5
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Making sense of missense variants in TTN-related congenital myopathies

      research-article
      1 , 1 , 1 , 1 , 2 , 2 , 3 , 4 , 5 , 6 , 5 , 6 , 1 , 7 , 1 , 7 , 1 , 1 , 8 , 9 , 10 , 11 , 11 , 12 , 13 , 12 , 12 , 12 , 12 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 27 , 28 , 29 , 30 , 31 , 5 , 6 , 32 , 33 , 34 , 1 , 2 , 35 , 1 ,
      Acta Neuropathologica
      Springer Berlin Heidelberg

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Mutations in the sarcomeric protein titin, encoded by TTN, are emerging as a common cause of myopathies. The diagnosis of a TTN-related myopathy is, however, often not straightforward due to clinico-pathological overlap with other myopathies and the prevalence of TTN variants in control populations. Here, we present a combined clinico-pathological, genetic and biophysical approach to the diagnosis of TTN-related myopathies and the pathogenicity ascertainment of TTN missense variants. We identified 30 patients with a primary TTN-related congenital myopathy (CM) and two truncating variants, or one truncating and one missense TTN variant, or homozygous for one TTN missense variant. We found that  TTN-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of certain clinico-pathological features. Presentation was typically at birth with the clinical course characterized by variable progression of weakness, contractures, scoliosis and respiratory symptoms but sparing of extraocular muscles. Cardiac involvement depended on the variant position. Our biophysical analyses demonstrated that missense mutations associated with CMs are strongly destabilizing and exert their effect when expressed on a truncating background or in homozygosity. We hypothesise that destabilizing TTN missense mutations phenocopy truncating variants and are a key pathogenic feature of recessive titinopathies that might be amenable to therapeutic intervention.

          Supplementary Information

          The online version contains supplementary material available at 10.1007/s00401-020-02257-0.

          Related collections

          Most cited references63

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

          A global reference for human genetic variation

          The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Analysis of protein-coding genetic variation in 60,706 humans

            Summary Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. We describe the aggregation and analysis of high-quality exome (protein-coding region) sequence data for 60,706 individuals of diverse ethnicities generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of truncating variants with 72% having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human “knockout” variants in protein-coding genes.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              CADD: predicting the deleteriousness of variants throughout the human genome

              Abstract Combined Annotation-Dependent Depletion (CADD) is a widely used measure of variant deleteriousness that can effectively prioritize causal variants in genetic analyses, particularly highly penetrant contributors to severe Mendelian disorders. CADD is an integrative annotation built from more than 60 genomic features, and can score human single nucleotide variants and short insertion and deletions anywhere in the reference assembly. CADD uses a machine learning model trained on a binary distinction between simulated de novo variants and variants that have arisen and become fixed in human populations since the split between humans and chimpanzees; the former are free of selective pressure and may thus include both neutral and deleterious alleles, while the latter are overwhelmingly neutral (or, at most, weakly deleterious) by virtue of having survived millions of years of purifying selection. Here we review the latest updates to CADD, including the most recent version, 1.4, which supports the human genome build GRCh38. We also present updates to our website that include simplified variant lookup, extended documentation, an Application Program Interface and improved mechanisms for integrating CADD scores into other tools or applications. CADD scores, software and documentation are available at https://cadd.gs.washington.edu.
                Bookmark

