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1. Quantification of the spread of SARS-CoV-2 variant B.1.1.7 in Switzerland

Author

Chaoran Chen, Sarah Ann Nadeau, Ivan Topolsky, Marc Manceau, Jana S. Huisman, Kim Philipp Jablonski, Lara Fuhrmann, David Dreifuss, Katharina Jahn, Christiane Beckmann, Maurice Redondo, Christoph Noppen, Lorenz Risch, Martin Risch, Nadia Wohlwend, Sinem Kas, Thomas Bodmer, Tim Roloff, Madlen Stange, Adrian Egli, Isabella Eckerle, Laurent Kaiser, Rebecca Denes, Mirjam Feldkamp, Ina Nissen, Natascha Santacroce, Elodie Burcklen, Catharine Aquino, Andreia Cabral de Gouvea, Maria Domenica Moccia, Simon Grüter, Timothy Sykes, Lennart Opitz, Griffin White, Laura Neff, Doris Popovic, Andrea Patrignani, Jay Tracy, Ralph Schlapbach, Emmanouil T. Dermitzakis, Keith Harshman, Ioannis Xenarios, Henri Pegeot, Lorenzo Cerutti, Deborah Penet, Anthony Blin, Melyssa Elies, Christian L. Althaus, Christian Beisel, Niko Beerenwinkel, Martin Ackermann, and Tanja Stadler

Subjects
Pandemic, SARS-CoV-2, COVID-19, B.1.1.7, Transmission advantage, Infectious and parasitic diseases, RC109-216
Abstract

Background: In December 2020, the United Kingdom (UK) reported a SARS-CoV-2 Variant of Concern (VoC) which is now named B.1.1.7. Based on initial data from the UK and later data from other countries, this variant was estimated to have a transmission fitness advantage of around 40–80 % (Volz et al., 2021; Leung et al., 2021; Davies et al., 2021). Aim: This study aims to estimate the transmission fitness advantage and the effective reproductive number of B.1.1.7 through time based on data from Switzerland. Methods: We generated whole genome sequences from 11.8 % of all confirmed SARS-CoV-2 cases in Switzerland between 14 December 2020 and 11 March 2021. Based on these data, we determine the daily frequency of the B.1.1.7 variant and quantify the variant’s transmission fitness advantage on a national and a regional scale. Results: We estimate B.1.1.7 had a transmission fitness advantage of 43–52 % compared to the other variants circulating in Switzerland during the study period. Further, we estimate B.1.1.7 had a reproductive number above 1 from 01 January 2021 until the end of the study period, compared to below 1 for the other variants. Specifically, we estimate the reproductive number for B.1.1.7 was 1.24 [1.07–1.41] from 01 January until 17 January 2021 and 1.18 [1.06–1.30] from 18 January until 01 March 2021 based on the whole genome sequencing data. From 10 March to 16 March 2021, once B.1.1.7 was dominant, we estimate the reproductive number was 1.14 [1.00–1.26] based on all confirmed cases. For reference, Switzerland applied more non-pharmaceutical interventions to combat SARS-CoV-2 on 18 January 2021 and lifted some measures again on 01 March 2021. Conclusion: The observed increase in B.1.1.7 frequency in Switzerland during the study period is as expected based on observations in the UK. In absolute numbers, B.1.1.7 increased exponentially with an estimated doubling time of around 2–3.5 weeks. To monitor the ongoing spread of B.1.1.7, our plots are available online.

Published
2021
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2. Evaluating next-generation sequencing in neuromuscular diseases with neonatal respiratory distress

Author

Marie Laure Martin Negrier, John Rendu, François Rivier, Valérie Rigau, Emmanuelle Uro-Coste, Henri Pegeot, Anne Cécile Coville, Delphine Lacourt, Raul Juntas Morales, Caroline Espil-Taris, Claude Cances, Mireille Cossée, Pierre Beze-Beyrie, C. Thèze, Marie-Céline François-Heude, Ulrike Walther-Louvier, Eloise Baudou, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), [GIN] Grenoble Institut des Neurosciences (GIN), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)

