Hereditary optic neuropathies (HON) are a group of diseases due to genetic defects either in mitochondria or in nuclear genomes. The increasing availability of genetic testing has expanded a broader genetic and phenotypic spectrum of HON than previously recognized. To provide systematic insight into the genetic and phenotypic landscape of HON attributed to 50 nuclear genes, we conducted genetic analysis on part of 4776 index patients with clinical diagnosis of HON following our previous study on 1516 probands with Leber hereditary optic neuropathy (LHON) and mitochondrial DNA variants. Exome sequencing was performed in 473 patients diagnosed with nuclear gene-related HON (nHON) and 353 cases with unsolved LHON. Sequencing and variant interpretation in 50 causative nuclear genes indicated that the diagnostic yield of exome sequencing for nHON was 31.50% (149/473), while it was markedly lower at 1.42% (5/353) for LHON patients without primary mtDNA mutations. The top five implicated genes causing nHON in our in-house cohort, OPA1, WFS1, FDXR, ACO2, and AFG3L2, account for 82.46% of mutations. Although OPA1 was the most prevalent causative gene of nHON in both our cohort (53.25%) and literature review (37.09%), the prevalence of OPA1, WFS1, and FDXR differed significantly between our in-house cohort and the literature review (P-adjusted<0.001). Fundus changes in nHON could be stratified into three categories, the most common is optic atrophy at the examination (78.79%), the rarest is LHON-like optic atrophy (3.64%), and the intermediate is optic atrophy with concurrent retinal degeneration (17.57%), which was an independent risk factor for visual prognosis in nHON. A systematic genotype-phenotype analysis highlighted different genetic contributions for ocular, extraocular neurological, and extraocular non-neurological phenotypes. In addition, systemic variant analysis at the individual gene level suggested a revised interpretation of the pathogenicity of a WFS1 heterozygous truncation variant. This study provides a panoramic summary of both the genetic and phenotypic profiles of HON in real-world studies and literature. The category for nHON fundus phenotypes is built for future studies on molecular mechanisms underlying HON and targeted therapies. In addition to routine ophthalmic examinations, careful examination of the extraocular symptoms and meaningful genetic counseling are warranted for patients with nHON.

中文翻译：

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826 个家系视神经萎缩的临床和遗传景观：来自 50 个核基因的见解


遗传性视神经病变 （HON） 是一组由线粒体或核基因组遗传缺陷引起的疾病。基因检测的日益普及扩大了 HON 的遗传和表型谱，比以前认识到的更广泛。为了系统地了解归因于 50 个核基因的 HON 的遗传和表型景观，我们在之前对 1516 名先证者患有 Leber 遗传性视神经病变 （LHON） 和线粒体 DNA 变异之后，对 4776 名临床诊断为 HON 的指示患者的一部分进行了遗传分析。对 473 例诊断为核基因相关 HON （nHON） 的患者和 353 例未解决的 LHON 患者进行了外显子组测序。对 50 个致病核基因的测序和变异解释表明，外显子组测序对 nHON 的诊断率为 31.50% （149/473），而对于无原发性 mtDNA 突变的 LHON 患者，外显子组测序的诊断率显著降低至 1.42% （5/353）。在我们的内部队列中，导致 nHON 的前五个相关基因，OPA1、WFS1、FDXR、ACO2 和 AFG3L2，占突变的 82.46%。尽管 OPA1 在我们的队列 （53.25%） 和文献综述 （37.09%） 中都是 nHON 最普遍的致病基因，但 OPA1 、 WFS1 和 FDXR 的患病率在我们的内部队列和文献综述之间存在显著差异 （P-adjusted<0.001）。nHON的眼底改变可分为三类，最常见的是检查时的视神经萎缩（78.79%），最罕见的是LHON样视神经萎缩（3.64%），中间是视神经萎缩伴并发视网膜变性（17.57%），这是nHON视力预后的独立危险因素。 一项系统的基因型 - 表型分析强调了眼、眼外神经和眼外非神经表型的不同遗传贡献。此外，单个基因水平的系统变异分析表明对 WFS1 杂合截断变异的致病性的解释得到了修订。本研究对 HON 在现实世界研究和文献中的遗传和表型特征进行了全景总结。nHON 眼底表型类别是为未来研究 HON 和靶向治疗的分子机制而建立的。除了常规眼科检查外，还需要仔细检查眼外症状和对 nHON 患者进行有意义的遗传咨询。