Dominant optic atrophy (DOA) is an inherited optic neuropathy that mainly affects visual acuity, central visual fields and color vision due to a progressive loss of retinal ganglion cells and their axons that form the optic nerve. Approximately 45–90% of affected individuals with DOA harbor pathogenic variants in the OPA1 gene. The mutation spectrum of OPA1 comprises nonsense, canonical and non-canonical splice site, frameshift and missense as well as copy number variants, but intragenic inversions have not been reported so far. We report a 33-year-old male with characteristic clinical features of DOA. Whole-genome sequencing identified a structural variant of 2.4 kb comprising an inversion of 937 bp at the OPA1 locus. Fine mapping of the breakpoints to single nucleotide level revealed that the structural variation was an inversion flanked by two deletions. As this rearrangement inverts the entire first exon of OPA1, it was classified as likely pathogenic. We report the first DOA case harboring an inversion in the OPA1 gene. Our study demonstrates that copy-neutral genomic rearrangements have to be considered as a possible cause of disease in DOA cases.

中文翻译：

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在显性视神经萎缩中首次鉴定出OPA1基因的亚显微反转-病例报告

优势视神经萎缩（DOA）是一种遗传性视神经病变，由于视网膜神经节细胞及其形成视神经的轴突的逐渐丧失，其主要影响视敏度，中央视野和色觉。患DOA的受影响个体中约有45–90％的OPA1基因中含有致病性变异。OPA1的突变谱包括无意义的，规范的和非规范的剪接位点，移码和错义以及拷贝数变异，但是迄今为止尚未报道基因内倒位。我们报告了一名具有DOA特征性临床特征的33岁男性。全基因组测序确定了2.4 kb的结构变异，其中在OPA1位点包含937 bp的反向。断点到单核苷酸水平的精细映射揭示了结构变异是一个侧翼为两个缺失的倒位。由于这种重排使OPA1的整个第一个外显子反转，因此被归类为可能的致病菌。我们报告的第一例DOA病例在OPA1基因中存在一个倒位。我们的研究表明，必须将复制中性基因组重排视为DOA病例中可能的疾病原因。