Subjects
Male, Pediatrics, medicine.medical_specialty, Neuromuscular disease, [SDV]Life Sciences [q-bio], Cohort Studies, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, 030225 pediatrics, medicine, Humans, ComputingMilieux_MISCELLANEOUS, Exome sequencing, Retrospective Studies, Whole genome sequencing, Sanger sequencing, Respiratory Distress Syndrome, Newborn, business.industry, Infant, Newborn, High-Throughput Nucleotide Sequencing, Infant, Retrospective cohort study, Neuromuscular Diseases, General Medicine, medicine.disease, Congenital myopathy, Hypotonia, 3. Good health, Pediatrics, Perinatology and Child Health, symbols, Congenital muscular dystrophy, Female, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

With the exception of infantile spinal muscular atrophy (SMA) and congenital myotonic dystrophy 1 (DM1), congenital myopathies and muscular dystrophies with neonatal respiratory distress pose diagnostic challenges. Next-generation sequencing (NGS) provides hope for the diagnosis of these rare diseases. We evaluated the efficiency of next-generation sequencing (NGS) in ventilated newborns with peripheral hypotonia. We compared the results of our previous study in a cohort of 19 patients analysed by Sanger sequencing from 2007 to 2012, with a diagnostic yield of 26% (5/19), and those of a new retrospective study in 28 patients from 2007 to 2018 diagnosed using MyoPanel, a neuromuscular disease panel, with a diagnostic yield of 43% (12/28 patients). Pathogenic variants were found in five genes: ACTA1 (n = 4 patients), RYR1 (n = 2), CACNA1S (n = 1), NEB (n = 3), and MTM1 (n = 2). Myopanel increased the diagnosis of congenital neuromuscular diseases, but more than half the patients remained undiagnosed. Whole exome sequencing did not seem to fully respond to this diagnostic limitation. Therefore, explorations with whole genome sequencing will be the next step.

Published
2021
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3. Clinical phenotype and loss of the slow skeletal muscle troponin T in three new patients with recessive TNNT1 nemaline myopathy

Author

A. Madelaine, Julie Brocard, Mireille Cossée, Isabelle Marty, Anne-Cécile Coville, Michel Koenig, Christine Ioos, C. Thèze, John Rendu, Klaus Dieterich, Aurore Siegfried, Julien Fauré, Claude Cances, Henri Pegeot, Eloïse Baudou, Pascale Marcorelle, Norma B. Romero, Emmanuelle Lacène, Emmanuelle Uro Coste, Murielle Dobrzynski, Raul Juntas Morales, Justine Géraud, Neurologie générale et maladies inflammatoires du système nerveux [Toulouse], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Groupe d'imagerie neurofonctionnelle (GIN), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHRU Brest, Pôle de Biologie Pathologie (CHU - BREST - Biologie pathologie), Hôpital Raymond Poincaré [AP-HP], Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Institut des Neurosciences de Montpellier (INM)

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, diagnosis, [SDV]Life Sciences [q-bio], Biopsy, Nonsense mutation, neuromuscular diseases, Slow skeletal muscle troponin T, Myopathies, Nemaline, 03 medical and health sciences, Exon, 0302 clinical medicine, Nemaline myopathy, Troponin T, Genetics, medicine, Humans, Genetic Predisposition to Disease, Diagnostics, Genetics (clinical), Genetic Association Studies, Sequence Deletion, business.industry, Homozygote, Skeletal muscle, Muscle weakness, Computational Biology, High-Throughput Nucleotide Sequencing, Infant, Sequence Analysis, DNA, medicine.disease, musculoskeletal system, Immunohistochemistry, Hypotonia, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Phenotype, Child, Preschool, Mutation, Female, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

BackgroundCongenital nemaline myopathies are rare pathologies characterised by muscle weakness and rod-shaped inclusions in the muscle fibres.MethodsUsing next-generation sequencing, we identified three patients with pathogenic variants in the Troponin T type 1 (TNNT1) gene, coding for the troponin T (TNT) skeletal muscle isoform.ResultsThe clinical phenotype was similar in all patients, associating hypotonia, orthopaedic deformities and progressive chronic respiratory failure, leading to early death. The anatomopathological phenotype was characterised by a disproportion in the muscle fibre size, endomysial fibrosis and nemaline rods. Molecular analyses of TNNT1 revealed a homozygous deletion of exons 8 and 9 in patient 1; a heterozygous nonsense mutation in exon 9 and retention of part of intron 4 in muscle transcripts in patient 2; and a homozygous, very early nonsense mutation in patient 3.Western blot analyses confirmed the absence of the TNT protein resulting from these mutations.DiscussionThe clinical and anatomopathological presentations of our patients reinforce the homogeneous character of the phenotype associated with recessive TNNT1 mutations. Previous studies revealed an impact of recessive variants on the tropomyosin-binding affinity of TNT. We report in our patients a complete loss of TNT protein due to open reading frame disruption or to post-translational degradation of TNT.

