BACKGROUND: Extensive genetic screening results in the identification of thousands of rare variants that are difficult to interpret. Because of its sheer size, rare variants in the titin gene (TTN) are detected frequently in any individual. Unambiguous interpretation of molecular findings is almost impossible in many patients with myopathies or cardiomyopathies. OBJECTIVE: To refine the current classification framework for TTN-associated skeletal muscle disorders and standardize the interpretation of TTN variants. METHODS: We used the guidelines issued by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) to re-analyze TTN genetic findings from our patient cohort. RESULTS: We identified in the classification guidelines three rules that are not applicable to titin-related skeletal muscle disorders; six rules that require disease-/gene-specific adjustments and four rules requiring quantitative thresholds for a proper use. In three cases, the rule strength need to be modified. CONCLUSIONS: We suggest adjustments are made to the guidelines. We provide frequency thresholds to facilitate filtering of candidate causative variants and guidance for the use and interpretation of functional data and co-segregation evidence. We expect that the variant classification framework for TTN-related skeletal muscle disorders will be further improved along with a better understanding of these diseases.

Centre of Molecular Biology and Gene Therapy University Hospital Brno and Masaryk University Brno Brno Czech Republic

Clinical Institute of Medical Genetics University Medical Centre Ljubljana Ljubljana Slovenia

Department of Neuropediatrics and Muscle Disorders Medical Center University of Freiburg Faculty of Medicine Freiburg Germany Centro Nacional de Análisis Genómico Barcelona Spain Children's Hospital of Eastern Ontario Research Institute University of Ottawa Ottawa Canada Division of Neurology Department of Medicine The Ottawa Hospital Ottawa Canada

Dipartimento di Medicina di Precisione Universitá degli Studi della Campania Luigi Vanvitelli Naples Italy Telethon Institute of Genetics and Medicine Pozzuoli Italy

Folkhälsan Research Center Helsinki Finland Department of Medical Genetics Medicum University of Helsinki Helsinki Finland

Folkhälsan Research Center Helsinki Finland Department of Medical Genetics Medicum University of Helsinki Helsinki Finland Department of Neurology Vaasa Central Hospital Vaasa Finland Neuromuscular Research Center Tampere University and University Hospital Tampere Finland

Friedrich Baur Institut Neurologische Klinik Ludwig Maximilians Universität München Munich Germany

Genetikum Neu Ulm Germany

IRCCS Fondazione Stella Maris Pisa Italy

Neurogenetics Branch National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda Maryland Unites States

Neuromuscular Diseases and Neuroimmunology Unit Fondazione IRCCS Istituto Neurologico Carlo Besta Milano Italy

Neuromuscular Diseases and Neuroimmunology Unit Fondazione IRCCS Istituto Neurologico Carlo Besta Milano Italy Department of Molecular and Translation Medicine Unit of Biology and Genetics University of Brescia Brescia Italy

Neuromuscular Research Center Department of Genetics Fimlab Laboratories Tampere Finland

The John Walton Muscular Dystrophy Research Centre Institute of Genetic Medicine Newcastle University Newcastle upon Tyne UK

Unit for Neuromuscular and Neurodegenerative Disorders Bambino Gesù Children's Hospital Rome Italy

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$a Savarese, Marco $u Folkhälsan Research Center, Helsinki, Finland. Department of Medical Genetics, Medicum, University of Helsinki, Helsinki, Finland.

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$a Improved Criteria for the Classification of Titin Variants in Inherited Skeletal Myopathies / $c M. Savarese, M. Johari, K. Johnson, M. Arumilli, A. Torella, A. Töpf, A. Rubegni, M. Kuhn, T. Giugliano, D. Gläser, F. Fattori, R. Thompson, S. Penttilä, S. Lehtinen, S. Gibertini, A. Ruggieri, M. Mora, A. Maver, B. Peterlin, A. Mankodi, H. Lochmüller, FM. Santorelli, B. Schoser, L. Fajkusová, V. Straub, V. Nigro, P. Hackman, B. Udd,

