Seo Yuri, Kim Tae Young, Won Dongju, Shin Saeam, Choi Jong Rak, Lee Seung-Tae, Lee Byung Joo, Lim Hyun Taek, Han Sueng-Han, Han Jinu
Department of Ophthalmology, Institute of Vision Research, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, South Korea.
Department of Ophthalmology, Institute of Vision Research, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.
Front Neurol. 2022 Aug 22;13:978532. doi: 10.3389/fneur.2022.978532. eCollection 2022.
To evaluate the clinical characteristics and causative genetic variants in autosomal optic atrophy diagnosed using next-generation sequencing (NGS).
A cohort of 57 unrelated families affected with bilateral optic atrophy were recruited from two university-based tertiary referral hospitals from May 2016 to April 2022. Genetic variants were detected using a target enrichment panel consisting of 429 or 595 genes and known deep intronic variants associated with inherited eye diseases, exome sequencing, or genome sequencing. The results of detailed clinical examinations, disease-causing variants, and clinical diagnoses were analyzed.
Among the 57 probands, 33 (57.9%) were men, and the median age at genetic testing was 19.1 years (interquartile range, 7.6-42.5 years). We identified 22 likely causative variants in 18 families and corresponding diagnostic yields of 31.6% (95% confidence interval, 21.0-44.5%). The diagnostic rate of NGS was higher in patients with infantile or early childhood onset optic atrophy than in those with late-onset or unknown optic atrophy (18/39, 46.2% vs. 0/18, 0%, < 0.001). Among the 22 variants, 15 were novel in our cohort. The variants ( = 7) were found to be the major genetic causes, followed by the variant ( = 4). The causative variants in , and genes were identified in 4 probands with a recessive form of optic atrophy.
Based on the results of diagnostic NGS for optic atrophy, the causative variant could be detected in 31.6% of patients. Our study also demonstrated that NGS is unlikely to help identify molecular causes in late-onset unexplained optic atrophy.
评估使用下一代测序（NGS）诊断的常染色体显性遗传性视神经萎缩的临床特征和致病基因变异。
2016年5月至2022年4月期间，从两家大学附属医院招募了57个双侧视神经萎缩的无关家庭。使用包含429或595个基因以及与遗传性眼病相关的已知内含子深处变异的目标富集panel、外显子组测序或基因组测序来检测基因变异。分析详细临床检查、致病变异和临床诊断结果。
57名先证者中，33名（57.9%）为男性，基因检测时的中位年龄为19.1岁（四分位间距，7.6 - 42.5岁）。我们在18个家庭中鉴定出22个可能的致病变异，相应诊断率为31.6%（95%置信区间，21.0 - 44.5%）。婴儿期或儿童早期发病的视神经萎缩患者中NGS诊断率高于晚发性或不明原因视神经萎缩患者（18/39，46.2%对0/18，0%，<0.001）。在这22个变异中，15个在我们的队列中是新发现的。 变异（n = 7）被发现是主要遗传原因，其次是 变异（n = 4）。在4名隐性形式视神经萎缩的先证者中鉴定出 、 和 基因的致病变异。
基于视神经萎缩诊断性NGS结果，31.6%的患者可检测到致病变异。我们的研究还表明，NGS不太可能有助于识别晚发性不明原因视神经萎缩的分子病因。
