title: Muscular dystrophies and myopathies: the spectrum of mutated genes in the Czech Republic.
abstract: Inherited neuromuscular disorder (NMD) is a wide term covering different genetic disorders affecting muscles, nerves, and neuromuscular junctions. Genetic and clinical heterogeneity is the main drawback in a routine gene-by-gene diagnostics. We present Czech NMD patients with a genetic cause identified using targeted next-generation sequencing (NGS) and the spectrum of these causes. Overall 167 unrelated patients presenting NMD falling into categories of muscular dystrophies, congenital muscular dystrophies, congenital myopathies, distal myopathies, and other myopathies were tested by targeted NGS of 42 known NMD-related genes. Pathogenic or probably pathogenic sequence changes were identified in 79 patients (47.3%). In total, 37 novel and 51 known disease-causing variants were detected in 23 genes. In addition, variants of uncertain significance were suspected in 7 cases (4.2%), and in 81 cases (48.5%) sequence changes associated with NMD were not found. Our results strongly indicate that for molecular diagnostics of heterogeneous disorders such as NMDs, targeted panel testing has a high-clinical yield and should therefore be the preferred first-tier approach. Further, we show that in the genetic diagnostic practice of NMDs, it is necessary to take into account different types of inheritance including the occurrence of an autosomal recessive disorder in two generations of one family.
authors.affiliation: Centre of Molecular Biology and Gene Therapy, University Hospital Brno and Masaryk University, Brno, Czech Republic.
authors.forename: K
authors.initials: K
authors.lastname: Stehlíková
authors.affiliation: Centre of Molecular Biology and Gene Therapy, University Hospital Brno and Masaryk University, Brno, Czech Republic.
authors.forename: D
authors.initials: D
authors.lastname: Skálová
authors.affiliation: Centre of Molecular Biology and Gene Therapy, University Hospital Brno and Masaryk University, Brno, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Zídková
authors.affiliation: Department of Child Neurology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Haberlová
authors.affiliation: Department of Neurology, University Hospital Brno, Brno, Czech Republic.
authors.forename: S
authors.initials: S
authors.lastname: Voháňka
authors.affiliation: Department of Neurology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: R
authors.initials: R
authors.lastname: Mazanec
authors.affiliation: Department of Child Neurology, University Hospital Brno, Brno, Czech Republic.
authors.forename: L
authors.initials: L
authors.lastname: Mrázová
authors.affiliation: Department of Child Neurology, University Hospital Brno, Brno, Czech Republic.
authors.forename: P
authors.initials: P
authors.lastname: Vondráček
authors.affiliation: Department of Child Neurology, University Hospital Brno, Brno, Czech Republic.
authors.forename: H
authors.initials: H
authors.lastname: Ošlejšková
authors.affiliation: Department of Pathology and Molecular Medicine, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Zámečník
authors.affiliation: Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
authors.forename: T
authors.initials: T
authors.lastname: Honzík
authors.affiliation: Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Zeman
authors.affiliation: Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Magner
authors.affiliation: Child Neurology, Thomayer's Hospital, Prague, Czech Republic.
authors.forename: D
authors.initials: D
authors.lastname: Šišková
authors.affiliation: Department of Medical Genetics, Thomayer's Hospital, Prague, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Langová
authors.affiliation: Department of Medical Genetics, Thomayer's Hospital, Prague, Czech Republic.
authors.forename: V
authors.initials: V
authors.lastname: Gregor
authors.affiliation: Centre of Fetal Medicine and Genetics, Olomouc, Czech Republic.
authors.forename: M
authors.identifier: 0000-0002-8824-7918
authors.initials: M
authors.lastname: Godava
authors.affiliation: Department of Paediatrics, University Hospital Olomouc, Olomouc, Czech Republic.
authors.forename: V
authors.initials: V
authors.lastname: Smolka
authors.affiliation: Centre of Molecular Biology and Gene Therapy, University Hospital Brno and Masaryk University, Brno, Czech Republic.|Central European Institute of Technology, Masaryk University, Brno, Czech Republic.|Laboratory of Functional Genomics and Proteomics, NCBR, Faculty of Science, Masaryk University, Brno, Czech Republic.
authors.forename: L
authors.initials: L
authors.lastname: Fajkusová
mesh_terms: D000293:Adolescent; D000328:Adult; D018153:Czech Republic / Q000453:epidemiology; D005260:Female; D005820:Genetic Testing; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009135:Muscular Diseases / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D009136:Muscular Dystrophies / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D017422:Sequence Analysis, DNA; D055815:Young Adult
keywords: DNA diagnostics; LGMD; neuromuscular disorders; targeted next-generation sequencing