PDF(Pubmed)
Abstract：
Background and Objectives. Retinitis pigmentosa (RP) is the most common inherited rod-cone dystrophy (RCD), resulting in nyctalopia, progressive visual field, and visual acuity decay in the late stages. The autosomal dominant form (ADRP) accounts for about 20% of RPs. Among the over 30 genes found to date related to ADRP, RP1 pathogenic variants have been identified in 5-10% of cases. In a cohort of RCD patients from the Palermo province on the island of Sicily, we identified a prevalent nonsense variant in RP1, which was associated with ADRP. The objective of our study was to analyse the clinical and molecular data of this patient cohort and to evaluate the potential presence of a founder effect. Materials and Methods. From 2005 to January 2023, 84 probands originating from Western Sicily (Italy) with a diagnosis of RCD or RP and their relatives underwent deep phenotyping, which was performed in various Italian clinical institutions. Molecular characterisation of patients and familial segregation of pathogenic variants were carried out in different laboratories using Sanger and/or next-generation sequencing (NGS). Results. Among 84 probands with RCD/RP, we found 28 heterozygotes for the RP1 variant c.2219C>G, p.Ser740* ((NM_006269.2)*, which was therefore significantly prevalent in this patient cohort. After a careful interview process, we ascertained that some of these patients shared the same pedigree. Therefore, we were ultimately able to define 20 independent family groups with no traceable consanguinity. Lastly, analysis of clinical data showed, in our patients, that the p.Ser740* nonsense variant was often associated with a late-onset and relatively mild phenotype. Conclusions. The high prevalence of the p.Ser740* variant in ADRP patients from Western Sicily suggests the presence of a founder effect, which has useful implications for the molecular diagnosis of RCD in patients coming from this Italian region. This variant can be primarily searched for in RP-affected subjects displaying compatible modes of transmission and phenotypes, with an advantage in terms of the required costs and time for analysis. Moreover, given its high prevalence, the RP1 p.Ser740* variant could represent a potential candidate for the development of therapeutic strategies based on gene editing or translational read-through therapy for suppression of nonsense variants.
摘要：
背景和目标。色素性视网膜炎（RP）是最常见的遗传性视锥营养不良（RCD），导致夜蛾，渐进视野，后期视力衰退。常染色体显性形式（ADRP）约占RP的20％。在迄今为止发现的与ADRP相关的30多个基因中，已在5-10%的病例中鉴定出RP1致病变体。在西西里岛巴勒莫省的一群刚果民盟患者中，我们在RP1中发现了一个普遍的无义变体，该变体与ADRP相关。我们研究的目的是分析该患者队列的临床和分子数据，并评估潜在的创始人效应。材料和方法。从2005年到2023年1月，来自西西里岛西部（意大利）的84名先证者被诊断为RCD或RP及其亲属进行了深度表型鉴定，这是在各种意大利临床机构进行的。使用Sanger和/或下一代测序（NGS）在不同的实验室中进行患者的分子表征和致病变体的家族分离。结果。在拥有刚果民盟/RP的84位先证者中，我们发现了RP1变体c.2219C>G的28个杂合子，p.Ser740*（（NM_006269.2）*，因此，在该患者队列中非常普遍。经过仔细的面试过程，我们确定其中一些患者具有相同的谱系。因此,我们最终能够定义20个独立的家庭群体，没有可追溯的血缘关系。最后,临床数据分析显示，在我们的病人身上，p.Ser740*无义变体通常与迟发性和相对温和的表型有关。Conclusions.来自西西西里岛的ADRP患者中p.Ser740*变体的高患病率表明存在创始人效应，这对来自该意大利地区的患者的RCD分子诊断具有有用的意义。这种变异可以主要在RP受影响的受试者中搜索，这些受试者显示出兼容的传播方式和表型，在分析所需的成本和时间方面具有优势。此外，鉴于其患病率高，RP1p.Ser740*变体可能是开发基于基因编辑或翻译通读疗法抑制无义变体的治疗策略的潜在候选者.
