{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:24:40Z","timestamp":1787315080407,"version":"build-2736575974"},"reference-count":44,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,17]],"date-time":"2022-01-17T00:00:00Z","timestamp":1642377600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fighting Blindness","award":["FB16FAR, FB18CRE, FB20DOC"],"award-info":[{"award-number":["FB16FAR, FB18CRE, FB20DOC"]}]},{"name":"Health Reasearch Board of Ireland","award":["POR\/2010\/97"],"award-info":[{"award-number":["POR\/2010\/97"]}]},{"name":"Health Research Charities Ireland","award":["MRCG-2013-8, MRCG-2016-14"],"award-info":[{"award-number":["MRCG-2013-8, MRCG-2016-14"]}]},{"DOI":"10.13039\/501100002081","name":"Irish Research Council","doi-asserted-by":"publisher","award":["GOIPG\/2017\/1631"],"award-info":[{"award-number":["GOIPG\/2017\/1631"]}],"id":[{"id":"10.13039\/501100002081","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001602","name":"Science Foundation Ireland","doi-asserted-by":"publisher","award":["16\/1A\/4452"],"award-info":[{"award-number":["16\/1A\/4452"]}],"id":[{"id":"10.13039\/501100001602","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Although rare, inherited retinal degenerations (IRDs) are the most common reason for blind registration in the working age population. They are highly genetically heterogeneous (&gt;300 known genetic loci), and confirmation of a molecular diagnosis is a prerequisite for many therapeutic clinical trials and approved treatments. First-tier genetic testing of IRDs with panel-based next-generation sequencing (pNGS) has a diagnostic yield of \u224870\u201380%, leaving the remaining more challenging cases to be resolved by second-tier testing methods. This study describes the phenotypic reassessment of patients with a negative result from first-tier pNGS and the rationale, outcomes, and cost of second-tier genetic testing approaches. Removing non-IRD cases from consideration and utilizing case-appropriate second-tier genetic testing techniques, we genetically resolved 56% of previously unresolved pedigrees, bringing the overall resolve rate to 92% (388\/423). At present, pNGS remains the most cost-effective first-tier approach for the molecular assessment of diverse IRD populations Second-tier genetic testing should be guided by clinical (i.e., reassessment, multimodal imaging, electrophysiology), and genetic (i.e., single alleles in autosomal recessive disease) indications to achieve a genetic diagnosis in the most cost-effective manner.<\/jats:p>","DOI":"10.3390\/ijms23020995","type":"journal-article","created":{"date-parts":[[2022,1,17]],"date-time":"2022-01-17T08:20:42Z","timestamp":1642407642000},"page":"995","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Clinical and Genetic Re-Evaluation of Inherited Retinal Degeneration Pedigrees following Initial Negative Findings on Panel-Based Next Generation Sequencing"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7462-7725","authenticated-orcid":false,"given":"Kirk A. J.","family":"Stephenson","sequence":"first","affiliation":[{"name":"Mater Clinical Ophthalmic Genetics Unit, The Mater Misericordiae University Hospital, D07 R2WY Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Zhu","sequence":"additional","affiliation":[{"name":"Mater Clinical Ophthalmic Genetics Unit, The Mater Misericordiae University Hospital, D07 R2WY 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":"Next Generation Sequencing Laboratory, Pathology Department, The Mater Misericordiae University Hospital, D07 R2WY Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Whelan","sequence":"additional","affiliation":[{"name":"The School of Genetics & Microbiology, Trinity College Dublin, D02 PN40 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom\u00e1s","family":"Burke","sequence":"additional","affiliation":[{"name":"Mater Clinical Ophthalmic Genetics Unit, The Mater Misericordiae University Hospital, D07 R2WY Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Turner","sequence":"additional","affiliation":[{"name":"Mater Clinical Ophthalmic Genetics Unit, The Mater Misericordiae University Hospital, D07 R2WY Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James J.","family":"O\u2019Byrne","sequence":"additional","affiliation":[{"name":"Mater Clinical Ophthalmic Genetics Unit, The Mater Misericordiae University Hospital, D07 R2WY Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. Jane","family":"Farrar","sequence":"additional","affiliation":[{"name":"The School of Genetics & Microbiology, Trinity College Dublin, D02 PN40 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Keegan","sequence":"additional","affiliation":[{"name":"Mater Clinical Ophthalmic Genetics Unit, The Mater Misericordiae University Hospital, D07 R2WY Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,17]]},"reference":[{"key":"ref_1","unstructured":"Daiger, S.P. (2021, October 05). Summaries of Genes and Loci Causing Retinal Diseases (RetNet). 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