AbstractInherited retinal dystrophies (IRDs) and inherited optic neuropathies (IONs) are characterized by distinct genetic causes and molecular mechanisms that can lead to varying degrees of visual impairment. The discovery of pathogenic variants in numerous genes associated with these conditions has deepened our understanding of the molecular pathways that influence both vision and disease manifestation and may ultimately lead to novel therapeutic approaches.

摘要遗传性视网膜营养不良（IRD）和遗传性视神经病变（ION）的特征在于不同的遗传原因和分子机制，可导致不同程度的视力障碍。在与这些疾病相关的许多基因中发现致病变异，加深了我们对影响视力和疾病表现的分子途径的理解，并可能最终导致新的治疗方法。

Over the past 18 years, our DNA diagnostics unit has been performing genetic testing on patients suspected of having IRD or ION, using state-of-the-art mutation detection technologies that are continuously updated. This report presents a retrospective analysis of genetic data from 6237 IRD and 780 ION patients.

在过去的18年中，我们的DNA诊断部门一直在使用不断更新的最先进突变检测技术，对怀疑患有IRD或离子的患者进行基因检测。本报告对6237名IRD和780名ION患者的遗传数据进行了回顾性分析。

Out of these, 3054 IRD patients (49.0%) and 211 ION patients (27.1%) received a definitive molecular diagnosis, with disease-causing variants identified in 139 different genes. The genes most implicated in disease pathologies are ABCA4, accounting for 23.8% of all IRD/ION index cases, followed by BEST1 (7.8%), USH2A (6.2%), PRPH2 (5.7%), RPGR (5.6%), RS1 (5.5%), OPA1 (4.3%), and RHO (3.1%).

其中，3054名IRD患者（49.0%）和211名ION患者（27.1%）接受了明确的分子诊断，并在139个不同基因中鉴定出致病变异。与疾病病理最相关的基因是ABCA4，占所有IRD/离子指数病例的23.8%，其次是BEST1（7.8%），USH2A（6.2%），PRPH2（5.7%），RPGR（5.6%），RS1（5.5%），OPA1（4.3%）和RHO（3.1%）。

Our study has compiled the most extensive dataset in combined IRD/ION diagnostics to date and offers valuable insights into the frequencies of mutant alleles and the efficiency of mutation detection in various inherited retinal conditions..

我们的研究汇编了迄今为止IRD/离子联合诊断中最广泛的数据集，并为各种遗传性视网膜疾病中突变等位基因的频率和突变检测的效率提供了有价值的见解。。

IntroductionInherited retinal dystrophies (IRDs) and inherited optic neuropathies (IONs) are genetic disorders that significantly contribute to global blindness. These conditions consist of a diverse group of single-gene disorders, characterized by substantial variability in onset and clinical presentation.

引言遗传性视网膜营养不良（IRD）和遗传性视神经病变（ION）是遗传性疾病，对全球失明有重要贡献。这些疾病由多种单基因疾病组成，其特征是发病和临床表现存在很大差异。

Symptoms can appear at any point from birth through late adulthood, often manifesting as increased sensitivity to glare, night and peripheral vision difficulties, decreased central visual acuity, scotomas, or color vision abnormalities. While some forms of IRD and ION are mild and remain stable for many years, most are progressive and may eventually result in legal blindness.Data on disease prevalence across various populations indicate that IRDs affect approximately 1 in 1340 individuals1,2.

症状可以在出生到成年后期的任何时候出现，通常表现为对眩光，夜间和周围视力困难的敏感性增加，中央视力下降，暗点或色觉异常。虽然某些形式的IRD和ION是温和的，并且多年来保持稳定，但大多数是渐进的，最终可能导致法律失明。关于不同人群疾病患病率的数据表明，IRD影响1340个人中的大约1,2。

It is estimated that approximately 5.5 million individuals worldwide are affected by autosomal recessive IRD subtypes alone, with a global carrier frequency of 36% for mutations that cause these diseases1. Autosomal dominant optic atrophy (ADOA) and Leber hereditary optic neuropathy (LHON) are the most common IONs with a prevalence of ADOA of 1 in 25,0003, while the values for LHON range from 1 in 31,000 to 1 in 68,0004,5,6,7.

据估计，全世界约有550万人仅受常染色体隐性IRD亚型的影响，导致这些疾病的突变的全球携带者频率为36%1。常染色体显性遗传性视神经萎缩（ADOA）和Leber遗传性视神经病变（LHON）是最常见的离子，ADOA的患病率为250003分之一，而LHON的值范围为31000分之一至680004分之一,5,6,7。

Autosomal dominant, X-linked, and mitochondrial-associated IRDs/IONs often exhibit reduced penetrance8,9.IRDs may affect specific cell types, like cone dystrophy, or specific regions, such as macular dystrophy, but often spread across the entire retina as the disease progresses10. IONs refer to a spectrum of optic nerve diseases mainly due to ganglion cell degeneration11.

。离子是指主要由神经节细胞变性引起的一系列视神经疾病11。

Additionally, IRDs and IONs can be part of multisystemic diseases, with over 80 syndromic IRD forms identified to date12. Both syndromic and non-syndromic diseases arise from pathogenic s.

此外，IRD和离子可能是多系统疾病的一部分，迄今已鉴定出80多种综合征IRD形式12。综合征和非综合征疾病均来自致病性s。

Data availability

数据可用性

The entirety of data analysed in this study has been incorporated within the published article and its Supplementary Information file. A total of 5254 variants identified in this study have been submitted to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) under accession numbers SCV005068380 – SCV005073654 to ensure community-wide access..

