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

Fingerprint

Genes
Muscles
Dystrophin
Comparative Genomic Hybridization
Muscular Diseases
Switzerland
Causality
Multicenter Studies
Cohort Studies
Technology
Phenotype
Mutation

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

Cite this

Giugliano, T., Savarese, M., Garofalo, A., Picillo, E., Fiorillo, C., D’amico, A., ... Nigro, V. (2018). Copy number variants account for a tiny fraction of undiagnosed myopathic patients. Genes, 9(11). https://doi.org/10.3390/genes9110524

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

In: Genes, Vol. 9, No. 11, 2018.

Research output: Contribution to journalArticle

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, Mercuri, E, Toscano, A, Mora, M, Santoro, L, Mongini, T, Bertini, E, Bruno, C, Minetti, C, Comi, GP, Santorelli, FM, Angelini, C, Politano, L, Piluso, G & Nigro, V 2018, 'Copy number variants account for a tiny fraction of undiagnosed myopathic patients', Genes, vol. 9, no. 11. https://doi.org/10.3390/genes9110524
Giugliano T, Savarese M, Garofalo A, Picillo E, Fiorillo C, D’amico A et al. Copy number variants account for a tiny fraction of undiagnosed myopathic patients. Genes. 2018;9(11). https://doi.org/10.3390/genes9110524
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. ; 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. In: Genes. 2018 ; Vol. 9, No. 11.
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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. {\circledC} 2018 by the authors. Licensee MDPI, Basel, Switzerland.",
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T1 - Copy number variants account for a tiny fraction of undiagnosed myopathic patients

AU - Giugliano, T.

AU - Savarese, M.

AU - Garofalo, A.

AU - Picillo, E.

AU - Fiorillo, C.

AU - D’amico, A.

AU - Maggi, L.

AU - Ruggiero, L.

AU - Vercelli, L.

AU - Magri, F.

AU - Fattori, F.

AU - Torella, A.

AU - Ergoli, M.

AU - Rubegni, A.

AU - Fanin, M.

AU - Musumeci, O.

AU - De Bleecker, J.

AU - Peverelli, L.

AU - Moggio, M.

AU - Mercuri, E.

AU - Toscano, A.

AU - Mora, M.

AU - Santoro, L.

AU - Mongini, T.

AU - Bertini, E.

AU - Bruno, C.

AU - Minetti, C.

AU - Comi, G.P.

AU - Santorelli, F.M.

AU - Angelini, C.

AU - Politano, L.

AU - Piluso, G.

AU - Nigro, V.

N1 - cited By 0

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

KW - complementary DNA

KW - dystrophin

KW - genomic DNA

KW - merosin

KW - sarcoglycan

KW - spastin, Article

KW - cohort analysis

KW - comparative genomic hybridization

KW - copy number variation

KW - DMD gene

KW - DNA determination

KW - fluorometry

KW - gene

KW - gene deletion

KW - gene duplication

KW - human

KW - LAMA2 gene

KW - major clinical study

KW - multiplex ligation dependent probe amplification

KW - myopathy

KW - next generation sequencing

KW - pathogenesis

KW - phenotype

KW - real time polymerase chain reaction

KW - SGCD gene

KW - SPAST gene

KW - spectrophotometry

U2 - 10.3390/genes9110524

DO - 10.3390/genes9110524

M3 - Article

VL - 9

JO - Genes

JF - Genes

SN - 2073-4425

IS - 11

ER -