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

Autor: 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
Přispěvatelé: 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)., Retiveau, Nolwenn
Rok vydání: 2021
Předmět:
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
Zdroj: Genes; Volume 12; Issue 8; Pages: 1199
Genes, Vol 12, Iss 1199, p 1199 (2021)
Genes
Genes, MDPI, 2021, 12 (8), pp.1199. ⟨10.3390/genes12081199⟩
Genes, 2021, 12 (8), pp.1199. ⟨10.3390/genes12081199⟩
ISSN: 2073-4425
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: