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Copy Number Variants Account for a Tiny Fraction of Undiagnosed Myopathic Patients

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Dipartimento di Medicina di Precisione, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Napoli, Italy
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Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, Italy
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Folkhälsan Research Center, Medicum, University of Helsinki, FI-00290 Helsinki, Finland
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Cardiomiologia e Genetica Medica, Dipartimento di Medicina Sperimentale, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Napoli, Italy
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U.O.C. Neurologia Pediatrica e Malattie Muscolari, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy
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Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, “Bambino Gesù” Children’s Hospital, IRCCS, 00146 Roma, Italy
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Neuromuscular Diseases and Neuroimmunology Unit, Istituto Besta, 20133 Milano, Italy
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Dipartimento di Neuroscienze e Scienze Riproduttive ed Odontostomatologiche, Università degli Studi di Napoli “Federico II”, 80131 Napoli, Italy
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S.S. Malattie Neuromuscolari, Università degli Studi di Torino, 10124 Torino, Italy
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Centro Dino Ferrari, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milano, Italy
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Medicina Molecolare, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy
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Fondazione Hospital S.Camillo IRCCS, 30126 Venezia, Italy
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Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy
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Department of Neurology, Ghent University Hospital, 9000 Ghent, Belgium
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Neuromuscular and Rare Disease Unit, Dipartimento di Neuroscienze, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milano, Italy
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Istituto di Neurologia, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli”, 00168 Roma, Italy
*
Author to whom correspondence should be addressed.
Genes 2018, 9(11), 524; https://doi.org/10.3390/genes9110524
Received: 14 September 2018 / Revised: 19 October 2018 / Accepted: 23 October 2018 / Published: 26 October 2018
(This article belongs to the Section Human Genomics and Genetic Diseases)
Next-generation sequencing (NGS) technologies have led to an increase in the diagnosis of heterogeneous genetic conditions. However, over 50% of patients with a genetically inherited disease are still without a diagnosis. In these cases, different hypotheses are usually postulated, including variants in novel genes or elusive mutations. Although the impact of copy number variants (CNVs) in neuromuscular disorders has been largely ignored to date, missed CNVs are predicted to have a major role in disease causation as some very large genes, such as the dystrophin gene, have prone-to-deletion regions. Since muscle tissues express several large disease genes, the presence of elusive CNVs needs to be comprehensively assessed following an accurate and systematic approach. In this multicenter cohort study, we analyzed 234 undiagnosed myopathy patients using a custom array comparative genomic hybridization (CGH) that covers all muscle disease genes at high resolution. Twenty-two patients (9.4%) showed non-polymorphic CNVs. In 12 patients (5.1%), the identified CNVs were considered responsible for the observed phenotype. An additional ten patients (4.3%) presented candidate CNVs not yet proven to be causative. Our study indicates that deletions and duplications may account for 5–9% of genetically unsolved patients. This strongly suggests that other mechanisms of disease are yet to be discovered. View Full-Text
Keywords: copy number variants; skeletal muscle disorders; next-generation sequencing; variants of uncertain significance copy number variants; skeletal muscle disorders; next-generation sequencing; variants of uncertain significance
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Giugliano, T.; Savarese, M.; Garofalo, A.; Picillo, E.; Fiorillo, C.; D’Amico, A.; Maggi, L.; Ruggiero, L.; Vercelli, L.; Magri, F.; Fattori, F.; Torella, A.; Ergoli, M.; Rubegni, A.; Fanin, M.; Musumeci, O.; Bleecker, J.D.; Peverelli, L.; Moggio, M.; Mercuri, E.; Toscano, A.; Mora, M.; Santoro, L.; Mongini, T.; Bertini, E.; Bruno, C.; Minetti, C.; Comi, G.P.; Santorelli, F.M.; Angelini, C.; Politano, L.; Piluso, G.; Nigro, V. Copy Number Variants Account for a Tiny Fraction of Undiagnosed Myopathic Patients. Genes 2018, 9, 524.

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