{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T02:50:01Z","timestamp":1746499801782},"reference-count":36,"publisher":"Georg Thieme Verlag KG","issue":"03","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Klin Monbl Augenheilkd"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Over the past decade, novel high-throughput DNA sequencing technologies have revolutionised both research and diagnostic testing for monogenic disorders. This applies particularly to genetically very heterogeneous disorders like retinal dystrophies (RDs). Next-generation sequencing (NGS) today is considered as reliable as Sanger sequencing, which had been the gold standard for decades. Today, comprehensive NGS-based diagnostic testing reveals the causative mutations in the majority of RD patients, with important implications for genetic counselling for recurrence risks and personalised medical management (from interdisciplinary surveillance to prophylactic measures and, albeit yet rare, [gene] therapy). While DNA sequencing is \u2013 in most cases \u2013 no longer the diagnostic bottleneck, one needs to be aware of interpretation pitfalls and dead ends. The advent of new (NGS) technologies will solve some of these issues. However, specialised medical geneticists who are familiar\n\t\t\t\t\twith the peculiarities of certain RD genes and closely interact with ophthalmologists will remain key to successful RD research and diagnostic testing for the benefit of the patients. This review sheds light on the current state of the field, its challenges and potential solutions.<\/jats:p>","DOI":"10.1055\/a-1386-5361","type":"journal-article","created":{"date-parts":[[2021,3,30]],"date-time":"2021-03-30T22:38:51Z","timestamp":1617143931000},"page":"261-266","source":"Crossref","is-referenced-by-count":3,"title":["Diagnostic Analyses of Retinal Dystrophy Genes: Current Status and Perspective"],"prefix":"10.1055","volume":"238","author":[{"given":"Hanno J\u00f6rn","family":"Bolz","sequence":"additional","affiliation":[{"name":"Humangenetik, Senckenberg Zentrum f\u00fcr Humangenetik, Frankfurt, Germany"},{"name":"Humangenetik, University Hospital of Cologne, Cologne, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"194","published-online":{"date-parts":[[2021,3,30]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"e0207958","DOI":"10.1371\/journal.pone.0207958","article-title":"Next-generation sequencing identifies unexpected genotype-phenotype correlations in patients with retinitis pigmentosa","volume":"13","author":"J Birtel","year":"2018","journal-title":"PLoS One"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"e78496","DOI":"10.1371\/journal.pone.0078496","article-title":"Increasing the yield in targeted next-generation sequencing by implicating CNV analysis, non-coding exons and the overall variant load: the example of retinal dystrophies","volume":"8","author":"T Eisenberger","year":"2013","journal-title":"PLoS One"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1016\/j.ophtha.2020.04.008","article-title":"Genetic Basis of Inherited Retinal Disease in a Molecularly Characterized Cohort of More Than 3000 Families from the United Kingdom","volume":"127","author":"N Pontikos","year":"2020","journal-title":"Ophthalmology"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1002\/humu.22844","article-title":"GeneMatcher: a matching tool for connecting investigators with an interest in the same gene","volume":"36","author":"N Sobreira","year":"2015","journal-title":"Hum Mutat"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1086\/507318","article-title":"Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis","volume":"79","author":"AI den Hollander","year":"2006","journal-title":"Am J Hum Genet"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1038\/s41436-018-0414-9","article-title":"Deep-intronic ABCA4 variants explain missing heritability in Stargardt disease and allow correction of splice defects by antisense oligonucleotides","volume":"21","author":"R Sangermano","year":"2019","journal-title":"Genet Med"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1038\/s41436-018-0420-y","article-title":"ABCA4-associated disease as a model for missing heritability in autosomal recessive disorders: novel noncoding splice, cis-regulatory, structural, and recurrent hypomorphic variants","volume":"21","author":"M Bauwens","year":"2019","journal-title":"Genet Med"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1038\/s41436-020-0787-4","article-title":"Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics","volume":"22","author":"M Khan","year":"2020","journal-title":"Genet Med"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1038\/nature13394","article-title":"Genome sequencing identifies major causes of severe intellectual disability","volume":"511","author":"C Gilissen","year":"2014","journal-title":"Nature"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1167\/iovs.61.10.36","article-title":"Phenotype Driven Analysis of Whole Genome Sequencing Identifies Deep Intronic Variants that Cause Retinal Dystrophies by Aberrant Exonization","volume":"61","author":"M Di Scipio","year":"2020","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"eaal5209","DOI":"10.1126\/scitranslmed.aal5209","article-title":"Improving genetic diagnosis in Mendelian disease with transcriptome sequencing","volume":"9","author":"B B Cummings","year":"2017","journal-title":"Sci Transl Med"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"15824","DOI":"10.1038\/ncomms15824","article-title":"Genetic diagnosis of Mendelian disorders via RNA sequencing","volume":"8","author":"L S Kremer","year":"2017","journal-title":"Nat Commun"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.ajhg.2019.01.012","article-title":"Expanding the Boundaries of RNA Sequencing as a Diagnostic Tool for Rare Mendelian Disease","volume":"104","author":"H D Gonorazky","year":"2019","journal-title":"Am J Hum Genet"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1016\/j.ajhg.2020.09.002","article-title":"Structural Variants Create New Topological-Associated Domains and Ectopic Retinal Enhancer-Gene Contact in Dominant Retinitis Pigmentosa","volume":"107","author":"S E de Bruijn","year":"2020","journal-title":"Am J Hum Genet"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1038\/gim.2017.97","article-title":"Mapping the genomic landscape of inherited retinal disease genes prioritizes genes prone to coding