Abstract：
BACKGROUND: As gene-specific therapy for inherited retinal dystrophy (IRD) advances, unified variant interpretation across institutes is becoming increasingly important. This study aims to update the genetic findings of 86 retinitis pigmentosa (RP)-related genes in a large number of Japanese patients with RP by applying the standardised variant interpretation guidelines for Japanese patients with IRD (J-IRD-VI guidelines) built upon the American College of Medical Genetics and Genomics and the Association for Molecular Pathology rules, and assess the contribution of these genes in RP-allied diseases.
METHODS: We assessed 2325 probands with RP (n=2155, including n=1204 sequenced previously with the same sequencing panel) and allied diseases (n=170, newly analysed), including Usher syndrome, Leber congenital amaurosis and cone-rod dystrophy (CRD). Target sequencing using a panel of 86 genes was performed. The variants were interpreted according to the J-IRD-VI guidelines.
RESULTS: A total of 3564 variants were detected, of which 524 variants were interpreted as pathogenic or likely pathogenic. Among these 524 variants, 280 (53.4%) had been either undetected or interpreted as variants of unknown significance or benign variants in our earlier study of 1204 patients with RP. This led to a genetic diagnostic rate in 38.6% of patients with RP, with EYS accounting for 46.7% of the genetically solved patients, showing a 9% increase in diagnostic rate from our earlier study. The genetic diagnostic rate for patients with CRD was 28.2%, with RP-related genes significantly contributing over other allied diseases.
CONCLUSIONS: A large-scale genetic analysis using the J-IRD-VI guidelines highlighted the population-specific genetic findings for Japanese patients with IRD; these findings serve as a foundation for the clinical application of gene-specific therapies.
METHODS: We assessed 2325 probands with RP (n=2155, including n=1204 sequenced previously with the same sequencing panel) and allied diseases (n=170, newly analysed), including Usher syndrome, Leber congenital amaurosis and cone-rod dystrophy (CRD). Target sequencing using a panel of 86 genes was performed. The variants were interpreted according to the J-IRD-VI guidelines.
RESULTS: A total of 3564 variants were detected, of which 524 variants were interpreted as pathogenic or likely pathogenic. Among these 524 variants, 280 (53.4%) had been either undetected or interpreted as variants of unknown significance or benign variants in our earlier study of 1204 patients with RP. This led to a genetic diagnostic rate in 38.6% of patients with RP, with EYS accounting for 46.7% of the genetically solved patients, showing a 9% increase in diagnostic rate from our earlier study. The genetic diagnostic rate for patients with CRD was 28.2%, with RP-related genes significantly contributing over other allied diseases.
CONCLUSIONS: A large-scale genetic analysis using the J-IRD-VI guidelines highlighted the population-specific genetic findings for Japanese patients with IRD; these findings serve as a foundation for the clinical application of gene-specific therapies.
摘要：
背景：随着基因特异性治疗遗传性视网膜营养不良（IRD）的进展，跨机构的统一变体解释变得越来越重要。这项研究旨在通过应用基于美国医学遗传学和基因组学学院以及分子病理学规则协会的日本IRD患者标准化变异解释指南（J-IRD-VI指南），更新大量日本RP患者中86个色素性视网膜炎（RP）相关基因的遗传发现。并评估这些基因在RP相关疾病中的贡献。
方法：我们评估了2325名先证者的RP（n=2155，包括以前用相同测序组测序的n=1204）和相关疾病（n=170，新分析），包括Usher综合征,Leber先天性黑蒙和锥棒营养不良（CRD）。使用一组86个基因进行靶测序。根据J-IRD-VI指南解释变体。
结果：共检测到3564个变异，其中524个变体被解释为致病性或可能致病性。在这524个变体中，在我们对1204例RP患者的早期研究中，有280例（53.4％）未被发现或被解释为未知意义的变体或良性变体。这导致38.6％的RP患者的遗传诊断率，EYS占基因解决患者的46.7%，与我们之前的研究相比，诊断率提高了9%。CRD患者的基因诊断率为28.2%,与RP相关的基因对其他相关疾病有重要贡献。
结论：使用J-IRD-VI指南的大规模遗传分析强调了日本IRD患者的群体特异性遗传发现；这些发现为基因特异性疗法的临床应用奠定了基础。
方法：我们评估了2325名先证者的RP（n=2155，包括以前用相同测序组测序的n=1204）和相关疾病（n=170，新分析），包括Usher综合征,Leber先天性黑蒙和锥棒营养不良（CRD）。使用一组86个基因进行靶测序。根据J-IRD-VI指南解释变体。
结果：共检测到3564个变异，其中524个变体被解释为致病性或可能致病性。在这524个变体中，在我们对1204例RP患者的早期研究中，有280例（53.4％）未被发现或被解释为未知意义的变体或良性变体。这导致38.6％的RP患者的遗传诊断率，EYS占基因解决患者的46.7%，与我们之前的研究相比，诊断率提高了9%。CRD患者的基因诊断率为28.2%,与RP相关的基因对其他相关疾病有重要贡献。
结论：使用J-IRD-VI指南的大规模遗传分析强调了日本IRD患者的群体特异性遗传发现；这些发现为基因特异性疗法的临床应用奠定了基础。
