Queen Square Centre for Neuromuscular Diseases and Department of Neuromuscular Diseases, Queen Square Institute of Neurology, UCL and National Hospital for Neurology and Neurosurgery , London, UK.
Expert Rev Mol Diagn. 2020 Jul;20(7):725-736. doi: 10.1080/14737159.2020.1782195. Epub 2020 Jul 12.
Skeletal muscle channelopathies are rare inherited conditions that cause significant morbidity and impact on quality of life. Some subsets have a mortality risk. Improved genetic methodology and understanding of phenotypes have improved diagnostic accuracy and yield.
We discuss diagnostic advances since the advent of next-generation sequencing and the role of whole exome and genome sequencing. Advances in genotype-phenotype-functional correlations have improved understanding of inheritance and phenotypes. We outline new phenotypes, particularly in the pediatric setting and consider co-existing mutations that may act as genetic modifiers. We also discuss four newly identified genes associated with skeletal muscle channelopathies.
Next-generation sequencing using gene panels has improved diagnostic rates, identified new mutations, and discovered patients with co-existing pathogenic mutations ('double trouble'). This field has previously focussed on single genes, but we are now beginning to understand interactions between co-existing mutations, genetic modifiers, and their role in pathomechanisms. New genetic observations in pediatric presentations of channelopathies broadens our understanding of the conditions. Genetic and mechanistic advances have increased the potential to develop treatments.
骨骼肌通道病是罕见的遗传性疾病，会导致严重的发病率和生活质量下降。某些亚型有死亡风险。遗传方法的改进和对表型的理解提高了诊断的准确性和效果。
我们讨论了自下一代测序出现以来的诊断进展，以及外显子组和全基因组测序的作用。基因型-表型-功能相关性的进展提高了对遗传和表型的理解。我们概述了新的表型，特别是在儿科环境中，并考虑了可能作为遗传修饰因子的共存突变。我们还讨论了四个与骨骼肌通道病相关的新鉴定基因。
使用基因面板的下一代测序提高了诊断率，发现了新的突变，并发现了共存致病性突变的患者（双重麻烦）。该领域以前专注于单个基因，但我们现在开始了解共存突变、遗传修饰因子及其在发病机制中的作用之间的相互作用。在通道病的儿科表现中，新的遗传观察结果拓宽了我们对这些疾病的认识。遗传和机制上的进展增加了开发治疗方法的潜力。
