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Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain

The term neuromuscular disorder (NMD) includes many genetic and acquired diseases and differential diagnosis can be challenging. Next-generation sequencing (NGS) is especially useful in this setting given the large number of possible candidate genes, the clinical, pathological, and genetic heterogen...

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Autores principales: Gonzalez-Quereda, Lidia, Rodriguez, Maria Jose, Diaz-Manera, Jordi, Alonso-Perez, Jorge, Gallardo, Eduard, Nascimento, Andres, Ortez, Carlos, Natera-de Benito, Daniel, Olive, Montse, Gonzalez-Mera, Laura, Lopez de Munain, Adolfo, Zulaica, Miren, Poza, Juan Jose, Jerico, Ivonne, Torne, Laura, Riera, Pau, Milisenda, Jose, Sanchez, Aurora, Garrabou, Gloria, Llano, Isabel, Madruga-Garrido, Marcos, Gallano, Pia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288461/
https://www.ncbi.nlm.nih.gov/pubmed/32403337
http://dx.doi.org/10.3390/genes11050539
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author Gonzalez-Quereda, Lidia
Rodriguez, Maria Jose
Diaz-Manera, Jordi
Alonso-Perez, Jorge
Gallardo, Eduard
Nascimento, Andres
Ortez, Carlos
Natera-de Benito, Daniel
Olive, Montse
Gonzalez-Mera, Laura
Lopez de Munain, Adolfo
Zulaica, Miren
Poza, Juan Jose
Jerico, Ivonne
Torne, Laura
Riera, Pau
Milisenda, Jose
Sanchez, Aurora
Garrabou, Gloria
Llano, Isabel
Madruga-Garrido, Marcos
Gallano, Pia
author_facet Gonzalez-Quereda, Lidia
Rodriguez, Maria Jose
Diaz-Manera, Jordi
Alonso-Perez, Jorge
Gallardo, Eduard
Nascimento, Andres
Ortez, Carlos
Natera-de Benito, Daniel
Olive, Montse
Gonzalez-Mera, Laura
Lopez de Munain, Adolfo
Zulaica, Miren
Poza, Juan Jose
Jerico, Ivonne
Torne, Laura
Riera, Pau
Milisenda, Jose
Sanchez, Aurora
Garrabou, Gloria
Llano, Isabel
Madruga-Garrido, Marcos
Gallano, Pia
author_sort Gonzalez-Quereda, Lidia
collection PubMed
description The term neuromuscular disorder (NMD) includes many genetic and acquired diseases and differential diagnosis can be challenging. Next-generation sequencing (NGS) is especially useful in this setting given the large number of possible candidate genes, the clinical, pathological, and genetic heterogeneity, the absence of an established genotype-phenotype correlation, and the exceptionally large size of some causative genes such as TTN, NEB and RYR1. We evaluated the diagnostic value of a custom targeted next-generation sequencing gene panel to study the mutational spectrum of a subset of NMD patients in Spain. In an NMD cohort of 207 patients with congenital myopathies, distal myopathies, congenital and adult-onset muscular dystrophies, and congenital myasthenic syndromes, we detected causative mutations in 102 patients (49.3%), involving 42 NMD-related genes. The most common causative genes, TTN and RYR1, accounted for almost 30% of cases. Thirty-two of the 207 patients (15.4%) carried variants of uncertain significance or had an unidentified second mutation to explain the genetic cause of the disease. In the remaining 73 patients (35.3%), no candidate variant was identified. In combination with patients’ clinical and myopathological data, the custom gene panel designed in our lab proved to be a powerful tool to diagnose patients with myopathies, muscular dystrophies and congenital myasthenic syndromes. Targeted NGS approaches enable a rapid and cost-effective analysis of NMD- related genes, offering reliable results in a short time and relegating invasive techniques to a second tier.
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spelling pubmed-72884612020-06-17 Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain Gonzalez-Quereda, Lidia Rodriguez, Maria Jose Diaz-Manera, Jordi Alonso-Perez, Jorge Gallardo, Eduard Nascimento, Andres Ortez, Carlos Natera-de Benito, Daniel Olive, Montse Gonzalez-Mera, Laura Lopez de Munain, Adolfo Zulaica, Miren Poza, Juan Jose Jerico, Ivonne Torne, Laura Riera, Pau Milisenda, Jose Sanchez, Aurora Garrabou, Gloria Llano, Isabel Madruga-Garrido, Marcos Gallano, Pia Genes (Basel) Article The term neuromuscular disorder (NMD) includes many genetic and acquired diseases and differential diagnosis can be challenging. Next-generation sequencing (NGS) is especially useful in this setting given the large number of possible candidate genes, the clinical, pathological, and genetic heterogeneity, the absence of an established genotype-phenotype correlation, and the exceptionally large size of some causative genes such as TTN, NEB and RYR1. We evaluated the diagnostic value of a custom targeted next-generation sequencing gene panel to study the mutational spectrum of a subset of NMD patients in Spain. In an NMD cohort of 207 patients with congenital myopathies, distal myopathies, congenital and adult-onset muscular dystrophies, and congenital myasthenic syndromes, we detected causative mutations in 102 patients (49.3%), involving 42 NMD-related genes. The most common causative genes, TTN and RYR1, accounted for almost 30% of cases. Thirty-two of the 207 patients (15.4%) carried variants of uncertain significance or had an unidentified second mutation to explain the genetic cause of the disease. In the remaining 73 patients (35.3%), no candidate variant was identified. In combination with patients’ clinical and myopathological data, the custom gene panel designed in our lab proved to be a powerful tool to diagnose patients with myopathies, muscular dystrophies and congenital myasthenic syndromes. Targeted NGS approaches enable a rapid and cost-effective analysis of NMD- related genes, offering reliable results in a short time and relegating invasive techniques to a second tier. MDPI 2020-05-11 /pmc/articles/PMC7288461/ /pubmed/32403337 http://dx.doi.org/10.3390/genes11050539 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Gonzalez-Quereda, Lidia
Rodriguez, Maria Jose
Diaz-Manera, Jordi
Alonso-Perez, Jorge
Gallardo, Eduard
Nascimento, Andres
Ortez, Carlos
Natera-de Benito, Daniel
Olive, Montse
Gonzalez-Mera, Laura
Lopez de Munain, Adolfo
Zulaica, Miren
Poza, Juan Jose
Jerico, Ivonne
Torne, Laura
Riera, Pau
Milisenda, Jose
Sanchez, Aurora
Garrabou, Gloria
Llano, Isabel
Madruga-Garrido, Marcos
Gallano, Pia
Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain
title Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain
title_full Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain
title_fullStr Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain
title_full_unstemmed Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain
title_short Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain
title_sort targeted next-generation sequencing in a large cohort of genetically undiagnosed patients with neuromuscular disorders in spain
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288461/
https://www.ncbi.nlm.nih.gov/pubmed/32403337
http://dx.doi.org/10.3390/genes11050539
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