Congenital Titinopathy: Comprehensive characterization and pathogenic insights
Authors: Oates Emily C. , Jones Kristi J. , Donkervoort Sandra , Charlton Amanda , Brammah Susan , Smith John E. , Ware James S. , Yau Kyle S. , Swanson Lindsay C. , Whiffin Nicola , Peduto Anthony J. , Bournazos Adam , Waddell Leigh B. , Farrar Michelle A. , Sampaio Hugo A. , Teoh Hooi Ling , Lamont Phillipa J. , Mowat David , Fitzsimons Robin B. , Corbett Alastair J. , Ryan Monique M. , O'Grady Gina L. , Sandaradura Sarah A. , Ghaoui Roula , Joshi Himanshu , Marshall Jamie L. , Nolan Melinda A. , Kaur Simranpreet , Punetha Jaya , Töpf Ana , Harris Elizabeth , Bakshi Madhura , Genetti Casie A. , Marttila Minttu , Werlauff Ulla , Streichenberger Nathalie , Pestronk Alan , Mazanti Ingrid , Pinner Jason R. , Vuillerot Carole , Grosmann Carla , Camacho Ana , Mohassel Payam , Leach Meganne E. , Foley A. Reghan , Bharucha‐Goebel Diana , Collins James , Connolly Anne M. , Gilbreath Heather R. , Iannaccone Susan T. , Castro Diana , Cummings Beryl B. , Webster Richard I. , Lazaro Leïla , Vissing John , Coppens Sandra , Deconinck Nicolas , Luk Ho‐Ming , Thomas Neil H. , Foulds Nicola C. , Illingworth Marjorie A. , Ellard Sian , McLean Catriona A. , Phadke Rahul , Ravenscroft Gianina , Witting Nanna , Hackman Peter , Richard Isabelle , Cooper Sandra T. , Kamsteeg Erik‐Jan , Hoffman Eric P. , Bushby Kate , Straub Volker , Udd Bjarne , Ferreiro Ana , North Kathryn N. , Clarke Nigel F. , Lek Monkol , Beggs Alan H. , Bönnemann Carsten G. , MacArthur Daniel G. , Granzier Henk , Davis Mark R. , Laing Nigel G. 
Published: April 2018

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