ArticleAnnals of neurology2018
Congenital Titinopathy: Comprehensive characterization and pathogenic insights.
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Article in Annals of neurology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers.
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70 citing papers in PubMed, 155 citations in OpenAlex.
- The actomyosin cortex controls t-tubule remodeling in skeletal muscle.Science advances · 2026Article
- Arthrogryposis Multiplex Congenita: Comprehensive Review from a Neuromuscular Standpoint.Genes · 2026Review
- Prenatal-Onset Recessive Titinopathies: Clinical Spectrum, Genotype-Phenotype Correlations, and Outcomes.Diagnostics (Basel, Switzerland) · 2026Article
- Early Clinical, Imaging, and Pathological Characteristics of SRPK3/TTN-Digenic Myopathy.Annals of clinical and translational neurology · 2026Article
- Phenotypic Heterogeneity in Titinopathies with Peripheral Nerve Involvement in Pediatric Age: Two Case Reports.Journal of clinical medicine · 2026Article
- Mending the Achilles heels of titin in cardiac and musculoskeletal disease.Biophysical reviews · 2026Review
- Location-Dependent Differences in Cardiac and Skeletal Muscle Dysfunction Associated With Truncating Titin (Circulation research · 2026Article
- NGS Approaches in Clinical Diagnostics: From Workflow to Disease-Specific Applications.International journal of molecular sciences · 2025Review
- Mechanically knocking out titin reveals protein tension loss as a trigger of muscle disease.Nature biomedical engineering · 2025Article
- Different Lower Limb Muscle MRI Patterns in Autosomal Dominant Titinopathies.European journal of neurology · 2025Article
- The evolving genetic landscape of neuromuscular fetal akinesias.Journal of neuromuscular diseases · 2025Review
- Titinopathies: Phenotype - genotype heterogeneity in an Indian cohort.Journal of neuromuscular diseases · 2025Article
- An attractive alternative to prenatal diagnosis: a case report of preimplantation genetic testing in familial cardiomyopathy.AJOG global reports · 2025Article
- Disease Trajectories of a Large French Cohort of 142 Congenital Myopathy Patients in Adult Age.European journal of neurology · 2025Observational
- Congenital Titinopathy: Comprehensive Characterization of the Most Severe End of the Disease Spectrum.Annals of neurology · 2025Article
- Proteomic Profiling Towards a Better Understanding of Genetic Based Muscular Diseases: The Current Picture and a Look to the Future.Biomolecules · 2025Review
- Congenital Titinopathies Linked to Mutations inInternational journal of molecular sciences · 2024Article
- Pathomechanisms of Monoallelic variants in TTN causing skeletal muscle disease.Human molecular genetics · 2024Article
- Taking on the Titin: Muscle imaging as a diagnostic marker of biallelicJournal of neuromuscular diseases · 2024Article
- Reanalysis of RNA sequencing data ends diagnostic odyssey and expands the phenotypic spectrum of congenital titinopathy.American journal of medical genetics. Part A · 2024Article
10 more citing papers are in PubMed but not listed here.
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Authors and funding
84 authors at 20 institutions in 11 countries.
Emily C OatesDubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
Kristi J JonesInstitute for Neuroscience and Muscle Research, Kid's Research Institute, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
Sandra DonkervoortNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
Amanda CharltonDiscipline of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
Susan BrammahElectron Microscope Unit, Department of Anatomical Pathology, Concord Repatriation General Hospital, Concord, Sydney, New South Wales, Australia.
John E SmithDepartment of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ.ORCID 0000-0002-0888-1274
James S WareNational Heart and Lung Institute and MRC London Institute of Medical Science, Imperial College London, London, United Kingdom.
Kyle S YauInstitute for Medical Research and Centre for Medical Research, University of Western Australia, Nedlands, Western Australia, Australia.
Lindsay C SwansonManton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA.
Nicola WhiffinNational Heart and Lung Institute and MRC London Institute of Medical Science, Imperial College London, London, United Kingdom.
Anthony J PedutoDepartment of Radiology, Westmead Hospital, Sydney, New South Wales, Australia.
Adam BournazosInstitute for Neuroscience and Muscle Research, Kid's Research Institute, Children's Hospital at Westmead, Sydney, New South Wales, Australia.ORCID 0000-0002-6464-4548
Leigh B WaddellInstitute for Neuroscience and Muscle Research, Kid's Research Institute, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
Michelle A FarrarDepartment of Neurology, Sydney Children's Hospital, Sydney, New South Wales, Australia.
