Farag Soma, Yusuf Imran H, Kaukonen Maria, Taylor Laura J, Charbel Issa Peter, MacLaren Robert E
Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
Ophthalmic Genet. 2024 Apr;45(2):201-206. doi: 10.1080/13816810.2023.2255265. Epub 2023 Sep 20.
Retinitis pigmentosa (RP) associated with biallelic variants in CDHR1 has rarely been reported, and detailed phenotyping data are not available. RP implies relative preservation of foveal cones, when compared to cone-rod dystrophy associated with biallelic null variants in CDHR1. We hypothesize that RP may occur in association with one or more hypomorphic CDHR1 alleles.
Retrospective report of a 48-year-old patient with CDHR1-associated RP with a hypomorphic missense variant c.562 G>A, p. (Gly188Ser) and a novel, unreported variant affecting a canonical splice acceptor site (c.784-1 G>C). Clinical examination, multimodal retinal imaging, electroretinography, visual field testing, and mesopic microperimetry were undertaken 8 years apart. Scotopic microperimetry was also performed. The DNA sequence context of the variants was examined to identify theoretical CRISPR-Cas9 base-editing strategies.
The patient presented at 35 years with a 12-year history of nyctalopia. His best corrected visual acuity was 20/20. Clinical presentation, multimodal retinal imaging studies, electroretinography, and mesopic microperimetry were typical of a progressive rod-cone dystrophy (i.e. classic RP). There were no scotomas within the central field as would be expected at this age in CDHR1-associated cone-rod dystrophy. Scotopic microperimetry suggested some preservation of macular cone over rod function, although both were severely impaired. A suitable CRISPR adenine base editor was identified that could theoretically correct the missense variant c.562 G>A, p. (Gly188Ser).
CDHR1-associated RP shows a relative preservation of cone function in the presence of a presumed hypomorphic allele and may be considered a hypomorphic disease phenotype. Further work is required to identify modifying factors that determine disease phenotype since macular dystrophy, with relative sparing of rods, may also occur with hypomorphic CDHR1 alleles.
与CDHR1双等位基因变异相关的视网膜色素变性（RP）鲜有报道，且尚无详细的表型数据。与CDHR1双等位基因无效变异相关的视锥-视杆营养不良相比，RP意味着中央凹视锥细胞相对保留。我们推测RP可能与一个或多个低表达的CDHR1等位基因有关。
对一名48岁患有与CDHR1相关的RP患者进行回顾性报告，该患者有一个低表达错义变异c.562 G>A，p.（Gly188Ser）和一个影响经典剪接受体位点的新的未报道变异（c.784-1 G>C）。相隔8年进行了临床检查、多模态视网膜成像、视网膜电图、视野测试和中视微视野检查。还进行了暗视微视野检查。检查变异的DNA序列背景以确定理论上的CRISPR-Cas9碱基编辑策略。
该患者35岁时就诊，有12年夜盲病史。他的最佳矫正视力为20/20。临床表现、多模态视网膜成像研究、视网膜电图和中视微视野检查是典型的进行性视杆-视锥营养不良（即经典RP）。在这个年龄的与CDHR1相关的视锥-视杆营养不良患者中，中央视野内没有暗点。暗视微视野检查表明黄斑区视锥细胞功能相对于视杆细胞功能有一定保留，尽管两者均严重受损。确定了一种合适的CRISPR腺嘌呤碱基编辑器，理论上可以纠正错义变异c.562 G>A，p.（Gly188Ser）。
与CDHR1相关的RP在存在假定的低表达等位基因时显示出视锥细胞功能的相对保留，可被视为一种低表达疾病表型。由于低表达的CDHR1等位基因也可能导致黄斑营养不良且视杆细胞相对 spared，因此需要进一步研究以确定决定疾病表型的修饰因素。