本研究中分析的全部数据已纳入已发表的文章及其补充信息文件中。本研究共鉴定出5254个变异，已提交给ClinVar(https://www.ncbi.nlm.nih.gov/clinvar/)登录号为SCV005068380–SCV005073654，以确保社区范围内的访问。。

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Download referencesAcknowledgementsThe authors are greatly indebted to the many physicians and genetic counsellors who referred patients for DNA testing at the Institute of Human Genetics Regensburg. Acknowledgment is also extended to Christoph Meier for his help with data collection, archiving and retrieval from the local database system.FundingOpen Access funding enabled and organized by Projekt DEAL.

下载参考文献致谢作者非常感谢许多医生和遗传咨询师，他们在雷根斯堡人类遗传学研究所（Institute of Human Genetics Regensburg）为患者推荐了DNA测试。感谢Christoph Meier在数据收集，存档和从当地数据库系统检索方面的帮助。资金开放获取资金由Projekt交易启用和组织。

Institutional Funding, Titel 77.Author informationAuthors and AffiliationsInstitute of Human Genetics, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, GermanyChristina Kiel, Fabiola Biasella, Heidi Stöhr & Bernhard H. F. WeberDepartment of Ophthalmology, University Hospital Essen, Hufelandstraße 55, 45147, Essen, GermanyPhilipp RatingAugenzentrum am St.

机构资金，Titel 77。作者信息作者和附属机构雷根斯堡大学人类遗传学研究所，Franz Josef Strauss Allee 1193053，雷根斯堡，GermanyChristina Kiel，Fabiola Biasella，Heidi Stöhr＆Bernhard H.F.WeberDepartment of Ophthalmology，University Hospital Essen，Hufelandstraße 5545147，Essen，GermanyPhilipp Ratingaugencentrum am St。

Franziskus-Hospital, Hohenzollernring 74, 48145, Münster, GermanyGeorg SpitalCenter for Rare Retinal Diseases, AugenZentrum Siegburg, Europaplatz 3, 53721, Siegburg, GermanyUlrich KellnerRetinaScience, Postfach 301212, 53192, Bonn, GermanyUlrich KellnerHannover Medical School, University Clinic of Ophthalmology, Carl-Neuberg-Straße 1, 30625, Hannover, GermanyKarsten HufendiekDepartment of Ophthalmology, University Hospital Erlangen, Schwabachanlage 6, 91054, Erlangen, GermanyCord HuchzermeyerDepartment of Ophthalmology, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, GermanyHerbert JaegleSpecialist Practice Ophthalmology, Dorotheenstraße 56, 10117, Berlin, GermanyKlaus RuetherInstitute of Clinical Human Genetics, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, GermanyBernhard H.

Franziskus医院，Hohenzollernring 7448145，Münster，GermanyGeorg SpitalCenter for Rare Retinal Diseases，AugenZentrum Siegburg，Europaplatz 353721，Siegburg，GermanyUlrich KellnerRetinaScience，Postfach 30121253192，波恩，GermanyUlrich KellnerHannover医学院，大学眼科诊所，Carl Neuberg Straße 130625，汉诺威，GermanyKarsten HufendiekDepartment of Ophthalmology，埃尔兰根大学医院，Schwabachanlage 691054，德国埃尔兰根Cord Huchzermeyer雷根斯堡大学医院眼科，Franz Josef Strauss Allee 1193053，德国雷根斯堡Herbert JaegleSpecialist Practice Ophthalmology，Dorotheenstraße 5610117，柏林，GermanyKlaus RuetherInstitute of Clinical Human Genetics，雷根斯堡大学医院，Franz Josef Strauss Allee 1193053，雷根斯堡，GermanyBernhard H。

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PubMed Google ScholarContributionsC.K., H.S., and B.H.F.W. contributed to the study conception, design, and final interpretation of data. B.H.F.W. and H.S. supervised the genetic analysis of patient samples, secured funding, and coordinated the research. C.K. and H.S. were responsible for data curation and formal analysis.

PubMed谷歌学术贡献中心。K、 ，H.S.和B.H.F.W.为研究概念，设计和数据的最终解释做出了贡献。B、 H.F.W.和H.S.监督患者样本的基因分析，获得资金并协调研究。C、 K.和H.S.负责数据管理和正式分析。

C.K., H.S., F.B., and B.H.F.W. contributed to the writing of the original draft. P.R., G.S., U.K., K.H., C.H., H.J., and K.R. were responsible for patient recruitment and clinical assessment. All authors contributed to the review and editing process and approved the submitted version of the manuscript.

C、 K.，H.S.，F.B。和B.H.F.W.为原稿的撰写做出了贡献。P、 R.，G.S.，英国，K.H.，C.H.，H.J。和K.R.负责患者招募和临床评估。所有作者都为审查和编辑过程做出了贡献，并批准了稿件的提交版本。

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Reprints and permissionsAbout this articleCite this articleKiel, C., Biasella, F., Stöhr, H. et al. 18-Years of single-centre DNA testing in over 7000 index cases with inherited retinal dystrophies and optic neuropathies.

转载和许可本文引用本文Kiel，C.，Biasella，F.，Stöhr，H。等人在7000多例遗传性视网膜营养不良和视神经病变的索引病例中进行了18年的单中心DNA检测。

Sci Rep 14, 25529 (2024). https://doi.org/10.1038/s41598-024-77014-4Download citationReceived: 17 June 2024Accepted: 18 October 2024Published: 26 October 2024DOI: https://doi.org/10.1038/s41598-024-77014-4Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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KeywordsInherited retinal diseaseIRDDNA testingNext-generation sequencingGenetic variantsDiagnostic yield

关键词遗传性视网膜疾病IRDDNA检测下一代测序遗传变异诊断率