Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester, UK.
Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK.
Acta Ophthalmol. 2022 Sep;100(6):e1332-e1339. doi: 10.1111/aos.15186. Epub 2022 May 28.
Congenital stationary night blindness (CSNB) is a heterogeneous group of Mendelian retinal disorders that present in childhood. Biallelic variants altering the protein-coding region of the TRPM1 gene are one of the commonest causes of CSNB. Here, we report the clinical and genetic findings in 10 unrelated individuals with TRPM1-retinopathy.
Study subjects were recruited through a tertiary clinical ophthalmic genetic service at Manchester, UK. All participants underwent visual electrodiagnostic testing and panel-based genetic analysis.
Study subjects had a median age of 8 years (range: 3-20 years). All probands were myopic and had electroretinographic findings in keeping with complete CSNB. Notably, three probands reported no night vision problems. Fourteen different disease-associated TRPM1 variants were detected. One individual was homozygous for the NM_001252024.2 (TRPM1):c.965 + 29G>A variant and a mini-gene assay highlighted that this change results in mis-splicing and premature protein termination. Additionally, two unrelated probands who had CSNB and mild neurodevelopmental abnormalities were found to carry a 15q13.3 microdeletion. This copy number variant encompasses seven genes, including TRPM1, and was encountered in the heterozygous state and in trans with a missense TRPM1 variant in each case.
Our findings highlight the importance of comprehensive genomic analysis, beyond the exons and protein-coding regions of genes, for individuals with CSNB. When this characteristic retinal phenotype is accompanied by extraocular findings (including learning and/or behavioural difficulties), a 15q13.3 microdeletion should be suspected. Focused analysis (e.g. microarray testing) is recommended to look for large-scale deletions encompassing TRPM1 in patients with CSNB and neurodevelopmental abnormalities.
先天性静止性夜盲症（CSNB）是一组异质性的孟德尔视网膜疾病，在儿童时期发病。改变 TRPM1 基因编码区的双等位基因变异是 CSNB 的最常见原因之一。在这里，我们报告了 10 名 TRPM1-视网膜病变无关个体的临床和遗传发现。
研究对象通过英国曼彻斯特的三级临床眼科遗传服务招募。所有参与者均接受了视觉电诊断测试和基于面板的基因分析。
研究对象的中位年龄为 8 岁（范围：3-20 岁）。所有先证者均为近视，且视网膜电图检查结果符合完全 CSNB。值得注意的是，有 3 名先证者报告没有夜视问题。检测到 14 种不同的与疾病相关的 TRPM1 变体。一名个体为 NM_001252024.2（TRPM1）：c.965+29G>A 变体的纯合子，迷你基因检测表明该变化导致剪接错误和过早的蛋白质终止。此外，两名患有 CSNB 和轻度神经发育异常的无关先证者携带 15q13.3 微缺失。该拷贝数变异包含 7 个基因，包括 TRPM1，在每种情况下均以杂合状态和与错义 TRPM1 变体共转存在。
我们的研究结果强调了对 CSNB 个体进行全面基因组分析的重要性，超越了基因的外显子和编码区。当这种特征性的视网膜表型伴有眼外表现（包括学习和/或行为困难）时，应怀疑存在 15q13.3 微缺失。建议对伴有神经发育异常的 CSNB 患者进行聚焦分析（例如微阵列测试），以寻找包含 TRPM1 的大规模缺失。