Published
2020
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4. Novel dominant distal titinopathy phenotype associated with copy number variation

Author

Nicolas Leboucq, Martial Mallaret, Raul Juntas Morales, Mireille Cossée, K. Gaudon, Emmanuelle Uro-Coste, Delphine Lacourt, Henri Pegeot, C. Thèze, Emmeline Lagrange, Aurélien Perrin, Pascale Richard, Corinne Metay, Valérie Rigau, Michel Koenig, Diane Giovannini, Françoise Chapon, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire [Grenoble] (CHU), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique [CHU Pitié Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), MORNET, Dominique, CHU Montpellier, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), CHU Grenoble, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), AFM 21384 grant (The French Muscular Dystrophy Association (AFM-Téléthon)), the Délégation à la Recherche Clinique et à l'Innovation du Groupement de Coopération Sanitaire de la Mission d'Enseignement, de Recherche, de Référence et d'Innovation (DRCI-GCS-MERRI) de Montpellier-Nîmes., Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and CHU Toulouse [Toulouse]

Subjects
Male, DNA Copy Number Variations, [SDV]Life Sciences [q-bio], Neurosciences. Biological psychiatry. Neuropsychiatry, Brief Communication, Muscular Dystrophies, Frameshift mutation, 03 medical and health sciences, 0302 clinical medicine, Medicine, Humans, In patient, Connectin, Copy-number variation, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Aberrant splicing, RC346-429, Gene, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Aged, Genetics, Aged, 80 and over, 0303 health sciences, business.industry, General Neuroscience, Middle Aged, Phenotype, Pedigree, [SDV] Life Sciences [q-bio], Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology. Diseases of the nervous system, Neurology (clinical), business, Haploinsufficiency, 030217 neurology & neurosurgery, RC321-571
Abstract

International audience; The aim of this study was to analyze patients from two distinct families with a novel distal titinopathy phenotype associated with exactly the same CNV in the TTN gene. We used an integrated strategy combining deep phenotyping and complete molecular analyses in patients. The CNV is the most proximal out-of-frame TTN variant reported and leads to aberrant splicing transcripts leading to a frameshift. In this case, the dominant effect would be due to dominant-negative and/or haploinsufficiency. Few CNV in TTN have been reported to date. Our data represent a novel phenotype-genotype association and provides hypotheses for its dominant effects.

Published
2021
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5. Quantification of the spread of SARS-CoV-2 variant B.1.1.7 in Switzerland

Author

Christoph Noppen, Doris Popovic, Christian L. Althaus, Lorenz Risch, Olivier Kobel, Deborah Penet, Sinem Kas, Martin Ackermann, Chaoran Chen, Ivan Topolsky, Lara Fuhrmann, Ina Nissen, Katharina Jahn, Rebecca Denes, Melyssa Elies, Christiane Beckmann, Keith Harshman, Christian Beisel, Tim Roloff, Simon Grüter, Natascha Santacroce, Kim Philipp Jablonski, Nadia Wohlwend, Maria Domenica Moccia, Catharine Aquino, Adrian Egli, Niko Beerenwinkel, Lennart Opitz, Maurice Redondo, Henri Pegeot, Jana S. Huisman, Thomas Bodmer, Laurent Kaiser, Ioannis Xenarios, Ralph Schlapbach, Andreia Cabral de Gouvea, Madlen Stange, Sarah Nadeau, Laura Neff, Jay Tracy, David Dreifuss, Elodie Burcklen, Tanja Stadler, Griffin White, Isabella Eckerle, Marc Manceau, Anthony Blin, Lorenzo Cerutti, Mirjam Feldkamp, Emmanouil T. Dermitzakis, Martin Risch, Andrea Patrignani, and Timothy Sykes

