{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:26:53Z","timestamp":1785432413162,"version":"3.56.0"},"reference-count":67,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T00:00:00Z","timestamp":1782000000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fighting Blindness Ireland","award":["FB22FAR"],"award-info":[{"award-number":["FB22FAR"]}]},{"name":"Fighting Blindness Ireland","award":["FB16FAR"],"award-info":[{"award-number":["FB16FAR"]}]},{"award":["FB22FAR"],"award-info":[{"award-number":["FB22FAR"]}],"id":[{"id":"https:\/\/ror.org\/05bz3n751","id-type":"ROR","asserted-by":"publisher"}]},{"award":["FB16FAR"],"award-info":[{"award-number":["FB16FAR"]}],"id":[{"id":"https:\/\/ror.org\/05bz3n751","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Fighting Blindness Ireland\/Health Research Board of Ireland\u2014Health Research Charities Ireland","award":["MRCG-2016-14"],"award-info":[{"award-number":["MRCG-2016-14"]}]},{"name":"Fighting Blindness Ireland\/Health Research Board of Ireland\u2014Health Research Charities Ireland","award":["HRCI-HRB-2020-007"],"award-info":[{"award-number":["HRCI-HRB-2020-007"]}]},{"name":"Fighting Blindness Ireland\/Health Research Board of Ireland\u2014Health Research Charities Ireland","award":["HRCI-HRB-2024-006"],"award-info":[{"award-number":["HRCI-HRB-2024-006"]}]},{"award":["MRCG-2016-14"],"award-info":[{"award-number":["MRCG-2016-14"]}],"id":[{"id":"https:\/\/ror.org\/003hb2249","id-type":"ROR","asserted-by":"publisher"}]},{"award":["HRCI-HRB-2020-007"],"award-info":[{"award-number":["HRCI-HRB-2020-007"]}],"id":[{"id":"https:\/\/ror.org\/003hb2249","id-type":"ROR","asserted-by":"publisher"}]},{"award":["HRCI-HRB-2024-006"],"award-info":[{"award-number":["HRCI-HRB-2024-006"]}],"id":[{"id":"https:\/\/ror.org\/003hb2249","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001602","name":"Science Foundation Ireland","doi-asserted-by":"publisher","award":["16\/IA\/4452"],"award-info":[{"award-number":["16\/IA\/4452"]}],"id":[{"id":"10.13039\/501100001602","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100025294","name":"Research Ireland","doi-asserted-by":"crossref","award":["22\/FFP-A\/10544"],"award-info":[{"award-number":["22\/FFP-A\/10544"]}],"id":[{"id":"10.13039\/501100025294","id-type":"DOI","asserted-by":"crossref"}]},{"award":["22\/FFP-A\/10544"],"award-info":[{"award-number":["22\/FFP-A\/10544"]}],"id":[{"id":"https:\/\/ror.org\/010t7sr36","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Irish Research Council","award":["GOIPG\/2017\/1631"],"award-info":[{"award-number":["GOIPG\/2017\/1631"]}]},{"name":"Irish Research Council","award":["GOIPG\/2025\/8455"],"award-info":[{"award-number":["GOIPG\/2025\/8455"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Objectives: This study investigated a variant, RPGR NM_001034853.2 c.1307G&gt;A, p.[Gly436Asp, p?], in a large Irish pedigree with severe X-Linked Retinitis Pigmentosa (XLRP). The effect of the variant on RNA splicing was interrogated using in vitro functional analysis to provide evidence of disease causality. Methods: Three related individuals presenting with XLRP underwent target-capture sequencing, together with confirmatory Sanger sequencing and cascade analyses, to identify candidate variants. In silico investigations were undertaken using SpliceAI (version 1.3.1) and Alamut Visual software (version 2.13), among others. Functional analyses using in vitro midigene splice assays employing gateway expression vectors were undertaken. Variant and wildtype RNA were amplified by RT-PCR to investigate effects on splicing. RPGR c.1307G&gt;A was subsequently reclassified using ACMG\/AMP and ClinGen SVI recommendations. Results: Midigene investigation confirmed a cryptic acceptor site is being utilised together with the cryptic branchpoint motif to excise intron 10 and 90 bases of exon 11, leading to a frameshift and the creation of a premature stop codon. No functional RPGR transcript is predicted to remain. Given evidence of aberrant splicing, the variant classification was upgraded to pathogenic. Conclusions: RPGR c.1307G&gt;A leads to creation of a cryptic branchpoint within an exon, resulting in protein truncation with deleterious effect(s). To the best of our knowledge, this is the first variant that leads to creation of a cryptic branchpoint within an exon associated with any IRD. The results illustrate the importance of investigating the functional consequences of both coding and non-coding variants with a predicted impact on splicing to understand their pathogenicity.