaou, Radka Pourová Kremliková, Ravishankara Bellampalli, Rebecca Schüle, Richard Moore, Richarda M. de Voer, Rita Barbosa-Matos, Rita Selvatici, Robert Lauerer-Braun, Roberta Zeuli, Sadegh Abadijou, Sai Anuhya Nalagandla, Sandro Banfi, Sanjay M. Sisodiya, Sarah Weckhuysen, Sebastian Köhler, Sergi Beltran, Séverine Drunat, Siddharth Banka, Sophia Peters, Sophie Hambleton, Spencer Gibson, Stefan Aretz, Stefania Bigoni, Stephan Lauxmann, Stephan Ossowski, Stephanie Efthymiou, Steven Laurie, Susana Fernandes, Tanya Stojkovic, Teresinha Evangelista, Thomas Keane, Tjitske Kleefstra, Tobias B. Haack, Umar Riaz, Valérie Allamand, Vera Franková, Veronica Pini, Victor Couturier, Vincent Timmerman, Vincenzo Nigro, Virginie Bros-Facer, Volker Straub, Wilhemina S. Kerstjens Frederikse, Willem De Ridder, Wouter Steyaert, Yannis Duffourd, Yunze Patrick Wang, Ales Maver, Alessandra Renieri, Alexander Münchau, Alfons Macaya, Ana Cazurro-Gutiérrez, Andrea Ciolfi, Andreas Laner, Andreas Roos, Andreas Rump, Andrés Caballero Garcia de Oteyza, Andrés Nascimento Osorio, Anna Marcé-Grau, Anne Destrée, Antonella Riva, Athanasios Evangeliou, Aurelien Trimouille, Ayşe Nazlı Başak, Bart Dermaut, Beatriz Martínez Delgado, Belén Pérez-Dueñas, Berta Estevez, Bjarne Udd, Bodo Grimbacher, Borut Peterlin, Bruce Poppe, Brunhilde Wirth, Bruno Dallapiccola, Caroline Rooryck, Catarina Olimpio, Chantal Depondt, Chiara Fallerini, Christel Depienne, Christian Korff, Christian Mertes, Claudia A.L. Ruivenkamp, Colombine Meunier, Damien Lederer, Daniel Natera de Benito, David Beeson, David Webb, Davide Mei, Deniz Karadurmus, Didier Lacombe, Dimitri Hemelsoet, Elena Parrini, Elisabeth Kapaki, Elke Bogaert, Elke Holinski-Feder, Elsa Leitão, Emilia K. Bijlsma, Erika Van Nieuwenhove, Estrella López Martín, Eva Bermejo Sánchez, Eva Hammar Bouveret, Evelin Schröck, Evelina Carpancea, Evgenia Kokosali, Federico Zara, Flavia Privitera, Francesca Clementina Radio, Francina Munell, Francisco Javier Alonso García de la Rosa, Frédéric Masclaux, Gabriel Capella, Gianpiero Cavalleri, Gijs W.E. Santen, Hamidah Ghani, Hannah Verdin, Hanns Lochmüller, Helen Leavis, Ioannis Zaganas, Isabell Cordts, Isabelle Maystadt, Joris van Montfrans, Judith Cossins, Julie Desir, Julien Gagneur, Kaan Boztug, Karin Dahan, Katherine Benson, Katherine Schon, Katja Lohmann, Kiran Polavarapu, Konrad Platzer, Kristina Zguro, Kristl Claeys, Lambros Mathioudakis, Lars van der Veken, Laura Batlle Masó, Laura Valle, Leon Krass, Manon Huibers, Manuel Posada De la Paz, Mara Bourbouli, Marc Abramowicz, Marcello Scala, Marco Ferilli, Marco Savarese, Marco Tartaglia, Marcus Deschauer, Maria Judit Molnar, Maria-Roberta Cilio, Marie Greally, Mariette J.V. Hoffer, Martha Spilioti, Martje Pauly, Mary O'Reghan, Matthias Haimel, Mert Karakaya, Michele Iacomino, Minas Drakos, Mridul Johari, Nicholas Allen, Nika Schuermans, Norman Delanty, Olivier Monestier, Özge Aksel Kiliçarslan, Paolo Scudieri, Paolo Uva, Pasquale Striano, Patrick F. Chinnery, Patrick May, Peter Balicza, Peter Hackman, Rachel Thompson, Rami Abou Jamra, Rebecca Herzog, Rebeka Luknárová, Renzo Guerrini, Rita Horvath, Roger Colobran, Roxane van Heurck, Sandrine Mary, Sarah Duerinckx, Simona Balestrini, Simone Furini, Sivasankar Malaichamy, Stéphanie Moortgat, Susan Byrne, Sylvain Brohée, Thiloka Ratnaike, Tobias Bartolomaeus, Valerie Benoit, Verena Steinke-Lange, Vicente A. Yépez, Yves Sznajer, Peter Hackman, Marco Savarese, Bjarne Udd
Institutions: Folkhälsans Forskningscentrum, University of Genoa, Centro Nacional de Análisis Genómico, Universitat de Barcelona, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle University, Radboud University Nijmegen, Radboud University Medical Center, Universitätsklinikum Tübingen, University of Tübingen, Donders Institute for Brain, Cognition and Behaviour, University Medical Center Groningen, University of Groningen, Meyer Children's Hospital, University of Florence, Hertie Institute for Clinical Brain Research, Lyon 1 Université, Centre National de la Recherche Scientifique, Inserm, Hospices Civils de Lyon, Institut NeuroMyoGène, Laboratoire Physiopathologie et Génétique du Neurone et du Muscle, Physiologie et Médecine Expérimentale du Coeur et des Muscles, Centre Hospitalier Universitaire de Montpellier, Great Ormond Street Hospital, University College London, Sorbonne Université, Institut de Myologie, Centre de Recherche en Myologie, Maastricht University Medical Centre, Maastricht University, The University of Western Australia, Harry Perkins Institute of Medical Research, Tampere University Hospital
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,110
Funders: Association Française contre les Myopathies, French Muscular Dystrophy Association, European Commission, Institut National de la Santé et de la Recherche Médicale, Rijksuniversiteit Groningen, Radboud Universiteit, Universiteit Maastricht, Academy of Finland, Eberhard Karls Universität Tübingen, Suomen Kulttuurirahasto, Università degli Studi di Firenze, Maastricht Universitair Medisch Centrum, Centre National de la Recherche Scientifique, Samfundet Folkhälsan, Sydäntutkimussäätiö, Universitat de Barcelona, Radboud Universitair Medisch Centrum, Sigrid Juséliuksen Säätiö, Hospices Civils de Lyon, Tays, Horizon 2020 Framework Programme, Medical Research Council, European Research Council, Third Health Programme
OpenAlex ID: W4416448573