Abstract：
It is of utmost importance to define the molecular diagnosis of patients with retinitis pigmentosa (RP) due to existing targeted therapeutic option: voretigene neparvovec.We provide clinical evidence for pathogenicity reclassification of variants of uncertain significance (VUSs) RPE65 c.1580A>G (p.His527Arg).
A case report of a 10-year-old boy with progressive vision loss. The patient manifested disease highly suggestive of RPE65 retinal dystrophy: nyctalopia, fairly good central vision, severely depressed full-field electroretinography responses and complete loss of peripheral fundus aut ofluorescence.
Invitae Inherited Retinal Disorders Panel identified likely pathogenic mutation RPE65 c.499G>T (p.Asp167Tyr) and RPE65 c.1580A>G (p.His527Arg), variant of uncertain significance. Segregation analysis confirmed that these variants are in trans.
We conclude that the variant RPE65 c.1580A>G (p.His527Arg) has contributed to the pathologic phenotype, demonstrating its significance clearly in the case presented, and should be reclassified according to the criteria of evidence as pathogenic. Therefore, patients with this specific variant in homozygous or compound heterozygous form would likely benefit from genetic treatment based on recombinant adeno-associated virus vector, providing a working RPE65 gene to act in place of a mutated RPE65 gene.
A case report of a 10-year-old boy with progressive vision loss. The patient manifested disease highly suggestive of RPE65 retinal dystrophy: nyctalopia, fairly good central vision, severely depressed full-field electroretinography responses and complete loss of peripheral fundus aut ofluorescence.
Invitae Inherited Retinal Disorders Panel identified likely pathogenic mutation RPE65 c.499G>T (p.Asp167Tyr) and RPE65 c.1580A>G (p.His527Arg), variant of uncertain significance. Segregation analysis confirmed that these variants are in trans.
We conclude that the variant RPE65 c.1580A>G (p.His527Arg) has contributed to the pathologic phenotype, demonstrating its significance clearly in the case presented, and should be reclassified according to the criteria of evidence as pathogenic. Therefore, patients with this specific variant in homozygous or compound heterozygous form would likely benefit from genetic treatment based on recombinant adeno-associated virus vector, providing a working RPE65 gene to act in place of a mutated RPE65 gene.
摘要：
■定义色素性视网膜炎（RP）患者的分子诊断至关重要，因为现有的靶向治疗选择：voretigeneneparvovovec。我们为意义不确定的变异体（VUS）RPE65c.1580A>G（p。His527Arg）。
■一例10岁男孩进行性视力丧失的病例报告。患者表现出高度提示RPE65视网膜营养不良的疾病：夜视，相当好的中央视力，全场视网膜电图反应严重抑制，周围眼底完全丧失。
■Invitae遗传性视网膜疾病小组鉴定出可能的致病突变RPE65c.499G>T（p。Asp167Tyr）和RPE65c.158A>G（p。His527Arg），不确定意义的变体。分离分析证实这些变体是反式的。
■我们得出结论，变体RPE65c.158A>G（p。His527Arg）对病理表型有贡献，在所陈述的案例中清楚地证明了其重要性，并应根据证据标准重新分类为致病性。因此,具有纯合或复合杂合形式的这种特定变体的患者可能会从基于重组腺相关病毒载体的基因治疗中受益。提供一个有效的RPE65基因来代替突变的RPE65基因。
■一例10岁男孩进行性视力丧失的病例报告。患者表现出高度提示RPE65视网膜营养不良的疾病：夜视，相当好的中央视力，全场视网膜电图反应严重抑制，周围眼底完全丧失。
■Invitae遗传性视网膜疾病小组鉴定出可能的致病突变RPE65c.499G>T（p。Asp167Tyr）和RPE65c.158A>G（p。His527Arg），不确定意义的变体。分离分析证实这些变体是反式的。
■我们得出结论，变体RPE65c.158A>G（p。His527Arg）对病理表型有贡献，在所陈述的案例中清楚地证明了其重要性，并应根据证据标准重新分类为致病性。因此,具有纯合或复合杂合形式的这种特定变体的患者可能会从基于重组腺相关病毒载体的基因治疗中受益。提供一个有效的RPE65基因来代替突变的RPE65基因。
