Congenital Titinopathy: Comprehensive characterization and pathogenic insights

Emily C. Oates, Kristi J. Jones, Sandra Donkervoort, Amanda Charlton, Susan Brammah, John E. Smith, James S. Ware, Kyle S. Yau, Lindsay C. Swanson, Nicola Whiffin, Anthony J. Peduto, Adam Bournazos, Leigh B. Waddell, Michelle A. Farrar, Hugo A. Sampaio, Hooi Ling Teoh, Phillipa J. Lamont, David Mowat, Robin B. Fitzsimons, Alastair J. CorbettMonique M. Ryan, Gina L. O'Grady, Sarah A. Sandaradura, Roula Ghaoui, Himanshu Joshi, Jamie L. Marshall, Melinda A. Nolan, Simranpreet Kaur, Jaya Punetha, Ana Toepf, Elizabeth Harris, Madhura Bakshi, Casie A. Genetti, Minttu Marttila, Ulla Werlauff, Nathalie Streichenberger, Alan Pestronk, Ingrid Mazanti, Jason R. Pinner, Carole Vuillerot, Carla Grosmann, Ana Camacho, Payam Mohassel, Meganne E. Leach, A. Reghan Foley, Diana Bharucha-Goebel, James Collins, Anne M. Connolly, Heather R. Gilbreath, Susan T. Iannaccone, Diana Castro, Beryl B. Cummings, Richard I. Webster, Leila Lazaro, John Vissing, Sandra Coppens, Nicolas Deconinck, Ho-Ming Luk, Neil H. Thomas, Nicola C. Foulds, Marjorie A. Illingworth, Sian Ellard, Catriona A. McLean, Rahul Phadke, Gianina Ravenscroft, Nanna Witting, Peter Hackman, Isabelle Richard, Sandra T. Cooper, Erik-Jan Kamsteeg, Eric P. Hoffman, Kate Bushby, Volker Straub, Bjarne Udd, Ana Ferreiro, Kathryn N. North, Nigel F. Clarke, Monkol Lek, Alan H. Beggs, Carsten G. Boennemann, Daniel G. MacArthur, Henk Granzier, Mark R. Davis, Nigel G. Laing

Research output: Contribution to journalArticlepeer-review

78 Citations (Scopus)


ObjectiveComprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder.

MethodsUsing massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients.

ResultsAll patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder.

InterpretationThis detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124

Original languageEnglish
Pages (from-to)1105-1124
Number of pages20
JournalAnnals of Neurology
Issue number6
Publication statusPublished - Jun 2018


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