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. 2020 May 11;11(5):539.
doi: 10.3390/genes11050539.

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

Lidia Gonzalez-Quereda  1   2 , Maria Jose Rodriguez  1 , Jordi Diaz-Manera  2   3 , Jorge Alonso-Perez  3 , Eduard Gallardo  2   3 , Andres Nascimento  2   4 , Carlos Ortez  4 , Daniel Natera-de Benito  2   4 , Montse Olive  5 , Laura Gonzalez-Mera  5   6 , Adolfo Lopez de Munain  7   8   9   10 , Miren Zulaica  7   8 , Juan Jose Poza  9 , Ivonne Jerico  11   12 , Laura Torne  11 , Pau Riera  1 , Jose Milisenda  13 , Aurora Sanchez  14 , Gloria Garrabou  2   15 , Isabel Llano  2   16   17 , Marcos Madruga-Garrido  18   19 , Pia Gallano  1   2
Affiliations

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

Lidia Gonzalez-Quereda et al. Genes (Basel). .

Abstract

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.

Keywords: congenital myasthenic syndromes; congenital myopathies; muscular dystrophies; neuromuscular diseases; targeted next-generation sequencing.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Causative genes of NMDs in our cohort. Percentages indicate the proportion of cases with the corresponding genetic defect among solved cases.
See this image and copyright information in PMC

References

    1. [(accessed on 10 May 2020)]; Available online: www.musclegenetable.fr.
    1. Kirschner J., Bonnemann C., Schorling D. Congenital Muscular Dystrophies and Myopathies: An Overview and Update. Neuropediatrics. 2017;48:247–261. doi: 10.1055/s-0037-1604154. - DOI - PubMed
    1. Scoto M., Finkel R., Mercuri E., Muntoni F. Genetic therapies for inherited neuromuscular disorders. Lancet Child Adolesc. Health. 2018;2:600–609. doi: 10.1016/S2352-4642(18)30140-8. - DOI - PubMed
    1. Emery A.E.H. Seminar: The muscular dystrophies. Lancet. 2002;359:687–695. doi: 10.1016/S0140-6736(02)07815-7. - DOI - PubMed
    1. Sewry C.A. Pathological defects in congenital myopathies. J. Muscle Res. Cell Motil. 2008;29:231–238. doi: 10.1007/s10974-008-9155-8. - DOI - PubMed

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