Hugo A SampaioDepartment of Neurology, Sydney Children's Hospital, Sydney, New South Wales, Australia.
Hooi Ling TeohDepartment of Neurology, Sydney Children's Hospital, Sydney, New South Wales, Australia.
Phillipa J LamontNeurogenetic Unit, Department of Neurology, Royal Perth Hospital, Perth, Western Australia, Australia.
David MowatSchool of Women's and Children's Health, University of New South Wales Sydney, Sydney, New South Wales, Australia.
Robin B FitzsimonsSydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
Alastair J CorbettDepartment of Neurology, Concord Repatriation General Hospital, Sydney, New South Wales, Australia.
Monique M RyanDepartment of Neurology, Royal Children's Hospital, Parkville, Victoria, Australia.
Gina L O'GradyInstitute for Neuroscience and Muscle Research, Kid's Research Institute, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
Sarah A SandaraduraInstitute for Neuroscience and Muscle Research, Kid's Research Institute, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
Roula GhaouiInstitute for Neuroscience and Muscle Research, Kid's Research Institute, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
Himanshu JoshiInstitute for Neuroscience and Muscle Research, Kid's Research Institute, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
Jamie L MarshallAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA.
Melinda A NolanPaediatric Neuroservices, Starship Child Health, Auckland, New Zealand.
Simranpreet KaurInstitute for Neuroscience and Muscle Research, Kid's Research Institute, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
Jaya PunethaResearch Center for Genetic Medicine, Children's National Medical Center, Washington, DC.
Ana TöpfJohn Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
Elizabeth HarrisJohn Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
Madhura BakshiDepartment of Clinical Genetics, Liverpool Hospital, Sydney, New South Wales, Australia.
Casie A GenettiManton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA.
Minttu MarttilaManton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA.
Ulla WerlauffDanish National Rehabilitation Center for Neuromuscular Diseases, Aarhus, Denmark.
Nathalie StreichenbergerNeuropathology Department, Hospices Civils Lyon, Claude Bernard University, Lyon1, France.
Alan PestronkDepartment of Neurology, Washington University School of Medicine, Saint Louis, MO.
Ingrid MazantiCellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
Jason R PinnerDepartment of Medical Genomics, Royal Prince Alfred Hospital, Camperdown, Sydney, New South Wales, Australia.
Carole VuillerotWoman-Mother-Child Hospital, Hospices Civils Lyon, Bron, France.ORCID 0000-0003-4995-0202
Carla GrosmannUniversity of California, San Diego/Rady Children's Hospital, San Diego, CA.
Ana CamachoChild Neurology Unit, Department of Neurology, October 12 University Hospital, Faculty of Medicine, Complutense University, Madrid, Spain.
Payam MohasselNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
Meganne E LeachNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
A Reghan FoleyNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
Diana Bharucha-GoebelNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
James CollinsMercy Clinic Pediatric Neurology, Springfield, MO.
Anne M ConnollyNeuromuscular Division, Departments of Neurology and Pediatrics, Washington University School of Medicine, Saint Louis, MO.
Heather R GilbreathDepartment of Advanced Practice, Children's Medical Center of Dallas, Dallas, TX.
Susan T IannacconeDepartment of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX.
Diana CastroDepartment of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX.
Beryl B CummingsAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA.
Richard I WebsterT. Y. Nelson Department of Neurology and Neurosurgery, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
Leïla LazaroPediatric Service, Basque Coast Hospital Center, Bayonne, France.
John VissingNeuromuscular Clinic and Research Unit, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Sandra CoppensDepartment of Pediatric Neurology, Neuromuscular Reference Center, Erasmus Hospital, Free University of Brussels, Brussels, Belgium.
Nicolas DeconinckDepartment of Pediatric Neurology, Neuromuscular Reference Center, Queen Fabiola Children's University Hospital, Free University of Brussels, Brussels, Belgium.
Ho-Ming LukClinical Genetic Service, Department of Health, Hong Kong, China.ORCID 0000-0003-4066-4066
Neil H ThomasDepartment of Paediatric Neurology, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
Nicola C FouldsWessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
Marjorie A IllingworthDepartment of Paediatric Neurology, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
Sian EllardUniversity of Exeter Medical School, Exeter, United Kingdom.
Catriona A McLeanDepartment of Anatomical Pathology, Alfred Hospital, Melbourne, Victoria, Australia.
Rahul PhadkeDubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
Gianina RavenscroftHarry Perkins Institute, University of Western Australia, Nedlands, Western Australia, Australia.
