Stehlíková K, Skálová D, Zídková J, Haberlová J, Voháňka S, Mazanec R, Mrázová L, Vondráček P, Ošlejšková H, Zámečník J, Honzík T, Zeman J, Magner M, Šišková D, Langová M, Gregor V, Godava M, Smolka V, Fajkusová L
Centre of Molecular Biology and Gene Therapy, University Hospital Brno and Masaryk University, Brno, Czech Republic.
Department of Child Neurology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
Clin Genet. 2017 Mar;91(3):463-469. doi: 10.1111/cge.12839. Epub 2016 Sep 26.
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.
遗传性神经肌肉疾病（NMD）是一个广义术语，涵盖影响肌肉、神经和神经肌肉接头的不同遗传疾病。基因和临床异质性是常规逐基因诊断的主要障碍。我们展示了通过靶向新一代测序（NGS）确定遗传病因的捷克NMD患者以及这些病因的谱系。总共对167例表现为NMD的无关患者进行了检测，这些患者分为肌营养不良症、先天性肌营养不良症、先天性肌病、远端肌病和其他肌病类别，通过对42个已知NMD相关基因进行靶向NGS检测。在79例患者（47.3%）中鉴定出致病或可能致病的序列变化。总共在23个基因中检测到37个新的和51个已知的致病变体。此外，在7例患者（4.2%）中怀疑存在意义不确定的变体，在81例患者（48.5%）中未发现与NMD相关的序列变化。我们的结果强烈表明，对于NMD等异质性疾病的分子诊断，靶向基因panel检测具有很高的临床检出率，因此应作为首选的一线方法。此外，我们表明，在NMD的基因诊断实践中，有必要考虑不同类型的遗传，包括一个家族两代人中出现常染色体隐性疾病的情况。