Subjects
2019-20 coronavirus outbreak, Transmission (mechanics), Surveillance data, Coronavirus disease 2019 (COVID-19), law, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Statistics, Point estimation, Biology, law.invention
Abstract

BackgroundIn December 2020, the United Kingdom (UK) reported a SARS-CoV-2 Variant of Concern (VoC) which is now named B.1.1.7. Based on initial data from the UK and later data from other countries, this variant was estimated to have a transmission fitness advantage of around 40-80% [1, 2, 3].AimThis study aims to estimate the transmission fitness advantage and the effective reproductive number of B.1.1.7 through time based on data from Switzerland.MethodsWe generated whole genome sequences from 11.8% of all confirmed SARS-CoV-2 cases in Switzerland between 14 December 2020 and 11 March 2021. Based on these data, we determine the daily frequency of the B.1.1.7 variant and quantify the variant’s transmission fitness advantage on a national and a regional scale.ResultsWe estimate B.1.1.7 had a transmission fitness advantage of 43-52% compared to the other variants circulating in Switzerland during the study period. Further, we estimate B.1.1.7 had a reproductive number above 1 from 01 January 2021 until the end of the study period, compared to below 1 for the other variants. Specifically, we estimate the reproductive number for B.1.1.7 was 1.24 [1.07-1.41] from 01 January until 17 January 2021 and 1.18 [1.06-1.30] from 18 January until 01 March 2021 based on the whole genome sequencing data. From 10 March to 16 March 2021, once B.1.1.7 was dominant, we estimate the reproductive number was 1.14 [1.00-1.26] based on all confirmed cases. For reference, Switzerland applied more non-pharmaceutical interventions to combat SARS-CoV-2 on 18 January 2021 and lifted some measures again on 01 March 2021.ConclusionThe observed increase in B.1.1.7 frequency in Switzerland during the study period is as expected based on observations in the UK. In absolute numbers, B.1.1.7 increased exponentially with an estimated doubling time of around 2-3.5 weeks. To monitor the ongoing spread of B.1.1.7, our plots are available online.

Published
2021
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6. The importance of an integrated genotype-phenotype strategy to unravel the molecular bases of titinopathies

Author

Valérie Rigau, Michel Koenig, Edoardo Malfatti, Charles Van Goethem, Claude Cances, Aurélien Perrin, Nicolas Leboucq, Constance Delaby, C. Thèze, François Rivier, Raul Juntas Morales, Ulrike Walther-Louvier, Henri Pegeot, Reda Zenagui, Sylvain Lehmann, Mireille Cossée, Delphine Lacourt, Emmanuelle Uro-Coste, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de référence des Maladies Neuromusculaires AOC, CHU Toulouse [Toulouse], Département de Neuroradiologie[Montpellier], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Centre de Référence Maladies Neuromusculaires Nord-Est-Ile-de-France, CHU Raymond-Poincaré, Garches, France, Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), MORNET, Dominique, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Institut des Neurosciences de Montpellier (INM)

Subjects
0301 basic medicine, Adolescent, Genotype, [SDV]Life Sciences [q-bio], Population, Disease, DNA sequencing, Genotype phenotype, 03 medical and health sciences, 0302 clinical medicine, Muscular Diseases, medicine, Humans, Connectin, education, Child, Muscle, Skeletal, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, education.field_of_study, biology, Inheritance (genetic algorithm), High-Throughput Nucleotide Sequencing, Middle Aged, medicine.disease, Phenotype, Congenital myopathy, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Neurology, Pediatrics, Perinatology and Child Health, Mutation, biology.protein, Titin, Female, Neurology (clinical), 030217 neurology & neurosurgery
Abstract

Next generation sequencing (NGS) has allowed the titin gene (TTN) to be identified as a major contributor to neuromuscular disorders, with high clinical heterogeneity. The mechanisms underlying the phenotypic variability and the dominant or recessive pattern of inheritance are unclear. Titin is involved in the formation and stability of the sarcomeres. The effects of the different TTN variants can be harmless or pathogenic (recessive or dominant) but the interpretation is tricky because the current bioinformatics tools can not predict their functional impact effectively. Moreover, TTN variants are very frequent in the general population. The combination of deep phenotyping associated with RNA molecular analyses, western blot (WB) and functional studies is often essential for the interpretation of genetic variants in patients suspected of titinopathy. In line with the current guidelines and suggestions, we implemented for patients with skeletal myopathy and with potentially disease causing TTN variant(s) an integrated genotype-transcripts-protein-phenotype approach, associated with phenotype and variants segregation studies in relatives and confrontation with published data on titinopathies to evaluate pathogenic effects of TTN variants (even truncating ones) on titin transcripts, amount, size and functionality. We illustrate this integrated approach in four patients with recessive congenital myopathy.

