Copy number variants account for a tiny fraction of undiagnosed myopathic patients

T. Giugliano, M. Savarese, A. Garofalo, E. Picillo, C. Fiorillo, A. D’amico, L. Maggi, L. Ruggiero, L. Vercelli, F. Magri, F. Fattori, A. Torella, M. Ergoli, A. Rubegni, M. Fanin, O. Musumeci, J. De Bleecker, L. Peverelli, M. Moggio, E. MercuriA. Toscano, M. Mora, L. Santoro, T. Mongini, E. Bertini, C. Bruno, C. Minetti, G.P. Comi, F.M. Santorelli, C. Angelini, L. Politano, G. Piluso, V. Nigro

Research output: Contribution to journalArticle

Abstract

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. © 2018 by the authors. Licensee MDPI, Basel, Switzerland.
Original languageEnglish
JournalGenes
Volume9
Issue number11
DOIs
Publication statusPublished - 2018

Keywords

  • complementary DNA
  • dystrophin
  • genomic DNA
  • merosin
  • sarcoglycan
  • spastin, Article
  • cohort analysis
  • comparative genomic hybridization
  • copy number variation
  • DMD gene
  • DNA determination
  • fluorometry
  • gene
  • gene deletion
  • gene duplication
  • human
  • LAMA2 gene
  • major clinical study
  • multiplex ligation dependent probe amplification
  • myopathy
  • next generation sequencing
  • pathogenesis
  • phenotype
  • real time polymerase chain reaction
  • SGCD gene
  • SPAST gene
  • spectrophotometry

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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., De Bleecker, J., Peverelli, L., Moggio, M., ... Nigro, V. (2018). Copy number variants account for a tiny fraction of undiagnosed myopathic patients. Genes, 9(11). https://doi.org/10.3390/genes9110524