Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Sciences Key Lab. Beijing, China.
Invest Ophthalmol Vis Sci. 2022 Sep 1;63(10):9. doi: 10.1167/iovs.63.10.9.
To identify the missing heritability of patients with Wolfram syndrome 1 (WFS1) in a Chinese cohort and to report their clinical and genetic features.
We recruited 24 unrelated patients with suspected WFS1 who carried at least one variant in WFS1. All patients underwent ophthalmic examinations and comprehensive molecular genetic analyses, including Sanger-DNA sequencing of WFS1 and next-generation sequencing of the whole WFS1 sequence.
We identified 38 distinct pathogenic variants of WFS1 in the 24 probands, comprising 23 patients with biallelic variants and one patient with a monoallelic variant. Sanger-DNA sequencing of WFS1 initially detected 35 variants, and subsequent whole genome sequencing revealed three missing variants: one novel deep intronic variant (DIV), one copy number variant (CNV), and one variant in the promoter region. Minigene assays showed that the DIV activated cryptic splice sites, leading to the insertion of pseudoexons. Optic atrophy was observed in all patients, and diabetes mellitus (DM) was revealed in 21 patients (91.3%), hearing loss in nine patients (39.1%), renal tract abnormalities in nine patients (39.1%), and diabetes insipidus in five patients (21.7%). The mean onset age for DM was significantly younger in the patients with biallelic null variants than in the patients with biallelic missense variants.
Our results extend the pathogenic variant spectrum of WFS1. DIVs and CNVs explained rare unresolved Chinese cases with WFS1. The patients showed a wide and variable clinical spectrum, supporting the importance of genetic analysis for patients with atypical WFS1.
在中国人群中鉴定 Wolfram 综合征 1 (WFS1) 患者的遗传缺失，并报告其临床和遗传特征。
我们招募了 24 名疑似患有 WFS1 的无血缘关系患者，这些患者至少携带一个 WFS1 变异。所有患者均接受眼科检查和全面的分子遗传学分析，包括 WFS1 的 Sanger-DNA 测序和 WFS1 全序列的下一代测序。
我们在 24 名先证者中鉴定出 38 种不同的 WFS1 致病性变异，包括 23 名患者具有双等位基因变异，1 名患者具有单等位基因变异。WFS1 的 Sanger-DNA 测序最初检测到 35 种变异，随后的全基因组测序揭示了 3 种缺失变异：一种新的深内含子变异（DIV）、一种拷贝数变异（CNV）和一种启动子区域的变异。小基因检测显示，DIV 激活了隐匿性剪接位点，导致假外显子的插入。所有患者均出现视神经萎缩，21 名患者（91.3%）出现糖尿病（DM），9 名患者（39.1%）出现听力损失，9 名患者（39.1%）出现肾脏异常，5 名患者（21.7%）出现尿崩症。双等位基因无功能变异患者的 DM 发病年龄明显小于双等位基因错义变异患者。
我们的结果扩展了 WFS1 的致病变异谱。DIVs 和 CNVs 解释了罕见的中国未解决的 WFS1 病例。患者表现出广泛而多变的临床谱，支持对具有非典型 WFS1 的患者进行遗传分析的重要性。