and noncoding copy-number variations","volume":"20","author":"K Van Schil","year":"2018","journal-title":"Genet Med"},{"key":"ref16","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-020-00770-0","article-title":"Long-read trio sequencing of individuals with unsolved intellectual disability","author":"M Pauper","year":"2020","journal-title":"Eur J Hum Genet"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"105799","DOI":"10.1016\/j.biocel.2020.105799","article-title":"Long-read sequencing to understand genome biology and cell function","volume":"126","author":"F Kraft","year":"2020","journal-title":"Int J Biochem Cell Biol"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1038\/s41591-020-0763-1","article-title":"Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR","volume":"26","author":"J Cehajic-Kapetanovic","year":"2020","journal-title":"Nat Med"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"2594","DOI":"10.1093\/hmg\/ddv022","article-title":"Non-manifesting AHI1 truncations indicate localized loss-of-function tolerance in a severe Mendelian disease gene","volume":"24","author":"S M Elsayed","year":"2015","journal-title":"Hum Mol Genet"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1007\/s00439-020-02199-3","article-title":"The Human Gene Mutation Database (HGMD \u00ae): optimizing its use in a clinical diagnostic or research setting","volume":"139","author":"P D Stenson","year":"2020","journal-title":"Hum Genet"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nature19057","article-title":"Analysis of protein-coding genetic variation in 60,706 humans","volume":"536","author":"M Lek","year":"2016","journal-title":"Nature"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1038\/s41576-020-0255-7","article-title":"Exploring human genomic diversity with gnomAD","volume":"21","author":"L Koch","year":"2020","journal-title":"Nat Rev Genet"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"K J Karczewski","year":"2020","journal-title":"Nature"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1136\/jmedgenet-2018-105971","article-title":"Allele frequency analysis of variants reported to cause autosomal dominant inherited retinal diseases question the involvement of 19\u200a% of genes and 10\u200a% of reported pathogenic variants","volume":"56","author":"M Hanany","year":"2019","journal-title":"J Med Genet"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1111\/cge.13847","article-title":"Identifying haplotypes in recessive inherited retinal dystrophies using whole-genome linked-read sequencing","volume":"99","author":"P Repo","year":"2020","journal-title":"Clin Genet"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"e1005756","DOI":"10.1371\/journal.pgen.1005756","article-title":"Exonic Splicing Mutations Are More Prevalent than Currently Estimated and Can Be Predicted by Using In Silico Tools","volume":"12","author":"O Soukarieh","year":"2016","journal-title":"PLoS Genet"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"3388","DOI":"10.1167\/iovs.18-26415","article-title":"A Specific Macula-Predominant Retinal Phenotype Is Associated With the CDHR1 Variant c.783G>A, a\u00a0Silent Mutation Leading to In-Frame Exon Skipping","volume":"60","author":"P Charbel Issa","year":"2019","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1056\/NEJMe1614384","article-title":"When One Diagnosis Is Not Enough","volume":"376","author":"K M Boycott","year":"2017","journal-title":"N Engl J Med"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1056\/NEJMoa1516767","article-title":"Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation","volume":"376","author":"J E Posey","year":"2017","journal-title":"N Engl J Med"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"2343","DOI":"10.1212\/01.wnl.0000314731.65875.5c","article-title":"Double homozygosity for mutations of AGL and SCN9A mimicking neurohepatopathy syndrome","volume":"70","author":"I Ebermann","year":"2008","journal-title":"Neurology"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.ophtha.2014.07.040","article-title":"Mutations in MFSD8, encoding a lysosomal membrane protein, are associated with nonsyndromic autosomal recessive macular dystrophy","volume":"122","author":"S Roosing","year":"2015","journal-title":"Ophthalmology"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1007\/s00439-013-1381-5","article-title":"Next generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements","volume":"133","author":"F Wang","year":"2014","journal-title":"Hum Genet"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1136\/jmedgenet-2013-101558","article-title":"Comprehensive molecular diagnosis of 179 Leber congenital amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing","volume":"50","author":"X Wang","year":"2013","journal-title":"J Med Genet"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"368rv366","DOI":"10.1126\/scitranslmed.aaf2838","article-title":"Emerging therapies for inherited retinal degeneration","volume":"8","author":"H P Scholl","year":"2016","journal-title":"Sci Transl Med"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1093\/hmg\/ddz303","article-title":"Taurine treatment of retinal degeneration and cardiomyopathy in a consanguineous family with SLC6A6 taurine transporter deficiency","volume":"29","author":"M Ansar","year":"2020","journal-title":"Hum Mol Genet"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"11507","DOI":"10.1096\/fj.201900914RR","article-title":"Biallelic mutation of human SLC6A6 encoding the taurine transporter TAUT is linked to early retinal degeneration","volume":"33","author":"M N Preising","year":"2019","journal-title":"FASEB J"}],"container-title":["Klinische Monatsbl\u00e4tter f\u00fcr Augenheilkunde"],"original-title":[],"language":"de","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/a-1386-5361.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,30]],"date-time":"2021-03-30T22:41:01Z","timestamp":1617144061000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/a-1386-5361"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3]]},"references-count":36,"journal-issue":{"issue":"03","published-online":{"date-parts":[[2021,3,30]]},"published-print":{"date-parts":[[2021,3]]}},"URL":"https:\/\/doi.org\/10.1055\/a-1386-5361","relation":{},"ISSN":["0023-2165","1439-3999"],"issn-type":[{"value":"0023-2165","type":"print"},{"value":"1439-3999","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3]]}}}