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Invest Ophthalmol Vis Sci. 2020 Feb 7;61(2):38. doi: 10.1167/iovs.61.2.38.
Choroideremia is an inherited retinal degeneration caused by 280 different pathogenic variants in the CHM gene. Only one silent/synonymous variant (c.1359C>T; p.(Ser453=)) has been reported and was classified as inconclusive based on in silico analysis. This study elucidates the pathogenicity of this variant also found in a Brazilian patient.
Ophthalmological examinations such as color fundus photography, spectral-domain optical coherence tomography, fundus autofluorescence, and macular integrity assessment microperimetry were performed. The subjects' total RNA was extracted from peripheral blood cells. cDNA was synthesized and the amplification between exon 10 and 14 of the CHM mRNA was performed. The amplification products were sequenced by Sanger sequencing and the results were aligned to the reference sequence.
The synonymous variant c.1359C>T p.(Ser453=) in the CHM gene is associated with an error in mRNA processing, leading preferentially to production of an aberrant transcript without exon 11 (p.(Gln451Phefs*3)). This anomalous mRNA production is related to typical choroideremia phenotype.
These molecular findings reinforce the need for more detailed investigation of silent variants in patients with well-defined phenotype of retinal dystrophies. Molecular and clinical findings provided evidence that c.1359C>T (p.(Gln451Phefs*3)) in CHM should be considered a disease-causing variant.
脉络膜视网膜变性是一种遗传性视网膜疾病，由 CHM 基因中的 280 种不同的致病性变异引起。仅报道了一种沉默/同义变异（c.1359C>T；p.（Ser453=）），根据计算机分析被归类为不确定。本研究阐明了在一名巴西患者中发现的这种变异的致病性。
进行眼科检查，如眼底彩色照相、谱域光相干断层扫描、眼底自发荧光和黄斑完整性评估微视野检查。从外周血血细胞中提取受试者的总 RNA。合成 cDNA，并对 CHM mRNA 的外显子 10 和 14 之间进行扩增。通过 Sanger 测序对扩增产物进行测序，并将结果与参考序列进行比对。
CHM 基因中的同义变异 c.1359C>T p.（Ser453=）与 mRNA 加工错误相关，导致优先产生没有外显子 11 的异常转录本（p.（Gln451Phefs*3））。这种异常 mRNA 的产生与典型的脉络膜视网膜变性表型相关。
这些分子发现加强了在具有明确视网膜营养不良表型的患者中对沉默变异进行更详细调查的必要性。分子和临床发现提供了证据，表明 CHM 中的 c.1359C>T（p.（Gln451Phefs*3））应被视为致病变异。
