PHENOTYPIC VARIABILITY OF RECESSIVE RDH12-ASSOCIATED RETINAL DYSTROPHY
PHENOTYPIC VARIABILITY OF RECESSIVE RDH12-ASSOCIATED RETINAL DYSTROPHY
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DOI：
10.1097/iae.0000000000002242
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发表时间：
2019-10-01
影响因子：
3.3
通讯作者：
Sui, Ruifang
中科院分区：
文献类型：
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作者：
Zou, Xuan;Fu, Qing;Sui, Ruifang
目的：研究中国视黄醇脱氢酶12 （RDH12）基因双等位变异患者的表型变异性和遗传缺陷。方法：研究对象为38例来自38个无亲缘关系家族的双等位致病RDH12变异患者。采用系统的下一代测序数据分析、Sanger测序验证和分离分析来鉴定致病突变。详细的眼科检查包括视网膜电图、眼底摄影、眼底自身荧光和光学相干断层扫描，并进行统计分析以评估表型变异性。结果：在38个家族中鉴定出25种不同的RDH12突变。其中6种变体是新颖的。以Val146Asp的频率最高（23.7%），其次是Arg62Ter（14.5%）和Thr49Met（9.2%）。23例为早发性重度视网膜营养不良，6例为Leber先天性黑朦，7例为常染色体隐性视网膜色素变性，2例为锥杆营养不良。自述夜盲症发生率约为一半（55.3%），其中老年患者更为常见（P < 0.01）。夜盲症与最佳矫正视力无显著相关性（P = 0.72），但老年患者最佳矫正视力下降明显大于老年患者（P < 0.01）。只有15.8%的患者发生眼球震颤，而在36.8%的远视>3D患者中（P < 0.01）和/或最佳矫正视力降低的患者中（P = 0.01）发生眼球震颤的可能性更大，但与年龄无关（P = 0.87）。结论：在遗传性视网膜营养不良患者中发现了几种高频RDH12变异，其中大多数是错义突变。观察到进行性的可变但特征性表型。总的来说，研究结果表明，双等位基因RDH12突变是早发性视网膜营养不良的常见原因，是锥杆营养不良的罕见原因。
Purpose: To characterize the phenotypic variability and report the genetic defects in a cohort of Chinese patients with biallelic variants of the retinol dehydrogenase 12 (RDH12) gene.Methods: The study included 38 patients from 38 unrelated families with biallelic pathogenic RDH12 variants. Systematic next-generation sequencing data analysis, Sanger sequencing validation, and segregation analysis were used to identify the pathogenic mutations. Detailed ophthalmic examinations, including electroretinogram, fundus photography, fundus autofluorescence and optical coherence tomography, and statistical analysis were performed to evaluate phenotype variability.Results: Twenty-five different mutations of RDH12 were identified in the 38 families. Six of these variants were novel. Val146Asp was observed at the highest frequency (23.7%), and it was followed by Arg62Ter (14.5%) and Thr49Met (9.2%). Twenty-three probands were diagnosed with early-onset severe retinal dystrophy, 6 with Leber congenital amaurosis, 7 with autosomal recessive retinitis pigmentosa, and 2 with cone-rod dystrophy. Self-reported nyctalopia occurred in about a half of patients (55.3%) and was significantly more common among older patients (P < 0.01). Nyctalopia was not significantly associated with best-corrected visual acuity (P = 0.72), but older patients had significantly greater best-corrected visual acuity loss (P < 0.01). Only 15.8% of the patients had nystagmus, which was significantly more likely to occur among 36.8% of the patients with hyperopia >3D (P < 0.01) and/or in cases of reduced best-corrected visual acuity (P = 0.01), but was not associated with age (P = 0.87).Conclusion: Several high-frequency RDH12 variants were identified in patients with inherited retinal dystrophies, most of which were missense mutations. Variable but characteristic phenotypes of a progressive nature was observed. Overall, the findings indicated that biallelic RDH12 mutations are a common cause of early-onset retinal dystrophy and a rare cause of cone-rod dystrophy.