<\/jats:p>","DOI":"10.3390\/genes17060715","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T08:14:12Z","timestamp":1782375252000},"page":"715","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["First Exonic Cryptic Branchpoint Variant in an Inherited Retinal Degeneration Detected in an Irish RPGR Pedigree with X-Linked Retinitis Pigmentosa"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3977-851X","authenticated-orcid":false,"given":"Ella","family":"Kop\u010di\u0107","sequence":"first","affiliation":[{"name":"The School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, D02 VF25 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Whelan","sequence":"additional","affiliation":[{"name":"The School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, D02 VF25 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciara","family":"Shortall","sequence":"additional","affiliation":[{"name":"The School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, D02 VF25 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3533-3395","authenticated-orcid":false,"given":"Anna R.","family":"Ridgeway","sequence":"additional","affiliation":[{"name":"The School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, D02 VF25 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3395-1211","authenticated-orcid":false,"given":"Laura K.","family":"Finnegan","sequence":"additional","affiliation":[{"name":"The School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, D02 VF25 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3423-2542","authenticated-orcid":false,"given":"Adrian","family":"Dockery","sequence":"additional","affiliation":[{"name":"The School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, D02 VF25 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7470-0702","authenticated-orcid":false,"given":"Sophia","family":"Millington-Ward","sequence":"additional","affiliation":[{"name":"The School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, D02 VF25 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Duignan","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Royal Victoria Eye and Ear Hospital, Dublin 2, D02 XK51 Dublin, Ireland"},{"name":"The Research Foundation, Royal Victoria Eye and Ear Hospital, Dublin 2, D02 XK51 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul F.","family":"Kenna","sequence":"additional","affiliation":[{"name":"The School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, D02 VF25 Dublin, Ireland"},{"name":"Department of Ophthalmology, Royal Victoria Eye and Ear Hospital, Dublin 2, D02 XK51 Dublin, Ireland"},{"name":"The Research Foundation, Royal Victoria Eye and Ear Hospital, Dublin 2, D02 XK51 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. Jane","family":"Farrar","sequence":"additional","affiliation":[{"name":"The School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, D02 VF25 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1684-1598","authenticated-orcid":false,"given":"Naomi","family":"Chadderton","sequence":"additional","affiliation":[{"name":"The School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, D02 VF25 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"238","DOI":"10.2174\/138920211795860107","article-title":"Retinitis pigmentosa: Genes and disease mechanisms","volume":"12","author":"Parmeggiani","year":"2011","journal-title":"Curr. Genom."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1167\/iovs.06-0971","article-title":"Disease course of patients with X-linked retinitis pigmentosa due to RPGR gene mutations","volume":"48","author":"Sandberg","year":"2007","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1086\/379379","article-title":"RP2 and RPGR Mutations and Clinical Correlations in Patients with X-Linked Retinitis Pigmentosa","volume":"73","author":"Sharon","year":"2003","journal-title":"Am. J. Hum. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"8232","DOI":"10.1167\/iovs.12-11025","article-title":"Mutations in RPGR and RP2 account for 15% of males with simplex retinal degenerative disease","volume":"53","author":"Branham","year":"2012","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.1016\/j.ophtha.2015.05.039","article-title":"Visual Function in Carriers of X-linked RetinitisPigmentosa","volume":"122","author":"Comander","year":"2015","journal-title":"Ophthalmology"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Yang, J., Zhou, L., Ouyang, J., Xiao, X., Sun, W., Li, S., and Zhang, Q. (2021). Genotype\u2013Phenotype Analysis of RPGR Variations: Reporting of 62 Chinese Families and a Literature Review. Front. Genet., 12.","DOI":"10.3389\/fgene.2021.600210"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Gocuk, S.A., Edwards, T.L., Jolly, J.K., Chen, F.K., Sousa, D.C., McGuinness, M.B., McLaren, T.L., Lamey, T.M., Thompson, J.A., and Ayton, L.N. (2025). Retinal Disease Variability in Female Carriers of RPGR Variants Associated with Retinitis Pigmentosa: Clinical and Genetic Parameters. Genes, 16.","DOI":"10.3390\/genes16020221"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"D980","DOI":"10.1093\/nar\/gkt1113","article-title":"ClinVar: Public archive of relationships among sequence variation and human phenotype","volume":"42","author":"Landrum","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1146\/annurev-biochem-060614-034316","article-title":"Mechanisms and Regulation of Alternative Pre-mRNA Splicing","volume":"84","author":"Lee","year":"2015","journal-title":"Annu. Rev. Biochem."