Prevalence of RPGR-Mediated Retinal Dystrophy in an Unselected Cohort of Over 5000 Patients

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Tuupanen , S , Gall , K , Sistonen , J , Saarinen , I , Kämpjärvi , K , Wells , K , Merkkiniemi , K , von Nandelstadh , P , Sarantaus , L , Kansakoski , J , Martenson , E , Vastinsalo , H , Schleit , J , Sankila , E-M , Kere , A , Junnila , H , Siivonen , P , Andreevskaya , M , Kytola , V , Muona , M , Salmenpera , P , Myllykangas , S , Koskenvuo , J & Alastalo , T-P 2022 , ' Prevalence of RPGR-Mediated Retinal Dystrophy in an Unselected Cohort of Over 5000 Patients ' , Translational vision science & technology , vol. 11 , no. 1 , 6 .

Title: Prevalence of RPGR-Mediated Retinal Dystrophy in an Unselected Cohort of Over 5000 Patients
Author: Tuupanen, Sari; Gall, Kimberly; Sistonen, Johanna; Saarinen, Inka; Kämpjärvi, Kati; Wells, Kirsty; Merkkiniemi, Katja; von Nandelstadh, Pernilla; Sarantaus, Laura; Kansakoski, Johanna; Martenson, Emma; Vastinsalo, Hanna; Schleit, Jennifer; Sankila, Eeva-Marja; Kere, Annakarin; Junnila, Heidi; Siivonen, Pauli; Andreevskaya, Margarita; Kytola, Ville; Muona, Mikko; Salmenpera, Pertteli; Myllykangas, Samuel; Koskenvuo, Juha; Alastalo, Tero-Pekka
Contributor organization: HUS Head and Neck Center
Date: 2022-01
Language: eng
Number of pages: 8
Belongs to series: Translational vision science & technology
ISSN: 2164-2591
Abstract: 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.
Subject: retinitis pigmentosa
retinal dystrophy
next-generation sequencing
genetic testing
3125 Otorhinolaryngology, ophthalmology
Peer reviewed: Yes
Rights: cc_by_nc_nd
Usage restriction: openAccess
Self-archived version: publishedVersion

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