Published
2020
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7. An Integrated Clinical-Biological Approach to Identify Interindividual Variability and Atypical Phenotype-Genotype Correlations in Myopathies: Experience on A Cohort of 156 Families

Author

Valérie Rigau, Michel Koenig, Pascal Cintas, Blandine Acket, Elodie Cosset, André Maues De Paula, Aurélien Perrin, John Rendu, Pascale Richard, Kevin Yauy, Edoardo Malfatti, Marie-Laure Martin Negrier, Mireille Cossée, C. Espil, Henri Pegeot, Dimitri Renard, Emmanuelle Uro-Coste, Valérie Biancalana, Corinne Metay, Delphine Lacourt, C. Thèze, Ulrike Walther-Louvier, Raul Juntas Morales, Nicolas Leboucq, François Rivier, Guilhem Solé, Marie-Christine Arne-Bes, Reda Zenagui, Claude Cances, Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Bordeaux [Bordeaux], CHU Toulouse [Toulouse], Service de Neurologie [CHU Nimes] (Pôle NIRR), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), CHU Marseille, Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Hôpital Raymond Poincaré [AP-HP], Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Strasbourg (UNISTRA), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire [Grenoble] (CHU), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut Universitaire de Recherche Clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), This work was funded by the 'Agence de la Biomédecine' (Ref ABD/EBe-DLE) and TheFrench Muscular Dystrophy Association (AFM-Téléthon) (Ref 19958)., and Retiveau, Nolwenn

Subjects
Adult, Male, 0301 basic medicine, Genotype, [SDV]Life Sciences [q-bio], deep phenotyping, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, QH426-470, Bioinformatics, Article, inter-individual variability, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Muscular Diseases, Genetics, Humans, Medicine, FLNC, Copy-number variation, Child, Genetics (clinical), atypical phenotype-genotype associations, next generation sequencing, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Genetic heterogeneity, business.industry, High-Throughput Nucleotide Sequencing, Precision medicine, 3. Good health, Phenotype, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, myopathies, Cohort, [SDV.GEN.GPO] Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Etiology, Distal Myopathies, Female, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract

International audience; Diagnosis of myopathies is challenged by the high genetic heterogeneity and clinical overlap of the various etiologies. We previously reported a Next-Generation Sequencing strategy to identify genetic etiology in patients with undiagnosed Limb-Girdle Muscular Dystrophies, Congenital Myopathies, Congenital Muscular Dystrophies, Distal Myopathies, Myofibrillar Myopathies, and hyperCKemia or effort intolerance, using a large gene panel including genes classically associated with other entry diagnostic categories. In this study, we report the comprehensive clinical-biological strategy used to interpret NGS data in a cohort of 156 pediatric and adult patients, that included Copy Number Variants search, variants filtering and interpretation according to ACMG guidelines, segregation studies, deep phenotyping of patients and relatives, transcripts and protein studies, and multidisciplinary meetings. Genetic etiology was identified in 74 patients, a diagnostic yield (47.4%) similar to previous studies. We identified 18 patients (10%) with causative variants in different genes (ACTA1, RYR1, NEB, TTN, TRIP4, CACNA1S, FLNC, TNNT1, and PAPBN1) that resulted in milder and/or atypical phenotypes, with high intrafamilial variability in some cases. Mild phenotypes could mostly be explained by a less deleterious effect of variants on the protein. Detection of inter-individual variability and atypical phenotype-genotype associations is essential for precision medicine, patient care, and to progress in the understanding of the molecular mechanisms of myopathies.

