Cargando…
Prevalence of RPGR-Mediated Retinal Dystrophy in an Unselected Cohort of Over 5000 Patients
PURPOSE: Comprehensive genetic testing for inherited retinal dystrophy (IRD) is challenged by difficult-to-sequence genomic regions, which are often mutational hotspots, such as RPGR ORF15. The purpose of this study was to evaluate the diagnostic contribution of RPGR variants in an unselected IRD pa...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Association for Research in Vision and Ophthalmology
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8742508/ https://www.ncbi.nlm.nih.gov/pubmed/34985506 http://dx.doi.org/10.1167/tvst.11.1.6 |
_version_ | 1784629729048920064 |
---|---|
author | Tuupanen, Sari Gall, Kimberly Sistonen, Johanna Saarinen, Inka Kämpjärvi, Kati Wells, Kirsty Merkkiniemi, Katja von Nandelstadh, Pernilla Sarantaus, Laura Känsäkoski, Johanna Mårtenson, Emma Västinsalo, Hanna Schleit, Jennifer Sankila, Eeva-Marja Kere, Annakarin Junnila, Heidi Siivonen, Pauli Andreevskaya, Margarita Kytölä, Ville Muona, Mikko Salmenperä, Pertteli Myllykangas, Samuel Koskenvuo, Juha Alastalo, Tero-Pekka |
author_facet | Tuupanen, Sari Gall, Kimberly Sistonen, Johanna Saarinen, Inka Kämpjärvi, Kati Wells, Kirsty Merkkiniemi, Katja von Nandelstadh, Pernilla Sarantaus, Laura Känsäkoski, Johanna Mårtenson, Emma Västinsalo, Hanna Schleit, Jennifer Sankila, Eeva-Marja Kere, Annakarin Junnila, Heidi Siivonen, Pauli Andreevskaya, Margarita Kytölä, Ville Muona, Mikko Salmenperä, Pertteli Myllykangas, Samuel Koskenvuo, Juha Alastalo, Tero-Pekka |
author_sort | Tuupanen, Sari |
collection | PubMed |
description | PURPOSE: Comprehensive genetic testing for inherited retinal dystrophy (IRD) is challenged by difficult-to-sequence genomic regions, which are often mutational hotspots, such as RPGR ORF15. The purpose of this study was to evaluate the diagnostic contribution of RPGR variants in an unselected IRD patient cohort referred for testing in a clinical diagnostic laboratory. METHODS: A total of 5201 consecutive patients were analyzed with a clinically validated next-generation sequencing (NGS)–based assay, including the difficult-to-sequence RPGR ORF15 region. Copy number variant (CNV) detection from NGS data was included. Variant interpretation was performed per the American College of Medical Genetics and Genomics guidelines. RESULTS: A confirmed molecular diagnosis in RPGR was found in 4.5% of patients, 24.0% of whom were females. Variants in ORF15 accounted for 74% of the diagnoses; 29% of the diagnostic variants were in the most difficult-to-sequence central region of ORF15 (c.2470-3230). Truncating variants made up the majority (91%) of the diagnostic variants. CNVs explained 2% of the diagnostic cases, of which 80% were one- or two-exon deletions outside of ORF15. CONCLUSIONS: Our findings indicate that high-throughput, clinically validated NGS-based testing covering the difficult-to-sequence region of ORF15, in combination with high-resolution CNV detection, can help to maximize the diagnostic yield for patients with IRD. TRANSLATIONAL RELEVANCE: These results demonstrate an accurate and scalable method for the detection of RPGR-related variants, including the difficult-to-sequence ORF15 hotspot, which is relevant given current and emerging therapeutic opportunities. |
format | Online Article Text |
id | pubmed-8742508 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | The Association for Research in Vision and Ophthalmology |
record_format | MEDLINE/PubMed |
spelling | pubmed-87425082022-01-18 Prevalence of RPGR-Mediated Retinal Dystrophy in an Unselected Cohort of Over 5000 Patients Tuupanen, Sari Gall, Kimberly Sistonen, Johanna Saarinen, Inka Kämpjärvi, Kati Wells, Kirsty Merkkiniemi, Katja von Nandelstadh, Pernilla Sarantaus, Laura Känsäkoski, Johanna Mårtenson, Emma Västinsalo, Hanna Schleit, Jennifer Sankila, Eeva-Marja Kere, Annakarin Junnila, Heidi Siivonen, Pauli Andreevskaya, Margarita Kytölä, Ville Muona, Mikko Salmenperä, Pertteli Myllykangas, Samuel Koskenvuo, Juha Alastalo, Tero-Pekka Transl Vis Sci Technol Article PURPOSE: Comprehensive genetic testing for inherited retinal dystrophy (IRD) is challenged by difficult-to-sequence genomic regions, which are often mutational hotspots, such as RPGR ORF15. The purpose of this study was to evaluate the diagnostic contribution of RPGR variants in an unselected IRD patient cohort referred for testing in a clinical diagnostic laboratory. METHODS: A total of 5201 consecutive patients were analyzed with a clinically validated next-generation sequencing (NGS)–based assay, including the difficult-to-sequence RPGR ORF15 region. Copy number variant (CNV) detection from NGS data was included. Variant interpretation was performed per the American College of Medical Genetics and Genomics guidelines. RESULTS: A confirmed