Journal article

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 Corbett Show all

ANNALS OF NEUROLOGY | WILEY | Published : 2018

Abstract

OBJECTIVE: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder. METHODS: Using 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. RESULTS: All 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 ..

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Grants

Awarded by Australian NHMRC


Awarded by Centre of Research Excellence Grants


Awarded by Association Francaise contre les Myopathies


Awarded by National Heart, Lung and Blood Institute


Awarded by Muscular Dystrophy Association


Awarded by National Institute of Arthritis and Musculoskeletal and Skin Diseases


Awarded by National Institute of Child Health and Human Development


Awarded by Wellcome Trust


Awarded by EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT


Awarded by NATIONAL HEART, LUNG, AND BLOOD INSTITUTE


Awarded by NATIONAL HUMAN GENOME RESEARCH INSTITUTE


Awarded by NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES


Awarded by NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE


Funding Acknowledgements

The following authors were supported by the Australian NHMRC: N.G.L. (APP1117510), E.C.O. (APP0633194, APP1090428), G.L.O. (APP1056285), R.G. (APP1074954), and G.R. (APP1122952). Additional author funding was provided by Muscular Dystrophy NSW (G.L.O. and R.G.), the Royal Australasian College of Physicians (G.L.O.), and the Government of Western Australia Department of Health FutureHealth WA Merit Awards (G.R.). This work was further supported by NHMRC Project and Centre of Research Excellence Grants (APP1022707, APP1031893, APP1113531; K.N.N., N.G.L., N.F.C., S.C.); the Association Francaise contre les Myopathies (18724); the National Heart, Lung and Blood Institute (R01 HL115988; H.G., UM1 HG008900; D.G.M.); NIH Intramural Research Program funding from the National Institute of Neurological Disorders and Stroke (C.G.B.); the Muscular Dystrophy Association (MDA383249; A.H.B.); the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR044345; A.H.B, R01 NS029525: E.P.H.); the National Institute of Child Health and Human Development (R01 HD075802; A.H.B.); generous funding support from the Foye family (A.H.B.); the National Human Genome Research Institute (D.G.M.); the National Eye Institute (D.G.M.); the Leducq Foundation (I.R.); the Wellcome Trust (107469/Z/15/Z; J.S.W.); the NIHR Royal Brompton Cardiovascular Biomedical Research Unit (J.S.W.), the MRC (J.S.W.) and the Juselius Foundation and the Academy of Finland Foundation (B.U.). In addition, we thank the NIH Intramural Sequencing Center for performing exome sequencing in patients diagnosed by NIH-affiliated team members. NIH sequencing was partially funded through the Clinical Center Genomics Opportunity, which is sponsored by the National Human Genome Research Institute, the NIH Deputy Director for Intramural Research, and the NIH Clinical Center. We also acknowledge the Tissu-Tumorotheque Est (CRB-HCL Hospices Civils de Lyon BB-0033-00046) for provision of human biological samples and associated data used during the course of this study.We thank the patients and families for their involvement in this study; Dr Professor Caroline Sewry for her expert advice regarding the histopathology-focused aspects of the study; Professor Francesco Muntoni and the Dubowitz Neuromuscular Centre at the UCL Great Ormond Street Institute of Child Health for their support of this project during its final stages; and the following co-contributors: Dr Anna Sarkozy (John Walton Muscular Dystrophy Research Centre, Newcastle University, Newcastle upon Tyne, United Kingdom: clinical data acquisition), Karen Stals (Department of Molecular Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom: variant analysis), Chandra Saripalli (Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ: western blot analysis of patient samples), Dr Sylvie Odent, Dr Melanie Fradin and Professor Jean-Paul Leroy (Rennes Hospital: clinical data acquisition and patient sampling), and Laurene Ben Aim, Christophe Caloustian, and Dr Robert Olaso (Centre National de Genotypage, Evry, France).