Published
2021
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8. MoBiDiC Prioritization Algorithm, a Free, Accessible, and Efficient Pipeline for Single-Nucleotide Variant Annotation and Prioritization for Next-Generation Sequencing Routine Molecular Diagnosis

Author

Sylvie Tuffery-Giraud, Michel Koenig, Raul Juntas Morales, David Baux, Charles Van Goethem, Mireille Cossée, Charly Mathieu, Vilma-Lotta Lehtokari, Kevin Yauy, Gisèle Bonne, Martin Krahn, Thomas Guignard, Delphine Lacourt, Henri Pegeot, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Myologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Montpellier 1 (UM1)-IFR3, and Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
0301 basic medicine, Computer science, RNA Splicing, In silico, Mutation, Missense, High-Throughput Nucleotide Sequencing, Molecular Sequence Annotation, Molecular diagnostics, Polymorphism, Single Nucleotide, DNA sequencing, Pathology and Forensic Medicine, 03 medical and health sciences, Annotation, 030104 developmental biology, Molecular Diagnostic Techniques, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Humans, Molecular Medicine, Missense mutation, Computer Simulation, splice, Algorithm, Algorithms, Exome sequencing, Selection (genetic algorithm)
Abstract

International audience; Interpretation of next-generation sequencing constitutes the main limitation of molecular diagnostics. In diagnosing myopathies and muscular dystrophies, another issue is efficiency in predicting the pathogenicity of variants identified in large genes, especially TTN; current in silico prediction tools show limitations in predicting and ranking the numerous variants of such genes. We propose a variant-prioritization tool, the MoBiDiC prioritization algorithm (MPA). MPA is based on curated interpretation of data on previously reported variants, biological assumptions, and splice and missense predictors, and is used to prioritize all types of single-nucleotide variants. MPA was validated by comparing its sensitivity and specificity to those of dbNSFP database prediction tools, using a data set composed of DYSF, DMD, LMNA, NEB, and TTN variants extracted from expert-reviewed and ExAC databases. MPA obtained the best annotation rates for missense and splice variants. As MPA aggregates the results from several predictors, individual predictor errors are counterweighted, improving the sensitivity and specificity of missense and splice variant predictions. We propose a sequential use of MPA, beginning with the selection of variants with higher scores and followed by, in the absence of candidate pathologic variants, consideration of variants with lower scores. We provide scripts and documentation for free academic use and a validated annotation pipeline scaled for panel and exome sequencing to prioritize single-nucleotide variants from a VCF file.

Published
2018
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9. A Reliable Targeted Next-Generation Sequencing Strategy for Diagnosis of Myopathies and Muscular Dystrophies, Especially for the Giant Titin and Nebulin Genes

Author

Reda Zenagui, Cyril Goizet, Corine Theze, Marie-Christine Arne-Bes, Kevin Yauy, Claude Cances, Raul Juntas Morales, Dimitri Renard, Xavier Ferrer-Monasterio, Valérie Rigau, Michel Koenig, Pascal Cintas, Mireille Claustres, Eric Bieth, François Rivier, Guilhem Solé, Caroline Espil, Henri Pegeot, Mireille Cossée, Delphine Lacourt, Emmanuelle Uro-Coste, Ulrike Walther-Louvier, Marie-Laure Martin Negrier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de neurologie [Montpellier], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), CHU Toulouse [Toulouse], Centre de référence des maladies rares neuromusculaires Aquitaine-Grand Sud Ouest, CHU Bordeaux [Bordeaux], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service de neuropédiatrie, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), and CHU Strasbourg-Hôpital de Hautepierre [Strasbourg]

