Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
BMC Med Genet. 2020 Nov 26;21(1):236. doi: 10.1186/s12881-020-01166-z.
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.
显性视神经萎缩（DOA）是一种遗传性视神经病变，主要由于视网膜神经节细胞及其轴突的进行性丧失而导致视力、中心视野和色觉受损。大约 45-90%的 DOA 患者携带 OPA1 基因的致病性变异。OPA1 的突变谱包括无义、经典和非经典剪接位点、移码和错义以及拷贝数变异，但迄今尚未报道基因内倒位。
我们报告了一例 33 岁男性，具有 DOA 的典型临床特征。全基因组测序确定了一个 2.4kb 的结构变异，包括 OPA1 基因座 937bp 的倒位。对断点进行单核苷酸水平的精细作图显示，结构变异是由两个缺失侧翼的倒位。由于这种重排使 OPA1 的第一个外显子完全倒位，因此被归类为可能的致病性。
我们报告了首例携带 OPA1 基因倒位的 DOA 病例。我们的研究表明，在 DOA 病例中，必须考虑拷贝中性基因组重排作为疾病的可能原因。
