Giant axonal neuropathy (GAN) is a rare and grievous autosomal recessive neurodegenerative disease due to loss-of-function mutation in GAN. However, the chimerism of complex rearrangement sequences of GAN has not been reported so far, and the mechanism for its complex rearrangements remains to be determined. We identified a family with clinical symptoms of GAN and aimed to reveal a genetic cause underlying this disease. By whole-exome sequencing in the patient we identified a novel homozygous frameshift mutation with 1 bp deletion (c.27delC) in GAN. However, when analyzed the patient's genomic DNA (gDNA) by quantitative real-time PCR and breakpoint DNA sequencing, we found the chimerism of multiple complex rearrangement sequences encompassing exon 1 of GAN in the patient's genome. The microhomology and localization of the breakpoint indicated that they may be caused by Alu repeat elements. We also found that the mRNA expression level of GAN in patient's lymphocyte was decreased, confirming the pathogenicity of these mutations. Our study is the first reported on many complex rearrangement sequences mosaic in GAN mediated by Alu element. The patient here is not a simple homozygous frameshift mutation, but a compound heterozygous paternal c.27delC mutation and the chimerism of multiple de novo complex rearrangement sequences in GAN. Our results may also provide new insights into the formation and pathogenicity of complex rearrangement in GAN, and may be helpful to genetic counseling and genetic testing. It also enriches the Alu-mediated disease-associated database which are important for correct clinical interpretation.

中文翻译：

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GAN中罕见的Alus元素介导的多个从头复合物重排序列的嵌合体导致巨大的轴突神经病。

巨轴索神经病（GAN）是一种罕见且严重的常染色体隐性神经退行性疾病，归因于GAN的功能丧失突变。然而，到目前为止，尚未报道GAN的复杂重排序列的嵌合现象，并且其复杂重排的机制仍有待确定。我们确定了一个具有GAN临床症状的家庭，旨在揭示导致该疾病的遗传原因。通过对患者进行全外显子测序，我们确定了GAN中具有1 bp缺失（c.27delC）的新型纯合移码突变。但是，当通过定量实时PCR和断点DNA测序分析患者的基因组DNA（gDNA）时，我们发现在患者基因组中包含GAN外显子1的多个复杂重排序列的嵌合。断点的微观同源性和局部化表明它们可能是由Alu重复元件引起的。我们还发现患者淋巴细胞中GAN的mRNA表达水平降低，证实了这些突变的致病性。我们的研究首次报道了由Alu元素介导的GAN中许多复杂的重排序列镶嵌。这里的患者不是简单的纯合子移码突变，而是复合杂合的父本c.27delC突变和GAN中多个从头复合物重排序列的嵌合。我们的结果也可能为GAN中复杂重排的形成和致病性提供新的见解，并可能有助于遗传咨询和基因检测。它还丰富了Alu介导的疾病相关数据库，这对于正确的临床解释很重要。