Cutrupi Anthony N, Brewer Megan H, Nicholson Garth A, Kennerson Marina L
Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, NSW, Australia.
Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
Mol Genet Genomic Med. 2018 May;6(3):422-433. doi: 10.1002/mgg3.390. Epub 2018 Mar 23.
Inherited peripheral neuropathies (IPNs) are a clinically and genetically heterogeneous group of diseases affecting the motor and sensory peripheral nerves. IPNs have benefited from gene discovery and genetic diagnosis using next-generation sequencing with over 80 causative genes available for testing. Despite this success, up to 50% of cases remain genetically unsolved. In the absence of protein coding mutations, noncoding DNA or structural variation (SV) mutations are a possible explanation. The most common IPN, Charcot-Marie-Tooth neuropathy type 1A (CMT1A), is caused by a 1.5 Mb duplication causing trisomy of the dosage sensitive gene PMP22. Using genome sequencing, we recently identified two large genomic rearrangements causing IPN subtypes X-linked CMT (CMTX3) and distal hereditary motor neuropathy (DHMN1), thereby expanding the spectrum of SV mutations causing IPN. Understanding how newly discovered SVs can cause IPN may serve as a useful paradigm to examine the role of topologically associated domains (TADs), chromatin interactions, and gene dysregulation in disease. This review will describe the growing role of SV in the pathogenesis of IPN and the importance of considering this type of mutation in Mendelian diseases where protein coding mutations cannot be identified.
遗传性周围神经病（IPNs）是一组临床和遗传异质性疾病，影响运动和感觉周围神经。IPNs受益于基因发现和使用新一代测序的基因诊断，有超过80个致病基因可供检测。尽管取得了这一成功，但仍有高达50%的病例在遗传上无法确诊。在没有蛋白质编码突变的情况下，非编码DNA或结构变异（SV）突变可能是一种解释。最常见的IPN，1A型夏科-马里-图思病（CMT1A），是由一个1.5Mb的重复导致剂量敏感基因PMP22三体性引起的。利用基因组测序，我们最近发现了两个导致IPN亚型X连锁CMT（CMTX3）和远端遗传性运动神经病（DHMN1）的大型基因组重排，从而扩大了导致IPN的SV突变谱。了解新发现的SV如何导致IPN，可能成为研究拓扑相关结构域（TADs）、染色质相互作用和基因失调在疾病中的作用的有用范例。本综述将描述SV在IPN发病机制中日益重要的作用，以及在无法识别蛋白质编码突变的孟德尔疾病中考虑这种类型突变的重要性。