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Qian, X., Wang, J., Wang, M., Igelman, A.D., Jones, K.D., Li, Y., Wang, K., Goetz, K.E., Birch, D.G., and Yang, P. (2021). Identification of Deep-Intronic Splice Mutations in a Large Cohort of Patients With Inherited Retinal Diseases. Front. Genet., 12.","DOI":"10.3389\/fgene.2021.647400"},{"key":"ref_11","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":"Sangermano","year":"2019","journal-title":"Genet. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9380","DOI":"10.1038\/s41598-023-35889-9","article-title":"Detailed analysis of an enriched deep intronic ABCA4 variant in Irish Stargardt disease patients","volume":"13","author":"Whelan","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"100237","DOI":"10.1016\/j.xhgg.2023.100237","article-title":"Targeted sequencing and in vitro splice assays shed light on ABCA4-associated retinopathies missing heritability","volume":"4","author":"Corradi","year":"2023","journal-title":"Hum. Genet. Genom. Adv."},{"key":"ref_14","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":"Stenson","year":"2020","journal-title":"Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/s41525-025-00500-9","article-title":"New genetic diagnoses for inherited retinal dystrophies by integrating splicing tools into NGS pipelines","volume":"10","author":"Pozo","year":"2025","journal-title":"npj Genom. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.1093\/nar\/gkn073","article-title":"Human branch point consensus sequence is yUnAy","volume":"36","author":"Gao","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"a003707","DOI":"10.1101\/cshperspect.a003707","article-title":"Spliceosome Structure and Function","volume":"3","author":"Will","year":"2011","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.tig.2012.01.001","article-title":"New connections between splicing and human disease","volume":"28","author":"Padgett","year":"2012","journal-title":"Trends Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3078","DOI":"10.1093\/hmg\/ddad129","article-title":"Stargardt disease-associated missense and synonymous ABCA4 variants result in aberrant splicing","volume":"32","author":"Kaltak","year":"2023","journal-title":"Hum. Mol. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_21","unstructured":"Ellard, S., Baple, E.L., Callaway, A., Berry, I., Forrester, N., Turnball, C., Owens, M., Eccles, D.M., Abbs, S., and Scott, R. (2020). ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2020 Recommendations Ratified by ACGS Quality Subcommittee on 4 th Febuary 2020 (Version 4.01), ACGS."},{"key":"ref_22","unstructured":"Durkie, M., Cassidy, E.-J., Berry, I., Owens, M., Turnbull, C., Scott, R.H., Taylor, R.W., Deans, Z.C., Ellard, S., and Baple, E.L. (2024). ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2024, ACGS. Available online: http:\/\/gnomad.broadinstitute.org\/."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2235","DOI":"10.1056\/NEJMsr1406261","article-title":"ClinGen\u2014The Clinical Genome Resource","volume":"372","author":"Rehm","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_24","unstructured":"ClinGen Consortium (2025). The Clinical Genome Resource (ClinGen): Advancing genomic knowledge through global curation. Genet. Med., 27, 101228."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.ajhg.2023.11.009","article-title":"ClinGen guidance for use of the PP1\/BS4 co-segregation and PP4 phenotype specificity criteria for sequence variant pathogenicity classification","volume":"111","author":"Biesecker","year":"2024","journal-title":"Am. J. Hum. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s40246-023-00451-1","article-title":"SpliceAI-visual: A free online tool to improve SpliceAI splicing variant interpretation","volume":"17","author":"Filser","year":"2023","journal-title":"Hum. Genom."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1016\/j.ajhg.2023.06.002","article-title":"Using the ACMG\/AMP framework to capture evidence related to predicted and observed impact on splicing: Recommendations from the ClinGen SVI Splicing Subgroup","volume":"110","author":"Walker","year":"2023","journal-title":"Am. J. Hum. