A Description of the Yield of Genetic Reinvestigation in Patients with Inherited Retinal Dystrophies and Previous Inconclusive Genetic Testing
In the present era of evolving gene-based therapies for inherited retinal dystrophies (IRDs), it has become increasingly important to verify the genotype in every case, to identify all subjects eligible for treatment. Moreover, combined insight concerning phenotypes and genotypes is crucial for impr...
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MDPI AG
2023-07-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/14/7/1413 |
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| author | Maria Areblom Sten Kjellström Sten Andréasson Anders Öhberg Lotta Gränse Ulrika Kjellström |
| author_facet | Maria Areblom Sten Kjellström Sten Andréasson Anders Öhberg Lotta Gränse Ulrika Kjellström |
| author_sort | Maria Areblom |
| collection | DOAJ |
| description | In the present era of evolving gene-based therapies for inherited retinal dystrophies (IRDs), it has become increasingly important to verify the genotype in every case, to identify all subjects eligible for treatment. Moreover, combined insight concerning phenotypes and genotypes is crucial for improved understanding of thevisual impairment, prognosis, and inheritance. The objective of this study was to investigate to what extent renewed comprehensive genetic testing of patients diagnosed with IRD but with previously inconclusive DNA test results can verify the genotype, if confirmation of the genotype has an impact on the understanding of the clinical picture, and, to describe the genetic spectrum encountered in a Swedish IRD cohort. The study included 279 patients from the retinitis pigmentosa research registry (comprising diagnosis within the whole IRD spectrum), hosted at the Department of Ophthalmology, Skåne University hospital, Sweden. The phenotypes had already been evaluated with electrophysiology and other clinical tests, e.g., visual acuity, Goldmann perimetry, and fundus imaging at the first visit, sometime between 1988–2015 and the previous—in many cases, multiple—genetic testing, performed between 1995 and 2020 had been inconclusive. All patients were aged 0–25 years at the time of their first visit. Renewed genetic testing was performed using a next generation sequencing (NGS) IRD panel including 322 genes (Blueprint Genetics). Class 5 and 4 variants, according to ACMG guidelines, were considered pathogenic. Of the 279 samples tested, a confirmed genotype was determined in 182 (65%). The cohort was genetically heterogenous, including 65 different genes. The most prevailing were <i>ABCA4</i> (16.5%)<i>, RPGR</i> (6%), <i>CEP290</i> (6%), and <i>RS1</i> (5.5%). Other prevalent genes were <i>CACNA1F</i> (3%), <i>PROM1</i> (3%)<i>, CHM</i> (3%)<i>,</i> and <i>NYX</i> (3%). In 7% of the patients there was a discrepancy between the diagnosis made based on phenotypical or genotypical findings alone. To conclude, repeated DNA-analysis was beneficial also in previously tested patients and improved our ability to verify the genotype–phenotype association increasing the understanding of how visual impairment manifests, prognosis, and the inheritance pattern. Moreover, repeated testing using a widely available method could identify additional patients eligible for future gene-based therapies. |
| first_indexed | 2024-03-11T01:02:59Z |
| format | Article |
| id | doaj.art-aedf4572aa9d497f94f771f73ee897af |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-11T01:02:59Z |
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| spelling | doaj.art-aedf4572aa9d497f94f771f73ee897af2023-11-18T19:30:09ZengMDPI AGGenes2073-44252023-07-01147141310.3390/genes14071413A Description of the Yield of Genetic Reinvestigation in Patients with Inherited Retinal Dystrophies and Previous Inconclusive Genetic TestingMaria Areblom0Sten Kjellström1Sten Andréasson2Anders Öhberg3Lotta Gränse4Ulrika Kjellström5Ophthalmology, Department of Clinical Sciences Lund, Lund University, Skane University Hospital, 221 85 Lund, SwedenS:t Erik Eye Hospital, 171 64 Solna, SwedenOphthalmology, Department of Clinical Sciences Lund, Lund University, Skane University Hospital, 221 85 Lund, SwedenNovartis Sverige AB, 164 40 Stockholm, SwedenOphthalmology, Department of Clinical Sciences