Detailed analysis of an enriched deep intronic ABCA4 variant in Irish Stargardt disease patients
Abstract Over 15% of probands in a large cohort of more than 1500 inherited retinal degeneration patients present with a clinical diagnosis of Stargardt disease (STGD1), a recessive form of macular dystrophy caused by biallelic variants in the ABCA4 gene. Participants were clinically examined and un...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-06-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-35889-9 |
| _version_ | 1797806736916086784 |
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| author | Laura Whelan Adrian Dockery Kirk A. J. Stephenson Julia Zhu Ella Kopčić Iris J. M. Post Mubeen Khan Zelia Corradi Niamh Wynne James J. O’ Byrne Emma Duignan Giuliana Silvestri Susanne Roosing Frans P. M. Cremers David J. Keegan Paul F. Kenna G. Jane Farrar |
| author_facet | Laura Whelan Adrian Dockery Kirk A. J. Stephenson Julia Zhu Ella Kopčić Iris J. M. Post Mubeen Khan Zelia Corradi Niamh Wynne James J. O’ Byrne Emma Duignan Giuliana Silvestri Susanne Roosing Frans P. M. Cremers David J. Keegan Paul F. Kenna G. Jane Farrar |
| author_sort | Laura Whelan |
| collection | DOAJ |
| description | Abstract Over 15% of probands in a large cohort of more than 1500 inherited retinal degeneration patients present with a clinical diagnosis of Stargardt disease (STGD1), a recessive form of macular dystrophy caused by biallelic variants in the ABCA4 gene. Participants were clinically examined and underwent either target capture sequencing of the exons and some pathogenic intronic regions of ABCA4, sequencing of the entire ABCA4 gene or whole genome sequencing. ABCA4 c.4539 + 2028C > T, p.[= ,Arg1514Leufs*36] is a pathogenic deep intronic variant that results in a retina-specific 345-nucleotide pseudoexon inclusion. Through analysis of the Irish STGD1 cohort, 25 individuals across 18 pedigrees harbour ABCA4 c.4539 + 2028C > T and another pathogenic variant. This includes, to the best of our knowledge, the only two homozygous patients identified to date. This provides important evidence of variant pathogenicity for this deep intronic variant, highlighting the value of homozygotes for variant interpretation. 15 other heterozygous incidents of this variant in patients have been reported globally, indicating significant enrichment in the Irish population. We provide detailed genetic and clinical characterization of these patients, illustrating that ABCA4 c.4539 + 2028C > T is a variant of mild to intermediate severity. These results have important implications for unresolved STGD1 patients globally with approximately 10% of the population in some western countries claiming Irish heritage. This study exemplifies that detection and characterization of founder variants is a diagnostic imperative. |
| first_indexed | 2024-03-13T06:11:50Z |
| format | Article |
| id | doaj.art-c46ab88922e84dc084946bcf34d83944 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-13T06:11:50Z |
| publishDate | 2023-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-c46ab88922e84dc084946bcf34d839442023-06-11T11:14:18ZengNature PortfolioScientific Reports2045-23222023-06-0113111610.1038/s41598-023-35889-9Detailed analysis of an enriched deep intronic ABCA4 variant in Irish Stargardt disease patientsLaura Whelan0Adrian Dockery1Kirk A. J. Stephenson2Julia Zhu3Ella Kopčić4Iris J. M. Post5Mubeen Khan6Zelia Corradi7Niamh Wynne8James J. O’ Byrne9Emma Duignan10Giuliana Silvestri11Susanne Roosing12Frans P. M. Cremers13David J. Keegan14Paul F. Kenna15G. Jane Farrar16The School of Genetics and Microbiology, Trinity College DublinThe School of Genetics and Microbiology, Trinity College DublinDepartment of Ophthalmology, Royal Victoria Eye and Ear HospitalMater Clinical Ophthalmic Genetics Unit, The Mater Misericordiae University HospitalThe School of Genetics and Microbiology, Trinity College DublinThe School of Genetics and Microbiology, Trinity College DublinDepartment of Human Genetics, Radboud University Medical CenterDepartment of Human Genetics, Radboud University Medical CenterDepartment of Ophthalmology, Royal Victoria Eye and Ear HospitalMater Clinical Ophthalmic Genetics Unit, The Mater Misericordiae University HospitalDepartment of Ophthalmology, Royal Victoria Eye and Ear HospitalCentre for Experimental Medicine, Queen’s University BelfastDepartment of Human Genetics, Radboud University Medical CenterDepartment of Human Genetics, Radboud University Medical CenterMater Clinical Ophthalmic Genetics Unit, The Mater Misericordiae University HospitalThe School of Genetics and Microbiology, Trinity College DublinThe School of Genetics and Microbiology, Trinity College DublinAbstract Over 15% of probands in a large cohort of more than 1500 inherited retinal degeneration patients present with a clinical diagnosis of Stargardt disease (STGD1), a recessive form of macular dystrophy caused by biallelic variants in the ABCA4 gene. Participants were clinically examined and underwent either target capture sequencing of the exons and some pathogenic intronic regions of ABCA4, sequencing of the entire ABCA4 gene or whole genome sequencing. ABCA4 c.4539 + 2028C > T, p.[= ,Arg1514Leufs*36] is a pathogenic deep intronic variant that results in a retina-specific 345-nucleotide pseudoexon inclusion. Through analysis of the Irish STGD1 cohort, 25 individuals across 18 pedigrees harbour ABCA4 c.4539 + 2028C > T and another pathogenic variant. This includes, to the best of our knowledge, the only two homozygous patients identified to date. This provides important evidence of variant pathogenicity for this deep intronic variant, highlighting the value of homozygotes for variant interpretation. 15 other heterozygous incidents of this variant in patients have been reported globally, indicating significant enrichment in the Irish population. We provide detailed genetic and clinical characterization of these patients, illustrating that ABCA4 c.4539 + 2028C > T is a variant of mild to intermediate severity. These results have important implications for unresolved STGD1 patients globally with approximately 10% of the population in some western countries claiming Irish heritage. This study exemplifies that detection and characterization of founder variants is a diagnostic imperative.https://doi.org/10.1038/s41598-023-35889-9 |
| spellingShingle | Laura Whelan Adrian Dockery Kirk A. J. Stephenson Julia Zhu Ella Kopčić Iris J. M. Post Mubeen Khan Zelia Corradi Niamh Wynne James J. O’ Byrne Emma Duignan Giuliana Silvestri Susanne Roosing Frans P. M. Cremers David J. Keegan Paul F. Kenna G. Jane Farrar Detailed analysis of an enriched deep intronic ABCA4 variant in Irish Stargardt disease patients Scientific Reports |
| title | Detailed analysis of an enriched deep intronic ABCA4 variant in Irish Stargardt disease patients |
| title_full | Detailed analysis of an enriched deep intronic ABCA4 variant in Irish Stargardt disease patients |
| title_fullStr | Detailed analysis of an enriched deep intronic ABCA4 variant in Irish Stargardt disease patients |
| title_full_unstemmed | Detailed analysis of an enriched deep intronic ABCA4 variant in Irish Stargardt disease patients |
| title_short | Detailed analysis of an enriched deep intronic ABCA4 variant in Irish Stargardt disease patients |
| title_sort | detailed analysis of an enriched deep intronic abca4 variant in irish stargardt disease patients |
| url | https://doi.org/10.1038/s41598-023-35889-9 |
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