molecular diagnosis in RPGR was found in 4.5% of patients, 24.0% of whom were females. Variants in ORF15 accounted for 74% of the diagnoses; 29% of the diagnostic variants were in the most difficult-to-sequence central region of ORF15 (c.2470-3230). Truncating variants made up the majority (91%) of the diagnostic variants. CNVs explained 2% of the diagnostic cases, of which 80% were one- or two-exon deletions outside of ORF15. CONCLUSIONS: Our findings indicate that high-throughput, clinically validated NGS-based testing covering the difficult-to-sequence region of ORF15, in combination with high-resolution CNV detection, can help to maximize the diagnostic yield for patients with IRD. TRANSLATIONAL RELEVANCE: These results demonstrate an accurate and scalable method for the detection of RPGR-related variants, including the difficult-to-sequence ORF15 hotspot, which is relevant given current and emerging therapeutic opportunities. The Association for Research in Vision and Ophthalmology 2022-01-05 /pmc/articles/PMC8742508/ /pubmed/34985506 http://dx.doi.org/10.1167/tvst.11.1.6 Text en Copyright 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. |
spellingShingle | Article Tuupanen, Sari Gall, Kimberly Sistonen, Johanna Saarinen, Inka Kämpjärvi, Kati Wells, Kirsty Merkkiniemi, Katja von Nandelstadh, Pernilla Sarantaus, Laura Känsäkoski, Johanna Mårtenson, Emma Västinsalo, Hanna Schleit, Jennifer Sankila, Eeva-Marja Kere, Annakarin Junnila, Heidi Siivonen, Pauli Andreevskaya, Margarita Kytölä, Ville Muona, Mikko Salmenperä, Pertteli Myllykangas, Samuel Koskenvuo, Juha Alastalo, Tero-Pekka Prevalence of RPGR-Mediated Retinal Dystrophy in an Unselected Cohort of Over 5000 Patients |
title | Prevalence of RPGR-Mediated Retinal Dystrophy in an Unselected Cohort of Over 5000 Patients |
title_full | Prevalence of RPGR-Mediated Retinal Dystrophy in an Unselected Cohort of Over 5000 Patients |
title_fullStr | Prevalence of RPGR-Mediated Retinal Dystrophy in an Unselected Cohort of Over 5000 Patients |
title_full_unstemmed | Prevalence of RPGR-Mediated Retinal Dystrophy in an Unselected Cohort of Over 5000 Patients |
title_short | Prevalence of RPGR-Mediated Retinal Dystrophy in an Unselected Cohort of Over 5000 Patients |
title_sort | prevalence of rpgr-mediated retinal dystrophy in an unselected cohort of over 5000 patients |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8742508/ https://www.ncbi.nlm.nih.gov/pubmed/34985506 http://dx.doi.org/10.1167/tvst.11.1.6 |
work_keys_str_mv | AT tuupanensari prevalenceofrpgrmediatedretinaldystrophyinanunselectedcohortofover5000patients AT gallkimberly prevalenceofrpgrmediatedretinaldystrophyinanunselectedcohortofover5000patients AT sistonenjohanna prevalenceofrpgrmediatedretinaldystrophyinanunselectedcohortofover5000patients AT saarineninka prevalenceofrpgrmediatedretinaldystrophyinanunselectedcohortofover5000patients AT kampjarvikati prevalenceofrpgrmediatedretinaldystrophyinanunselectedcohortofover5000patients AT wellskirsty prevalenceofrpgrmediatedretinaldystrophyinanunselectedcohortofover5000patients AT merkkiniemikatja prevalenceofrpgrmediatedretinaldystrophyinanunselectedcohortofover5000patients AT vonnandelstadhpernilla prevalenceofrpgrmediatedretinaldystrophyinanunselectedcohortofover5000patients AT sarantauslaura prevalenceofrpgrmediatedretinaldystrophyinanunselectedcohortofover5000patients AT kansakoskijohanna prevalenceofrpgrmediatedretinaldystrophyinanunselectedcohortofover5000patients AT martensonemma prevalenceofrpgrmediatedretinaldystrophyinanunselectedcohortofover5000patients AT vastinsalohanna prevalenceofrpgrmediatedretinaldystrophyinanunselectedcohortofover5000patients AT schleitjennifer prevalenceofrpgrmediatedretinaldystrophyinanunselectedcohortofover5000patients AT sankilaeevamarja prevalenceofrpgrmediatedretinaldystrophyinanunselectedcohortofover5000patients AT kereannakarin prevalenceofrpgrmediatedretinaldystrophyinanunselectedcohortofover5000patients AT junnilaheidi prevalenceofrpgrmediatedretinaldystrophyinanunselectedcohortofover5000patients AT siivonenpauli prevalenceofrpgrmediatedretinaldystrophyinanunselectedcohortofover5000patients AT andreevskayamargarita prevalenceofrpgrmediatedretinaldystrophyinanunselectedcohortofover5000patients AT kytolaville prevalenceofrpgrmediatedretinaldystrophyinanunselectedcohortofover5000patients AT muonamikko prevalenceofrpgrmediatedretinaldystrophyinanunselectedcohortofover5000patients AT salmenperapertteli prevalenceofrpgrmediatedretinaldystrophyinanunselectedcohortofover5000patients AT myllykangassamuel prevalenceofrpgrmediatedretinaldystrophyinanunselectedcohortofover5000patients AT koskenvuojuha prevalenceofrpgrmediatedretinaldystrophyinanunselectedcohortofover5000patients AT alastaloteropekka prevalenceofrpgrmediatedretinaldystrophyinanunselectedcohortofover5000patients |