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Abstract：
BACKGROUND: Biallelic pathogenic variants in USH2A lead to Usher syndrome or non-syndromic retinitis pigmentosa, and shown to have geographical and ethnical distribution in previous studies. This study provided a deeper understanding of the detailed clinical features using multimodal imaging, genetic spectrum, and genotype-phenotype correlations of USH2A-related retinal dystrophies in Taiwan.
RESULTS: In our cohort, the mean age at first visit was 47.66 ± 13.54 years, and the mean age at symptom onset, which was referred to the onset of nyctalopia and/or visual field constriction, was 31.21 ± 15.24 years. Among the variants identified, 23 (50%) were missense, 10 (22%) were splicing variants, 8 (17%) were nonsense, and 5 (11%) were frameshift mutations. The most predominant variant was c.2802T>G, which accounted for 21% of patients, and was located in exon 13. Patients with truncated alleles had significantly earlier symptom onset and seemly poorer disease progression regarding visual acuity, ellipsoid zone line length, and hypofluorescent lesions in the macula than those who had the complete gene. However, the clinical presentation revealed similar progression between patients with and without the c.2802T>G variant. During long-term follow-up, the patients had different ellipsoid zone line progression rates and were almost evenly distributed in the fast, moderate, and slow progression subgroups. Although a younger onset age and a smaller baseline intact macular area was observed in the fast progression subgroup, the results showed no significant difference.
CONCLUSIONS: This is the first cohort study to provide detailed genetic and longitudinal clinical analyses of patients with USH2A-related retinal dystrophies in Taiwan. The mutated allele frequency in exon 13 was high in Taiwan due to the predominant c.2802T>G variant. Moreover, truncated variants greatly impacted disease progression and determined the length of therapeutic windows. These findings provide insight into the characteristics of candidates for future gene therapies.
RESULTS: In our cohort, the mean age at first visit was 47.66 ± 13.54 years, and the mean age at symptom onset, which was referred to the onset of nyctalopia and/or visual field constriction, was 31.21 ± 15.24 years. Among the variants identified, 23 (50%) were missense, 10 (22%) were splicing variants, 8 (17%) were nonsense, and 5 (11%) were frameshift mutations. The most predominant variant was c.2802T>G, which accounted for 21% of patients, and was located in exon 13. Patients with truncated alleles had significantly earlier symptom onset and seemly poorer disease progression regarding visual acuity, ellipsoid zone line length, and hypofluorescent lesions in the macula than those who had the complete gene. However, the clinical presentation revealed similar progression between patients with and without the c.2802T>G variant. During long-term follow-up, the patients had different ellipsoid zone line progression rates and were almost evenly distributed in the fast, moderate, and slow progression subgroups. Although a younger onset age and a smaller baseline intact macular area was observed in the fast progression subgroup, the results showed no significant difference.
CONCLUSIONS: This is the first cohort study to provide detailed genetic and longitudinal clinical analyses of patients with USH2A-related retinal dystrophies in Taiwan. The mutated allele frequency in exon 13 was high in Taiwan due to the predominant c.2802T>G variant. Moreover, truncated variants greatly impacted disease progression and determined the length of therapeutic windows. These findings provide insight into the characteristics of candidates for future gene therapies.
摘要：
背景：USH2A的双等位基因致病变异导致Usher综合征或非综合征性视网膜色素变性，在以前的研究中显示出地理和种族分布。这项研究提供了使用多模态成像的详细临床特征更深入的理解，遗传谱,台湾USH2A相关视网膜营养不良的基因型-表型相关性。
结果：在我们的队列中，首次就诊的平均年龄为47.66±13.54岁，以及症状发作时的平均年龄，指的是夜视和/或视野收缩的发作，为31.21±15.24岁。在确定的变体中，23（50％）是错误的，10个（22%）是剪接变体，8（17%）是胡说八道，和5（11％）是移码突变。最主要的变异是c.2802T>G，占21％的患者，位于外显子13.具有截短等位基因的患者在视力方面具有明显较早的症状发作和明显较差的疾病进展。椭球区线长度，和黄斑中的低荧光性病变比那些有完整基因的人。然而,临床表现显示有和没有c.2802T>G变异的患者的进展相似.在长期随访中，患者具有不同的椭球区线进展率，并且在快速，中度,和缓慢进展的亚组。尽管在快速进展亚组中观察到较年轻的发病年龄和较小的基线完整黄斑区,结果无显著性差异。
结论：这是第一个对台湾USH2A相关视网膜营养不良患者进行详细遗传和纵向临床分析的队列研究。由于主要的c.2802T>G变体，外显子13的突变等位基因频率在台湾很高。此外，截短的变体极大地影响疾病进展并确定治疗窗口的长度。这些发现为未来的基因治疗提供了对候选特征的见解。
结果：在我们的队列中，首次就诊的平均年龄为47.66±13.54岁，以及症状发作时的平均年龄，指的是夜视和/或视野收缩的发作，为31.21±15.24岁。在确定的变体中，23（50％）是错误的，10个（22%）是剪接变体，8（17%）是胡说八道，和5（11％）是移码突变。最主要的变异是c.2802T>G，占21％的患者，位于外显子13.具有截短等位基因的患者在视力方面具有明显较早的症状发作和明显较差的疾病进展。椭球区线长度，和黄斑中的低荧光性病变比那些有完整基因的人。然而,临床表现显示有和没有c.2802T>G变异的患者的进展相似.在长期随访中，患者具有不同的椭球区线进展率，并且在快速，中度,和缓慢进展的亚组。尽管在快速进展亚组中观察到较年轻的发病年龄和较小的基线完整黄斑区,结果无显著性差异。
结论：这是第一个对台湾USH2A相关视网膜营养不良患者进行详细遗传和纵向临床分析的队列研究。由于主要的c.2802T>G变体，外显子13的突变等位基因频率在台湾很高。此外，截短的变体极大地影响疾病进展并确定治疗窗口的长度。这些发现为未来的基因治疗提供了对候选特征的见解。
