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1. 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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2. Core-rod myopathy caused by mutations in the nebulin gene

Author

Michel Fardeau, Nicole Monnier, R Y Carlier, Norma B. Romero, N. Pellegrini, Carina Wallgren-Pettersson, A. Barois, Nigel G. Laing, Susana Quijano-Roy, David Orlikowski, Vilma-Lotta Lehtokari, Joël Lunardi, Kristl G. Claeys, Katarina Pelin, Thérapie des maladies du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de référence des maladies rares neuromusculaires [CHU Pitié-Salpétriêre], 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), Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Service de Pédiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP], Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Service de Radiologie et imagerie médicale, Service de Réanimation Adultes, Center for Medical Research, The University of Western Australia (UWA), Faculty of Biological and Environmental Sciences [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), the Association Française contre les Myopathies (AFM), the Association Institut de Myologie (AIM), the Australian National Health and Medical Research Council (Fellowship and Project Grant), US Muscular Dystrophy and Motor Neuron Disease Research Institute of Australia, and the Academy of Finland, the Sigrid Jusélius Foundation, the Finska La karesallskapet, and the Medicinska understodsforeningen Liv och Halsa, Finland. V.-L.L. is funded by grants allocated to the group of C.W.-P., Roux-Buisson, Nathalie, Centre de référence des maladies rares neuromusculaires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, University of Helsinki, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Adult, Male, medicine.medical_specialty, Pathology, MESH: Mutation, Muscle Fibers, Skeletal, Muscle Proteins, MESH: Microscopy, Electron, Biology, Myopathies, Nemaline, TPM2, MESH: Magnetic Resonance Imaging, 03 medical and health sciences, Nebulin, MESH: Muscle Proteins, 0302 clinical medicine, Nemaline myopathy, Internal medicine, medicine, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Myopathy, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, RYR1, 0303 health sciences, MESH: Humans, MESH: Muscle Fibers, Skeletal, Muscle weakness, Skeletal muscle, MESH: Adult, medicine.disease, Magnetic Resonance Imaging, MESH: Male, MESH: Myopathies, Nemaline, 3. Good health, Microscopy, Electron, Endocrinology, medicine.anatomical_structure, Mutation, biology.protein, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), medicine.symptom, 030217 neurology & neurosurgery, Central core disease
Abstract

Nemaline myopathy (NM) and central core disease (CCD), 2 of the most frequent congenital myopathies, are clinically and genetically heterogeneous disorders of skeletal muscle. NM (OMIM 161800) is caused by mutations in at least 6 different genes encoding thin filament proteins of the striated muscle sarcomere: skeletal alpha-actin ( ACTA1 ), nebulin ( NEB ), beta-tropomyosin ( TPM2 ), slow alpha-tropomyosin ( TPM3 ), slow skeletal muscle troponin-T ( TNNT1 ), and cofilin-2 ( CFL2 ). CCD (OMIM 117000) is mainly caused by mutations in the gene encoding the skeletal muscle ryanodine receptor ( RYR1 ), a Ca2+ channel involved in excitation-contraction coupling. Congenital myopathies with the combination of distinct “cores” and “rods” in the same muscle fibers have been described in a small number of cases. In 2 families mutations have been identified in RYR1 1,2 and in others, linkage has been found to a locus on chromosome 15.3 Here we report a patient with recessively inherited core-rod myopathy caused by compound heterozygous mutations in NEB . This observation broadens the spectrum of genes involved in core-rod myopathies. ### Case report. The patient is a 27-year-old white man. He presented at birth with generalized hypotonia and required immediate intubation and resuscitation. Spontaneous movements were very poor and he had seizures from the first week. Restrictive respiratory insufficiency led to continuous mechanical ventilation via tracheotomy at the age of 2 years. The patient did not acquire independent walking but was able to take a few steps with orthosis at the age of 4; diffuse muscle weakness with axial predominance was observed. Electromyography showed myopathic patterns and normal motor and sensory responses. Serum creatine kinase levels were normal. The patient developed …

Published
2009
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