The rare Alus element-mediated chimerism of multiple de novo complex rearrangement sequences in GAN result in giant axonal neuropathy

Abstract

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.

Keywords: Alu elements; Chimerism; Complex rearrangements; GAN; Giant axonal neuropathy; Gigaxonin.