背景:关于日本人群中RP1相关视网膜营养不良的基因型-表型相关性知之甚少。我们旨在研究RP1变异的遗传谱,并提供日本患者临床发现的详细描述。
方法:总共,使用全外显子组/全基因组测序(WES/WGS)检查了607例遗传性视网膜疾病患者。基于PCR的Alu元素插入筛选(c.4052_4053ins328/p。Tyr1352AlafsTer9)在18例常染色体隐性遗传(AR)-色素性视网膜炎(RP)或AR视锥细胞营养不良(COD)/视锥细胞营养不良(CORD)的患者中进行,包括通过WES/WGS分析鉴定的7例具有杂合RP1变异的患者,11例早发性AR-RP患者,在其中没有发现致病性变异。我们临床检查了25例(23个家庭)的致病性RP1变异,包括5例常染色体显性遗传(AD)-RP患者(5个家庭),13名患者(11个家庭)患有AR-RP,和7名患者(7个家庭)患有AR-COD/CORD。
结果:我们确定了18个致病性RP1变异,包括七个新颖的变体。有趣的是,Alu元素插入是最常见的变体(32.0%,16/50等位基因)。临床发现表明,与AD-RP或AR-COD/CORD患者相比,AR-RP患者的发病年龄和疾病进展明显更早,更快。
结论:我们的结果表明变异类型/位置和表型之间存在基因型-表型相关性(AD-RP,AR-RP,和AR-COD/CORD),在日本RP1相关视网膜营养不良患者中,Alu元素插入是最主要的变异。
BACKGROUND: Little is known about genotype-phenotype correlations of RP1-associated retinal dystrophies in the Japanese population. We aimed to investigate the genetic spectrum of RP1 variants and provide a detailed description of the clinical findings in Japanese patients.
METHODS: In total, 607 patients with inherited retinal diseases were examined using whole-exome/whole-genome sequencing (WES/WGS). PCR-based screening for an Alu element insertion (c.4052_4053ins328/p.Tyr1352AlafsTer9) was performed in 18 patients with autosomal-recessive (AR)-retinitis pigmentosa (RP) or AR-cone dystrophy (COD)/cone-rod dystrophy (CORD), including seven patients with heterozygous RP1 variants identified by WES/WGS analysis, and 11 early onset AR-RP patients, in whom no pathogenic variant was identified. We clinically examined 25 patients (23 families) with pathogenic RP1 variants, including five patients (five families) with autosomal-dominant (AD)-RP, 13 patients (11 families) with AR-RP, and seven patients (seven families) with AR-COD/CORD.
RESULTS: We identified 18 pathogenic RP1 variants, including seven novel variants. Interestingly, the Alu element insertion was the most frequent variant (32.0%, 16/50 alleles). The clinical findings revealed that the age at onset and disease progression occurred significantly earlier and faster in AR-RP patients compared to AD-RP or AR-COD/CORD patients.
CONCLUSIONS: Our results suggest a genotype-phenotype correlation between variant types/locations and phenotypes (AD-RP, AR-RP, and AR-COD/CORD), and the Alu element insertion was the most major variant in Japanese patients with RP1-associated retinal dystrophies.