                Author and article information

                Contributors
                mathias.gautel@kcl.ac.uk
                Journal
                Acta Neuropathol
                Acta Neuropathol
                Acta Neuropathologica
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0001-6322
                1432-0533
                15 January 2021
                15 January 2021
                2021
                : 141
                : 3
                : 431-453
                Affiliations
                [1 ]GRID grid.13097.3c, ISNI 0000 0001 2322 6764, Randall Centre for Cell and Molecular Biophysics, Muscle Biophysics, , King’s College London BHF Centre of Research Excellence, ; London, UK
                [2 ]GRID grid.420545.2, Department of Paediatric Neurology, , Evelina Children’s Hospital, Guy’s & St Thomas’ NHS Foundation Trust, ; London, UK
                [3 ]GRID grid.46699.34, ISNI 0000 0004 0391 9020, Department of Clinical Neuropathology, , King’s College Hospital, ; London, UK
                [4 ]GRID grid.239826.4, ISNI 0000 0004 0391 895X, Department of Clinical Genetics, , Guy’s Hospital, ; London, UK
                [5 ]GRID grid.6190.e, ISNI 0000 0000 8580 3777, Centre for Molecular Medicine, , University of Cologne, ; Cologne, Germany
                [6 ]GRID grid.6190.e, ISNI 0000 0000 8580 3777, Department of Pediatrics, , University Hospital Cologne and Faculty of Medicine, University of Cologne, ; Cologne, Germany
                [7 ]GRID grid.13097.3c, ISNI 0000 0001 2322 6764, School of Cardiovascular Medicine and Sciences, , King’s College London BHF Centre of Research Excellence, ; London, UK
                [8 ]GRID grid.150338.c, ISNI 0000 0001 0721 9812, Pediatric Neurology Unit, Paediatrics Subspecialties Service, , Geneva Children’s Hospital, ; Geneva, Switzerland
                [9 ]GRID grid.415490.d, ISNI 0000 0001 2177 007X, West of Scotland Regional Genetics Service, Laboratory Medicine Building, , Queen Elizabeth University Hospital, ; Glasgow, UK
                [10 ]GRID grid.415490.d, ISNI 0000 0001 2177 007X, Department of Neurology, , Queen Elizabeth University Hospital, ; Glasgow, UK
                [11 ]GRID grid.436283.8, ISNI 0000 0004 0612 2631, MRC Neuromuscular Centre, , National Hospital for Neurology and Neurosurgery, Queen’s Square, ; London, UK
                [12 ]GRID grid.420468.c, Dubowitz Neuromuscular Centre, , Great Ormond Street Hospital for Children, ; London, UK
                [13 ]GRID grid.83440.3b, ISNI 0000000121901201, NIHR Great Ormond Street Hospital Biomedical Research Centre, , Great Ormond Street Institute of Child Health, University College London, Great Ormond Street Hospital Trust, ; London, UK
                [14 ]GRID grid.1005.4, ISNI 0000 0004 4902 0432, School of Biotechnology and Biomolecular Sciences, , The University of New South Wales, ; Sidney, Australia
                [15 ]GRID grid.413973.b, ISNI 0000 0000 9690 854X, Kids Neuroscience Centre, Kids Research, , The Children’s Hospital at Westmead, ; Sydney, NSW Australia
                [16 ]Institute of Neuropathology, University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
                [17 ]GRID grid.5330.5, ISNI 0000 0001 2107 3311, Department of Genetics, , University of Erlangen, ; Erlangen, Germany
                [18 ]GRID grid.15090.3d, ISNI 0000 0000 8786 803X, Muscle Laboratory, Department of Neurology, , University of Bonn Medical Centre, ; Bonn, Germany
                [19 ]GRID grid.5590.9, ISNI 0000000122931605, Department of Neurology, , Donders Institute for Brain, Cognition and Behaviour, Radboud University, ; Nijmegen, The Netherlands
                [20 ]GRID grid.5590.9, ISNI 0000000122931605, Department of Paediatric Neurology, , Radboud University, ; Nijmegen, The Netherlands
                [21 ]GRID grid.10417.33, ISNI 0000 0004 0444 9382, Department of Human Genetics, , Radboud University Medical Center, ; Nijmegen, The Netherlands
                [22 ]GRID grid.266100.3, ISNI 0000 0001 2107 4242, UCSD, Rady Children’s Hospital, and VA San Diego Healthcare System, ; San Diego, USA
                [23 ]Gillette Children’s Specialty Care, St Paul, MN USA
                [24 ]GRID grid.412914.b, ISNI 0000 0001 0571 3462, Northern Ireland Regional Genetics Service, Belfast City Hospital, ; Belfast, UK
                [25 ]GRID grid.416092.8, ISNI 0000 0000 9403 9221, Department of Paediatric Neurology, , Royal Belfast Hospital for Sick Children, ; Belfast, UK
                [26 ]GRID grid.214572.7, ISNI 0000 0004 1936 8294, Department of Pathology, , The University of Iowa, ; Iowa City, IA USA
                [27 ]GRID grid.7450.6, ISNI 0000 0001 2364 4210, Department of Paediatric Neurology, , University of Göttingen, ; Göttingen, Germany
                [28 ]GRID grid.5570.7, ISNI 0000 0004 0490 981X, Institut Für Humangenetik, Ruhruniversität Bochum, ; Bochum, Germany
                [29 ]GRID grid.7429.8, ISNI 0000000121866389, Genethon and UMR_S951, INSERM, Université Evry, Université Paris Saclay, Evry, ; 91002 Evry, France
                [30 ]GRID grid.48769.34, ISNI 0000 0004 0461 6320, Neuromuscular Reference Centre, Department of Neurology, , University Hospital Saint-Luc, ; Brussels, Belgium
                [31 ]GRID grid.144756.5, ISNI 0000 0001 1945 5329, Reference Center for Neuromuscular Disorders, , Hospital Universitario 12 de Octubre, ; Madrid, Spain
                [32 ]GRID grid.6190.e, ISNI 0000 0000 8580 3777, Centre for Rare Diseases (ZSEK), , University of Cologne, ; Cologne, Germany
                [33 ]GRID grid.508487.6, ISNI 0000 0004 7885 7602, Basic and Translational Myology Laboratory, , Université de Paris, ; Paris, France
                [34 ]GRID grid.50550.35, ISNI 0000 0001 2175 4109, Centre de Référence Des Maladies Neuromusculaires, , APHP, Institut of Myology, GHU Pitié Salpêtrière- Charles Foix, ; Paris, France
                [35 ]GRID grid.13097.3c, ISNI 0000 0001 2322 6764, Department of Clinical and Basic Neuroscience, , IoPPN, King’s College London, ; London, UK
                Author information
                http://orcid.org/0000-0003-4027-9803
                Article
                2257
                10.1007/s00401-020-02257-0
                7882473
                33449170
                b59971dd-617b-4d47-ad81-ae0263174bfb
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 19 May 2020
                : 20 December 2020
                : 20 December 2020
                Funding
                Funded by: British Heart Foundation
                Award ID: RG/15/8/31480
                Award Recipient :
                Funded by: Medical Research Council UK
                Award ID: MR/R003106/1
                Award Recipient :
                Funded by: Myotubular Trust
                Award ID: 12KCL01
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: NS053672
                Award Recipient :
                Funded by: Princes Beatrix muscle fund
                Funded by: Deutsche Forschungsgemeinschaft
                Award ID: Cl 218/1-1
                Award Recipient :
                Funded by: Australian NHMRC
                Award ID: GNT1090428
                Award Recipient :
                Categories
                Original Paper
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2021

                Neurology
                Neurology

                Comments

                Comment on this article