Department of Ophthalmology, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou University, Zheng-zhou, 450003, China.
Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China.
BMC Ophthalmol. 2022 Jul 26;22(1):322. doi: 10.1186/s12886-022-02546-0.
To describe the genetic and clinical features of nineteen patients from eleven unrelated Chinese pedigrees with OPA1-related autosomal dominant optic atrophy (ADOA) and define the phenotype-genotype correlations.
Detailed ophthalmic examinations were performed. Targeted next-generation sequencing (NGS) was conducted in the eleven probands using a custom designed panel PS400. Sanger sequencing and cosegregation were used to verify the identified variants. The pathogenicity of gene variants was evaluated according to American College of Medical Genetics and Genomics (ACMG) guidelines.
Nineteen patients from the eleven unrelated Chinese ADOA pedigrees had impaired vision and optic disc pallor. Optical coherence tomography showed significant thinning of the retinal nerve fiber layer. The visual field showed varying degrees of central or paracentral scotoma. The onset of symptoms occurred between 3 and 24 years of age (median age 6 years). Eleven variants in OPA1 were identified in the cohort, and nine novel variants were identified. Among the novel variants, two splicing variants c.984 + 1_984 + 2delGT, c.1194 + 2 T > C, two stop-gain variants c.1937C > G, c.2830G > T, and one frameshift variant c.2787_2794del8, were determined to be pathogenic based on ACMG. A novel splicing variant c.1316-10 T > G was determined to be likely pathogenic. In addition, a novel missense c.1283A > C (p.N428T) and two novel splicing variants c.2496G > A and c.1065 + 5G > C were of uncertain significance.
Six novel pathogenic variants were identified. The findings will facilitate genetic counselling by expanding the pathogenic mutation spectrum of OPA1.
描述 11 个不相关的中国家系的 19 名OPA1 相关常染色体显性视神经萎缩（ADOA）患者的遗传和临床特征，并确定表型-基因型相关性。
对 11 名先证者进行详细的眼科检查。使用定制的 PS400 面板对 11 名先证者进行靶向下一代测序（NGS）。Sanger 测序和共分离用于验证鉴定的变体。根据美国医学遗传学与基因组学学院（ACMG）指南评估基因变异的致病性。
11 个不相关的中国 ADOA 家系的 19 名患者视力受损，视盘苍白。光学相干断层扫描显示视网膜神经纤维层明显变薄。视野显示不同程度的中央或旁中央暗点。症状发作年龄在 3 至 24 岁之间（中位年龄 6 岁）。在该队列中发现了 OPA1 中的 11 个变异，其中 9 个为新变异。在新发现的变异中，两个剪接变异 c.984 + 1_984 + 2delGT、c.1194 + 2T > C，两个无义突变 c.1937C > G、c.2830G > T 和一个移码变异 c.2787_2794del8，根据 ACMG 被确定为致病性。一个新的剪接变异 c.1316-10T > G 被确定为可能的致病性。此外，一个新的错义变异 c.1283A > C（p.N428T）和两个新的剪接变异 c.2496G > A 和 c.1065 + 5G > C 具有不确定的意义。
确定了 6 个新的致病变异。这些发现将通过扩大 OPA1 的致病突变谱，促进遗传咨询。