Subjects
0301 basic medicine, Heterozygote, DNA Copy Number Variations, Muscle Proteins, Computational biology, DNA sequencing, Muscular Dystrophies, Pathology and Forensic Medicine, 03 medical and health sciences, Nebulin, 0302 clinical medicine, INDEL Mutation, Humans, Connectin, Copy-number variation, Indel, Gene, ComputingMilieux_MISCELLANEOUS, biology, Genetic heterogeneity, Computational Biology, High-Throughput Nucleotide Sequencing, Reproducibility of Results, DNA, Exons, 3. Good health, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, Molecular Medicine, Titin, Trinucleotide repeat expansion, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Myopathies and muscular dystrophies (M-MDs) are genetically heterogeneous diseases, with >100 identified genes, including the giant and complex titin (TTN) and nebulin (NEB) genes. Next-generation sequencing technology revolutionized M-MD diagnosis and revealed high frequency of TTN and NEB variants. We developed a next-generation sequencing diagnostic strategy targeted to the coding sequences of 135 M-MD genes. Comparison of two targeted capture technologies (SeqCap EZ Choice library capture kit and Nextera Rapid Capture Custom Enrichment kit) and of two whole-exome sequencing kits (SureSelect V5 and TruSeq RapidExome capture) revealed best coverage with the SeqCap EZ Choice protocol. A marked decrease in coverage was observed with the other kits, affecting mostly the first exons of genes and the repeated regions of TTN and NEB. Bioinformatics analysis strategy was fine-tuned to achieve optimal detection of variants, including small insertions/deletions (INDELs) and copy number variants (CNVs). Analysis of a cohort of 128 patients allowed the detection of 52 substitutions, 13 INDELs (including a trinucleotide repeat expansion), and 3 CNVs. Two INDELs were localized in the repeated regions of NEB, suggesting that these mutations may be frequent but underestimated. A large deletion was also identified in TTN that is, to our knowledge, the first published CNV in this gene.

Published
2018
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10. NEXT GENERATION SEQUENCING AND EXPERIMENTAL MYOLOGY

Author

Nicolas Leboucq, Fanny Duval, Henri Pegeot, Dimitri Renard, R. Juntas Morales, Emmanuelle Uro-Coste, François Rivier, Claude Cances, Guilhem Solé, Valérie Rigau, D. Peyroulan, C. Espil, U. Walther Louvier, C. Thèze, Pascal Cintas, Mireille Cossée, Blandine Acket, Aurélien Perrin, and M. Arne-Bes

Subjects
Neurology, Pediatrics, Perinatology and Child Health, Myology, Neurology (clinical), Computational biology, Biology, Genetics (clinical), DNA sequencing
Published
2018
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11. P.237Functional analyses and phenotype-genotype correlation studies in patients suspected of titinopathy

Author

Valérie Rigau, Michel Koenig, Aurélien Perrin, M. Arne-Bes, Henri Pegeot, Pascal Cintas, D. Thorel, Mireille Cossée, Emmanuelle Uro-Coste, C. Espil, Nicolas Leboucq, Guilhem Solé, C. Thèze, Ulrike Walther-Louvier, Dimitri Renard, M. Martine Negrier, R. Juntas Morales, A. Maues de Paula, and Claude Cances

Subjects
Correlation, medicine.medical_specialty, Neurology, Internal medicine, Pediatrics, Perinatology and Child Health, medicine, Phenotype genotype, In patient, Neurology (clinical), Biology, Gastroenterology, Genetics (clinical)
Published
2019
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12. Adult onset distal myopathy secondary to nebulin gene mutations

Author

R. Juntas Morales, Nicolas Leboucq, D. Figarella, Henri Pegeot, Aurélien Perrin, Delphine Lacourt, Mireille Cossée, A. Maues de Paula, C. Thèze, and Kevin Yauy

Subjects
Genetics, Nebulin, Neurology, biology, Pediatrics, Perinatology and Child Health, biology.protein, medicine, Neurology (clinical), Gene mutation, medicine.symptom, Myopathy, Genetics (clinical)
Published
2017
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13. Novel dominant distal titinopathy phenotype associated with copy number variation

Author

Aurélien Perrin, Raul Juntas Morales, Françoise Chapon, Corinne Thèze, Delphine Lacourt, Henri Pégeot, Emmanuelle Uro‐Coste, Diane Giovannini, Nicolas Leboucq, Martial Mallaret, Emmeline Lagrange, Valérie Rigau, Karen Gaudon, Pascale Richard, Michel Koenig, Corinne Métay, and Mireille Cossée

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract The aim of this study was to analyze patients from two distinct families with a novel distal titinopathy phenotype associated with exactly the same CNV in the TTN gene. We used an integrated strategy combining deep phenotyping and complete molecular analyses in patients. The CNV is the most proximal out‐of‐frame TTN variant reported and leads to aberrant splicing transcripts leading to a frameshift. In this case, the dominant effect would be due to dominant‐negative and/or haploinsufficiency. Few CNV in TTN have been reported to date. Our data represent a novel phenotype–genotype association and provides hypotheses for its dominant effects.

Published
2021
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