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

Teresa Giugliano, Marco Savarese, Arcomaria Garofalo, Esther Picillo, Chiara Fiorillo, Adele D'Amico, Lorenzo Maggi, Lucia Ruggiero, Liliana Vercelli, Francesca Magri, Fabiana Fattori, Annalaura Torella, Manuela Ergoli, Anna Rubegni, Marina Fanin, Olimpia Musumeci, Jan De Bleecker, Lorenzo Peverelli, Maurizio Moggio, Eugenio MercuriAntonio Toscano, Marina Mora, Lucio Santoro, Tiziana Mongini, Enrico Bertini, Claudio Bruno, Carlo Minetti, Giacomo Pietro Comi, Filippo Maria Santorelli, Corrado Angelini, Luisa Politano, Giulio Piluso, Vincenzo 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.

Original languageEnglish
JournalGenes
Volume9
Issue number11
DOIs
Publication statusPublished - Oct 26 2018

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

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Copy Number Variants Account for a Tiny Fraction of Undiagnosed Myopathic Patients. / Giugliano, Teresa; Savarese, Marco; Garofalo, Arcomaria; Picillo, Esther; Fiorillo, Chiara; D'Amico, Adele; Maggi, Lorenzo; Ruggiero, Lucia; Vercelli, Liliana; Magri, Francesca; Fattori, Fabiana; Torella, Annalaura; Ergoli, Manuela; Rubegni, Anna; Fanin, Marina; Musumeci, Olimpia; Bleecker, Jan De; Peverelli, Lorenzo; Moggio, Maurizio; Mercuri, Eugenio; Toscano, Antonio; Mora, Marina; Santoro, Lucio; Mongini, Tiziana; Bertini, Enrico; Bruno, Claudio; Minetti, Carlo; Comi, Giacomo Pietro; Santorelli, Filippo Maria; Angelini, Corrado; Politano, Luisa; Piluso, Giulio; Nigro, Vincenzo.

In: Genes, Vol. 9, No. 11, 26.10.2018.

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, Bleecker, JD, 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, Teresa ; Savarese, Marco ; Garofalo, Arcomaria ; Picillo, Esther ; Fiorillo, Chiara ; D'Amico, Adele ; Maggi, Lorenzo ; Ruggiero, Lucia ; Vercelli, Liliana ; Magri, Francesca ; Fattori, Fabiana ; Torella, Annalaura ; Ergoli, Manuela ; Rubegni, Anna ; Fanin, Marina ; Musumeci, Olimpia ; Bleecker, Jan De ; Peverelli, Lorenzo ; Moggio, Maurizio ; Mercuri, Eugenio ; Toscano, Antonio ; Mora, Marina ; Santoro, Lucio ; Mongini, Tiziana ; Bertini, Enrico ; Bruno, Claudio ; Minetti, Carlo ; Comi, Giacomo Pietro ; Santorelli, Filippo Maria ; Angelini, Corrado ; Politano, Luisa ; Piluso, Giulio ; Nigro, Vincenzo. / Copy Number Variants Account for a Tiny Fraction of Undiagnosed Myopathic Patients. In: Genes. 2018 ; Vol. 9, No. 11.
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T1 - Copy Number Variants Account for a Tiny Fraction of Undiagnosed Myopathic Patients

AU - Giugliano, Teresa

AU - Savarese, Marco

AU - Garofalo, Arcomaria

AU - Picillo, Esther

AU - Fiorillo, Chiara

AU - D'Amico, Adele

AU - Maggi, Lorenzo

AU - Ruggiero, Lucia

AU - Vercelli, Liliana

AU - Magri, Francesca

AU - Fattori, Fabiana

AU - Torella, Annalaura

AU - Ergoli, Manuela

AU - Rubegni, Anna

AU - Fanin, Marina

AU - Musumeci, Olimpia

AU - Bleecker, Jan De

AU - Peverelli, Lorenzo

AU - Moggio, Maurizio

AU - Mercuri, Eugenio

AU - Toscano, Antonio

AU - Mora, Marina

AU - Santoro, Lucio

AU - Mongini, Tiziana

AU - Bertini, Enrico

AU - Bruno, Claudio

AU - Minetti, Carlo

AU - Comi, Giacomo Pietro

AU - Santorelli, Filippo Maria

AU - Angelini, Corrado

AU - Politano, Luisa

AU - Piluso, Giulio

AU - Nigro, Vincenzo

PY - 2018/10/26

Y1 - 2018/10/26

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.

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.

U2 - 10.3390/genes9110524

DO - 10.3390/genes9110524

M3 - Article

C2 - 30373198

VL - 9

JO - Genes

JF - Genes

SN - 2073-4425

IS - 11

ER -