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$a BACKGROUND: Extensive genetic screening results in the identification of thousands of rare variants that are difficult to interpret. Because of its sheer size, rare variants in the titin gene (TTN) are detected frequently in any individual. Unambiguous interpretation of molecular findings is almost impossible in many patients with myopathies or cardiomyopathies. OBJECTIVE: To refine the current classification framework for TTN-associated skeletal muscle disorders and standardize the interpretation of TTN variants. METHODS: We used the guidelines issued by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) to re-analyze TTN genetic findings from our patient cohort. RESULTS: We identified in the classification guidelines three rules that are not applicable to titin-related skeletal muscle disorders; six rules that require disease-/gene-specific adjustments and four rules requiring quantitative thresholds for a proper use. In three cases, the rule strength need to be modified. CONCLUSIONS: We suggest adjustments are made to the guidelines. We provide frequency thresholds to facilitate filtering of candidate causative variants and guidance for the use and interpretation of functional data and co-segregation evidence. We expect that the variant classification framework for TTN-related skeletal muscle disorders will be further improved along with a better understanding of these diseases.

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$a Johari, Mridul $u Folkhälsan Research Center, Helsinki, Finland. Department of Medical Genetics, Medicum, University of Helsinki, Helsinki, Finland.

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$a Johnson, Katherine $u The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

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$a Arumilli, Meharji $u Folkhälsan Research Center, Helsinki, Finland. Department of Medical Genetics, Medicum, University of Helsinki, Helsinki, Finland.

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$a Torella, Annalaura $u Dipartimento di Medicina di Precisione, Universitá degli Studi della Campania "Luigi Vanvitelli", Naples, Italy. Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.

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$a Töpf, Ana $u The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

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$a Rubegni, Anna $u IRCCS Fondazione Stella Maris, Pisa, Italy.

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$a Kuhn, Marius $u Genetikum, Neu-Ulm, Germany.

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$a Giugliano, Teresa $u Dipartimento di Medicina di Precisione, Universitá degli Studi della Campania "Luigi Vanvitelli", Naples, Italy. Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.

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$a Gläser, Dieter $u Genetikum, Neu-Ulm, Germany.

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$a Fattori, Fabiana $u Unit for Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, Rome, Italy.

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$a Thompson, Rachel $u The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

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$a Penttilä, Sini $u Neuromuscular Research Center, Department of Genetics, Fimlab Laboratories, Tampere, Finland.

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$a Lehtinen, Sara $u Neuromuscular Research Center, Department of Genetics, Fimlab Laboratories, Tampere, Finland.

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$a Gibertini, Sara $u Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.

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$a Ruggieri, Alessandra $u Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy. Department of Molecular and Translation Medicine, Unit of Biology and Genetics, University of Brescia, Brescia, Italy.

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$a Mora, Marina $u Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.

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$a Maver, Ales $u Clinical Institute of Medical Genetics, University Medical Centre Ljubljana, Ljubljana, Slovenia.

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$a Peterlin, Borut $u Clinical Institute of Medical Genetics, University Medical Centre Ljubljana, Ljubljana, Slovenia.

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$a Mankodi, Ami $u Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, Unites States.

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$a Lochmüller, Hanns $u Department of Neuropediatrics and Muscle Disorders, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany. Centro Nacional de Análisis Genómico (CNAG-CRG), Center for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada. Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, Canada.

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$a Santorelli, Filippo Maria $u IRCCS Fondazione Stella Maris, Pisa, Italy.

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$a Schoser, Benedikt $u Friedrich-Baur-Institut, Neurologische Klinik Ludwig-Maximilians-Universität München, Munich, Germany.

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$a Fajkusová, Lenka $u Centre of Molecular Biology and Gene Therapy, University Hospital Brno and Masaryk University Brno, Brno, Czech Republic.

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$a Straub, Volker $u The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

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$a Nigro, Vincenzo $u Dipartimento di Medicina di Precisione, Universitá degli Studi della Campania "Luigi Vanvitelli", Naples, Italy. Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.

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$a Hackman, Peter $u Folkhälsan Research Center, Helsinki, Finland. Department of Medical Genetics, Medicum, University of Helsinki, Helsinki, Finland.

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$a Udd, Bjarne $u Folkhälsan Research Center, Helsinki, Finland. Department of Medical Genetics, Medicum, University of Helsinki, Helsinki, Finland. Department of Neurology, Vaasa Central Hospital, Vaasa, Finland. Neuromuscular Research Center, Tampere University and University Hospital, Tampere, Finland.

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