Lund, Lund University, Skane University Hospital, 221 85 Lund, SwedenOphthalmology, Department of Clinical Sciences Lund, Lund University, Skane University Hospital, 221 85 Lund, SwedenIn the present era of evolving gene-based therapies for inherited retinal dystrophies (IRDs), it has become increasingly important to verify the genotype in every case, to identify all subjects eligible for treatment. Moreover, combined insight concerning phenotypes and genotypes is crucial for improved understanding of thevisual impairment, prognosis, and inheritance. The objective of this study was to investigate to what extent renewed comprehensive genetic testing of patients diagnosed with IRD but with previously inconclusive DNA test results can verify the genotype, if confirmation of the genotype has an impact on the understanding of the clinical picture, and, to describe the genetic spectrum encountered in a Swedish IRD cohort. The study included 279 patients from the retinitis pigmentosa research registry (comprising diagnosis within the whole IRD spectrum), hosted at the Department of Ophthalmology, Skåne University hospital, Sweden. The phenotypes had already been evaluated with electrophysiology and other clinical tests, e.g., visual acuity, Goldmann perimetry, and fundus imaging at the first visit, sometime between 1988–2015 and the previous—in many cases, multiple—genetic testing, performed between 1995 and 2020 had been inconclusive. All patients were aged 0–25 years at the time of their first visit. Renewed genetic testing was performed using a next generation sequencing (NGS) IRD panel including 322 genes (Blueprint Genetics). Class 5 and 4 variants, according to ACMG guidelines, were considered pathogenic. Of the 279 samples tested, a confirmed genotype was determined in 182 (65%). The cohort was genetically heterogenous, including 65 different genes. The most prevailing were <i>ABCA4</i> (16.5%)<i>, RPGR</i> (6%), <i>CEP290</i> (6%), and <i>RS1</i> (5.5%). Other prevalent genes were <i>CACNA1F</i> (3%), <i>PROM1</i> (3%)<i>, CHM</i> (3%)<i>,</i> and <i>NYX</i> (3%). In 7% of the patients there was a discrepancy between the diagnosis made based on phenotypical or genotypical findings alone. To conclude, repeated DNA-analysis was beneficial also in previously tested patients and improved our ability to verify the genotype–phenotype association increasing the understanding of how visual impairment manifests, prognosis, and the inheritance pattern. Moreover, repeated testing using a widely available method could identify additional patients eligible for future gene-based therapies.https://www.mdpi.com/2073-4425/14/7/1413inherited retinal dystrophynext generation sequencingDNA analysisphenotype–genotype correlationre-analysis |
| spellingShingle | Maria Areblom Sten Kjellström Sten Andréasson Anders Öhberg Lotta Gränse Ulrika Kjellström A Description of the Yield of Genetic Reinvestigation in Patients with Inherited Retinal Dystrophies and Previous Inconclusive Genetic Testing Genes inherited retinal dystrophy next generation sequencing DNA analysis phenotype–genotype correlation re-analysis |
| title | A Description of the Yield of Genetic Reinvestigation in Patients with Inherited Retinal Dystrophies and Previous Inconclusive Genetic Testing |
| title_full | A Description of the Yield of Genetic Reinvestigation in Patients with Inherited Retinal Dystrophies and Previous Inconclusive Genetic Testing |
| title_fullStr | A Description of the Yield of Genetic Reinvestigation in Patients with Inherited Retinal Dystrophies and Previous Inconclusive Genetic Testing |
| title_full_unstemmed | A Description of the Yield of Genetic Reinvestigation in Patients with Inherited Retinal Dystrophies and Previous Inconclusive Genetic Testing |
| title_short | A Description of the Yield of Genetic Reinvestigation in Patients with Inherited Retinal Dystrophies and Previous Inconclusive Genetic Testing |
| title_sort | description of the yield of genetic reinvestigation in patients with inherited retinal dystrophies and previous inconclusive genetic testing |
| topic | inherited retinal dystrophy next generation sequencing DNA analysis phenotype–genotype correlation re-analysis |
| url | https://www.mdpi.com/2073-4425/14/7/1413 |
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