PURPOSE To analyze the genetic and clinical findings in retinitis pigmentosa (RP) patients of Ashkenazi Jewish (AJ) descent, aiming to identify genotype-phenotype correlations. DESIGN Cohort study. PARTICIPANTS Retinitis pigmentosa patients from 230 families of AJ origin. METHODS Sanger sequencing was performed to detect specific founder mutations known to be prevalent in the AJ population. Ophthalmologic analysis included a comprehensive clinical examination, visual acuity (VA), visual fields, electroretinography, color vision testing, and retinal imaging by OCT, pseudocolor, and autofluorescence fundus photography. MAIN OUTCOME MEASURES Inheritance pattern and causative mutation; retinal function as assessed by VA, visual fields, and electroretinography results; and retinal structural changes observed on clinical funduscopy as well as by pseudocolor, autofluorescence, and OCT imaging. RESULTS The causative mutation was identified in 37% of families. The most prevalent RP-causing mutations are the Alu insertion (c.1297_8ins353, p.K433Rins31*) in the male germ cell-associated kinase (MAK) gene (39% of families with a known genetic cause for RP) and c.124A>G, p.K42E in dehydrodolichol diphosphate synthase (DHDDS) (33%). Additionally, disease-causing mutations were identified in 11 other genes. Analysis of clinical parameters of patients with mutations in the 2 most common RP-causing genes revealed that MAK patients had better VA and visual fields at relatively older ages in comparison with DHDDS patients. Funduscopic findings of DHDDS patients matched those of MAK patients who were 20 to 30 years older. Patients with DHDDS mutations were referred for electrophysiologic evaluation at earlier ages, and their cone responses became nondetectable at a much younger age than MAK patients. CONCLUSIONS Our AJ cohort of RP patients is the largest reported to date and showed a substantial difference in the genetic causes of RP compared with cohorts of other populations, mainly a high rate of autosomal recessive inheritance and a unique composition of causative genes. The most common RP-causing genes in our cohort, MAK and DHDDS, were not described as major causative genes in other populations. The clinical data show that in general, patients with biallelic MAK mutations had a later age of onset and a milder retinal phenotype compared with patients with biallelic DHDDS mutations.

中文翻译：

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Ashkenazi犹太人口中的非综合征性视网膜色素变性：遗传和临床方面。

目的分析Ashkenazi犹太人（AJ）血统的视网膜色素变性（RP）患者的遗传和临床发现，旨在鉴定基因型与表型的相关性。设计队列研究。参与者来自230例AJ家族的色素性视网膜炎患者。方法进行桑格测序，以检测已知在AJ人群中普遍存在的特定创始人突变。眼科分析包括全面的临床检查，视力（VA），视野，视网膜电图，彩色视力测试以及通过OCT，假色和自发荧光眼底照相术进行的视网膜成像。主要观察指标遗传模式和致病突变；通过VA，视野和视网膜电图检查结果评估的视网膜功能; 眼底镜检查以及假色，自发荧光和OCT成像观察到的视网膜结构变化。结果在37％的家庭中发现了致病突变。引起RP的最普遍的突变是雄性生殖细胞相关激酶（MAK）基因（39％的已知遗传原因是RP的家庭）中的Alu插入（c.1297_8ins353，p.K433Rins31 *）和c.124A > G，p.K42E在脱氢二氢二磷酸二磷酸合酶（DHDDS）中的含量（33％）。此外，在其他11个基因中发现了致病突变。对两个最常见的引起RP的基因突变的患者的临床参数进行分析后发现，与DHDDS患者相比，MAK患者在相对较高的年龄时具有更好的VA和视野。DHDDS患者的眼底镜检查结果与年龄在20至30岁的MAK患者的眼底观察结果相匹配。具有DHDDS突变的患者在较早的年龄就被转介进行电生理评估，并且他们的视锥反应在比MAK患者年轻得多的年龄就变得不可检测。结论我们的RP患者AJ队列是迄今为止最大的队列研究，与其他人群相比，RP的遗传原因显示出显着差异，主要是常染色体隐性遗传率高和致病基因的独特组成。在我们的队列中，最常见的引起RP的基因MAK和DHDDS在其他人群中没有被描述为主要致病基因。临床数据表明，与双等位基因DHDDS突变患者相比，双等位基因MAK突变患者一般发病年龄较晚，视网膜表型较轻。