The role of combined SNV and CNV burden in patients with distal symmetric polyneuropathy.
The role of combined SNV and CNV burden in patients with distal symmetric polyneuropathy.
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DOI：
10.1038/gim.2015.124
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发表时间：
2016-05
期刊：
影响因子：
--
通讯作者：
Lupski JR
中科院分区：
文献类型：
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作者：
Pehlivan D;Beck CR;Okamoto Y;Harel T;Akdemir ZH;Jhangiani SN;Withers MA;Goksungur MT;Carvalho CM;Czesnik D;Gonzaga-Jauregui C;Wiszniewski W;Muzny DM;Gibbs RA;Rautenstrauss B;Sereda MW;Lupski JR
腓骨肌萎缩症（CMT）是一组异质性周围神经系统遗传性疾病。拷贝数变异（CNV）对CMT有重要作用，因为大多数CMT 1病例的基础是PMP 22的重复。我们假设，CNVs和/或单核苷酸变异（SNVs）可能存在于CMT患者未知的分子遗传病因。通过高分辨率寡核苷酸阵列比较基因组杂交筛选了200例CMT患者的CNVs，这些患者在几个CMT基因中的SNV突变和涉及PMP 22的CNVs均为阴性。对具有罕见的潜在致病性CNV的个体进行全外显子组测序。在5名受试者（~2.5%）中鉴定出脓毒症致病CNV; 5名受试者中有4名映射到已知的神经病变基因。断裂点测序显示α-Alu介导的连接是主要的贡献者。外显子组测序在两个个体中鉴定了MFN 2 SNV。在CMT中，PMP 22基因座以外的神经病相关CNV是罕见的。然而，在CMT 1A重复阴性的CMT病例中检测CNV和外显子组测序具有潜在的临床实用性。这些发现表明，包括神经病在内的复杂表型可能是由SNV和CNV的组合引起的，SNV和CNV影响了一个以上的疾病相关基因座，并导致突变负担。
Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of genetic disorders of the peripheral nervous system. Copy-number variants (CNVs) contribute significantly to CMT, as duplication of PMP22 underlies the majority of CMT1 cases. We hypothesized that CNVs and/or single-nucleotide variants (SNVs) might exist in patients with CMT with an unknown molecular genetic etiology. Two hundred patients with CMT, negative for both SNV mutations in several CMT genes and for CNVs involving PMP22, were screened for CNVs by high-resolution oligonucleotide array comparative genomic hybridization. Whole-exome sequencing was conducted on individuals with rare, potentially pathogenic CNVs. Putatively causative CNVs were identified in five subjects (~2.5%); four of the five map to known neuropathy genes. Breakpoint sequencing revealed Alu-Alu-mediated junctions as a predominant contributor. Exome sequencing identified MFN2 SNVs in two of the individuals. Neuropathy-associated CNV outside of the PMP22 locus is rare in CMT. Nevertheless, there is potential clinical utility in testing for CNVs and exome sequencing in CMT cases negative for the CMT1A duplication. These findings suggest that complex phenotypes including neuropathy can potentially be caused by a combination of SNVs and CNVs affecting more than one disease-associated locus and contributing to a mutational burden.