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1101\/gr.226621.117","article-title":"ABCA4 midigenes reveal the full splice spectrum of all reported noncanonical splice site variants in Stargardt disease","volume":"28","author":"Sangermano","year":"2018","journal-title":"Genome Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"33248","DOI":"10.1038\/srep33248","article-title":"Panel-Based population next-generation sequencing for inherited retinal degenerations","volume":"6","author":"Carrigan","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Dockery, A., Stephenson, K., Keegan, D., Wynne, N., Silvestri, G., Humphries, P., Kenna, P.F., Carrigan, M., and Farrar, G.J. (2017). Target 5000: Target capture sequencing for inherited retinal degenerations. Genes, 8.","DOI":"10.3390\/genes8110304"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Whelan, L., Dockery, A., Wynne, N., Zhu, J., Stephenson, K., Silvestri, G., Turner, J., O\u2019byrne, J.J., Carrigan, M., and Humphries, P. (2020). Findings from a genotyping study of over 1000 people with inherited retinal disorders in Ireland. Genes, 11.","DOI":"10.3390\/genes11010105"},{"key":"ref_32","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":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1038\/s41431-021-00959-x","article-title":"The LOVD3 platform: Efficient genome-wide sharing of genetic variants","volume":"29","author":"Fokkema","year":"2021","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1093\/hmg\/ddu733","article-title":"Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies","volume":"24","author":"Dong","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1038\/ng.3703","article-title":"M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity","volume":"48","author":"Jagadeesh","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.ajhg.2016.08.016","article-title":"REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants","volume":"99","author":"Ioannidis","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1016\/j.ajhg.2022.10.013","article-title":"Calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for PP3\/BP4 criteria","volume":"109","author":"Pejaver","year":"2022","journal-title":"Am. J. Hum. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"101547","DOI":"10.1016\/j.gimo.2024.101547","article-title":"P641: Application of AlphaMissense prediction to pathogenicity classification of missense variants from clinical exome sequencing","volume":"2","author":"Zhuo","year":"2024","journal-title":"Genet. Med. Open"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"vbaf093","DOI":"10.1093\/bioadv\/vbaf093","article-title":"AlphaMissenseR: An integrated framework for investigating missense mutations in human protein-coding genes","volume":"5","author":"Nguyen","year":"2024","journal-title":"Bioinform. Adv."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2365","DOI":"10.1002\/humu.23890","article-title":"Identification of splice defects due to noncanonical splice site or deep-intronic variants in ABCA4","volume":"40","author":"Fadaie","year":"2019","journal-title":"Hum. Mutat."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1093\/hmg\/7.5.919","article-title":"Statistical Features of Human Exons and Their Flanking Regions","volume":"7","author":"Zhang","year":"1998","journal-title":"Hum. Mol. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1089\/1066527041410418","article-title":"Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals","volume":"11","author":"Yeo","year":"2004","journal-title":"J. Comput. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1089\/cmb.1997.4.311","article-title":"Improved splice site detection in Genie","volume":"4","author":"Reese","year":"1997","journal-title":"J. Comput. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1093\/nar\/29.5.1185","article-title":"GeneSplicer: A new computational method for splice site prediction","volume":"29","author":"Pertea","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"ref_45","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":"Khan","year":"2020","journal-title":"Genet. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1016\/j.ophtha.2016.01.053","article-title":"Photoreceptor Progenitor mRNA Analysis Reveals Exon Skipping Resulting from the ABCA4 c.5461-10T\u2192C Mutation in Stargardt Disease","volume":"123","author":"Sangermano","year":"2016","journal-title":"Ophthalmology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"D368","DOI":"10.1093\/nar\/gkad1011","article-title":"AlphaFold Protein Structure Database in 2024: Providing structure coverage for over 214 million protein sequences","volume":"52","author":"Varadi","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_48","unstructured":"The UniProt Consortium (2022). UniProt: The Universal Protein Knowledgebase in 2023. Nucleic Acids Res., 51, D523."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1002\/1098-1004(200102)17:2<151::AID-HUMU7>3.0.CO;2-W","article-title":"Five Novel RPGR Mutations in Families with X-Linked Retinitis Pigmentosa","volume":"17","author":"Fahrner","year":"2001","journal-title":"Hum. Mutat."