Nanna WittingCopenhagen Neuromuscular Unit and Department of Neurology, Rigshospitalet, Copenhagen University, Copenhagen, Denmark.ORCID 0000-0002-0664-0709
Peter HackmanFolkhälsan Institute of Genetics, Medicum, University of Helsinki, Helsinki, Finland.
Isabelle RichardGénéthon, INSERM U951, INTEGRARE Research Unit, Évry, France.
Sandra T CooperInstitute for Neuroscience and Muscle Research, Kid's Research Institute, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
Erik-Jan KamsteegDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
Eric P HoffmanResearch Center for Genetic Medicine, Children's National Medical Center, Washington, DC.
Kate BushbyJohn Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
Volker StraubJohn Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
Bjarne UddFolkhälsan Institute of Genetics, Medicum, University of Helsinki, Helsinki, Finland.
Ana FerreiroPathophysiology of Striated Muscles Laboratory, Unit of Functional and Adaptative Biology, BFA, Paris Diderot University/CNRS, Sorbonne Paris Cité, Paris, France.
Kathryn N NorthInstitute for Neuroscience and Muscle Research, Kid's Research Institute, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
Nigel F ClarkeInstitute for Neuroscience and Muscle Research, Kid's Research Institute, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
Monkol LekAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA.
Alan H BeggsManton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA.ORCID 0000-0001-8818-0568
Carsten G BönnemannNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
Daniel G MacArthurAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA.
Henk GranzierDepartment of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ.
Mark R DavisDepartment of Diagnostic Genomics, PathWest Laboratory Medicine WA, Nedlands, Western Australia, Australia.
Nigel G LaingHarry Perkins Institute, University of Western Australia, Nedlands, Western Australia, Australia.
The University of Sydney · AUNational Institutes of Health · USBoston Children's Hospital · USBroad Institute · USMuscular Dystrophy UK · GBUniversity Hospital Southampton NHS Foundation Trust · GBUNSW Sydney · AUChildren's Hospital at Westmead · AUThe University of Western Australia · AUChildren's National · USConcord Repatriation General Hospital · AURoyal Brompton & Harefield NHS Foundation Trust · GBRoyal Children's Hospital · AUThe University of Texas Southwestern Medical Center · USUniversité Claude Bernard Lyon 1 · FRUniversity of Arizona · USUniversity of Copenhagen · DKUniversity of Helsinki · FIWashington University in St. Louis · USCentre Hospitalier de la Côte Basque · FR
Funding
Molecular and Clinical Manifestations of Matrix and Aggregate MyopathiesZIANS003129 · NINDS · NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE · PI BÖNNEMANN, CARSTEN · 2011 to 2025
$52.8MJoint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5MImproved Diagnostic of the Muscular DystrophiesR01NS029525 · NINDS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI HOFFMAN, ERIC P. · 1991 to 2015
$6.5MFunction of Giant Sarcomere Matrix Proteins in MuscleR01HL062881 · NHLBI · WASHINGTON STATE UNIVERSITY · PI GRANZIER, HENK L. · 1999 to 2018
$6.4MSARCOMERIC PROTEINS IN NORMAL AND DISEASED MUSCLER01AR044345 · NIAMS · CHILDREN'S HOSPITAL BOSTON · PI BEGGS, ALAN H. · 1997 to 2017
$5.3MA powerful web-based discovery platform for rare disease geneticsR01HG009141 · NHGRI · BROAD INSTITUTE, INC. · PI QUINLAN, AARON R, REHM, HEIDI L · 2017 to 2020
$2.9MTitin-Based Adaptations of Cardiac FunctionR01HL115988 · NHLBI · UNIVERSITY OF ARIZONA · PI GRANZIER, HENK L. · 2013 to 2019
$2.3MGenetic screening and therapies for nemaline myopathiesR01HD075802 · NICHD · BOSTON CHILDREN'S HOSPITAL · PI BEGGS, ALAN H. · 2014 to 2018
$1.8MDepartment of HealthMedical Research Council MC_UP_1102/20NHGRI NIH HHS UM1 HG008900NHLBI NIH HHS R01 HL062881NHLBI NIH HHS R01 HL115988NIAMS NIH HHS R01 AR044345NICHD NIH HHS R01 HD075802NINDS NIH HHS R01 NS029525Wellcome TrustWellcome Trust 107469/Z/15/Z
Abstract
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.
Indexed as
Cardiomyopathy, DilatedConnectinFemaleHumansMaleMuscle ProteinsMuscle, SkeletalMutationPhenotypeProtein IsoformsConnectinMuscle ProteinsProtein IsoformsTTN protein, human
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