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1016\/j.ajo.2015.06.032","article-title":"Multimodal imaging of central retinal disease progression in a 2 year mean follow up of Retinitis Pigmentosa","volume":"160","author":"Sujirakul","year":"2015","journal-title":"Am. J. Ophthalmol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4457","DOI":"10.1167\/iovs.17-22077","article-title":"High Symmetry of Visual Acuity and Visual Fields in RPGR-Linked Retinitis Pigmentosa","volume":"58","author":"Bellingrath","year":"2017","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3364","DOI":"10.1038\/s41598-020-60137-9","article-title":"Disease asymmetry and hyperautofluorescent ring shape in retinitis pigmentosa patients","volume":"10","author":"Jauregui","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.exer.2015.06.007","article-title":"RPGR: Its role in photoreceptor physiology, human disease, and future therapies","volume":"138","author":"Megaw","year":"2015","journal-title":"Exp. Eye Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1167\/tvst.11.1.6","article-title":"Prevalence of RPGR-Mediated Retinal Dystrophy in an Unselected Cohort of Over 5000 Patients","volume":"11","author":"Tuupanen","year":"2022","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1038\/78182","article-title":"Mutational hot spot within a new RPGR exon in X-linked retinitis pigmentosa","volume":"25","author":"Vervoort","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Ridgeway, A.R., Shortall, C., Finnegan, L.K., Long, R., Matthews, E., Dockery, A., Kop\u010di\u0107, E., Whelan, L., Kirk, C., and Silvestri, G. (2025). Novel Splice-Altering Variants in the CHM and CACNA1F Genes Causative of X-Linked Choroideremia and Cone Dystrophy. Genes, 16.","DOI":"10.3390\/genes16010025"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1016\/j.stem.2016.03.021","article-title":"Identification and Correction of Mechanisms Underlying Inherited Blindness in Human iPSC-Derived Optic Cups","volume":"18","author":"Parfitt","year":"2016","journal-title":"Cell Stem Cell"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.ajhg.2018.02.008","article-title":"Identification and Rescue of Splice Defects Caused by Two Neighboring Deep-Intronic ABCA4 Mutations Underlying Stargardt Disease","volume":"102","author":"Albert","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Galindo-Cabello, N., Caballano-Infantes, E., Benites, G., Pastor-Idoate, S., Diaz-Corrales, F.J., and Usategui-Mart\u00edn, R. (2025). Retinal Organoids: Innovative Tools for Understanding Retinal Degeneration. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26073263"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1111\/joa.13768","article-title":"Retinal organoids provide unique insights into molecular signatures of inherited retinal disease throughout retinogenesis","volume":"243","author":"Watson","year":"2023","journal-title":"J. Anat."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1172\/JCI118800","article-title":"An intronic mutation in a lariat branchpoint sequence is a direct cause of an inherited human disorder (fish-eye disease)","volume":"98","author":"Kuivenhoven","year":"1996","journal-title":"J. Clin. Investig."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1136\/jmedgenet-2020-107626","article-title":"BBS1 branchpoint variant is associated with non-syndromic retinitis pigmentosa","volume":"59","author":"Fadaie","year":"2022","journal-title":"J. Med. Genet."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1167\/iovs.63.4.20","article-title":"ABCA4 c.859-25A>G, a Frequent Palestinian Founder Mutation Affecting the Intron 7 Branchpoint, Is Associated With Early-Onset Stargardt Disease","volume":"63","author":"Corradi","year":"2022","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Rodr\u00edguez-Hidalgo, M., de Bruijn, S.E., Corradi, Z., Rodenburg, K., Lara-L\u00f3pez, A., Valverde-Meg\u00edas, A., \u00c1vila-Fern\u00e1ndez, A., Fernandez-Caballero, L., Del Pozo-Valero, M., and Corominas, J. (2023). ABCA4 c.6480-35A>G, a novel branchpoint variant associated with Stargardt disease. Front. Genet., 14.","DOI":"10.3389\/fgene.2023.1234032"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"R1","DOI":"10.1186\/gb-2006-7-1-r1","article-title":"A class of human exons with predicted distant branch points revealed by analysis of AG dinucleotide exclusion zones","volume":"7","author":"Gooding","year":"2006","journal-title":"Genome Biol."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Leman, R., Tubeuf, H., Raad, S., Tournier, I., Derambure, C., Lanos, R., Gaildrat, P., Castelain, G., Hauchard, J., and Killian, A. (2020). Assessment of branch point prediction tools to predict physiological branch points and their alteration by variants. BMC Genom., 21.","DOI":"10.1186\/s12864-020-6484-5"},{"key":"ref_67","unstructured":"(2026, April 01). ClinicalTrials.gov, Available online: https:\/\/clinicaltrials.gov\/."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/6\/715\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T05:02:00Z","timestamp":1782536520000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/6\/715"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,21]]},"references-count":67,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["genes17060715"],"URL":"https:\/\/doi.org\/10.3390\/genes17060715","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,21]]}}}