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

Overview

Journal Transl Vis Sci Technol

Specialties Biomedical Engineering
Ophthalmology

Date 2022 Jan 5

PMID 34985506

Citations 12

Authors

Sari Tuupanen

Kimberly Gall

Johanna Sistonen

Inka Saarinen

Kati Kampjarvi

Kirsty Wells

Katja Merkkiniemi

Pernilla von Nandelstadh

Laura Sarantaus

Johanna Kansakoski

Emma Martenson

Hanna Vastinsalo

Jennifer Schleit

Eeva-Marja Sankila

Annakarin Kere

Heidi Junnila

Pauli Siivonen

Margarita Andreevskaya

Ville Kytola

Mikko Muona

Pertteli Salmenpera

Samuel Myllykangas

Juha Koskenvuo

Tero-Pekka Alastalo

Affiliations

Soon will be listed here.

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.

Citing Articles

Retinal Disease Variability in Female Carriers of Variants Associated with Retinitis Pigmentosa: Clinical and Genetic Parameters.

Gocuk S, Edwards T, Jolly J, Chen F, Sousa D, McGuinness M Genes (Basel). 2025; 16(2).

PMID: 40004550 PMC: 11855607. DOI: 10.3390/genes16020221.

Whole-Exome Analysis for Polish Caucasian Patients with Retinal Dystrophies and the Creation of a Reference Genomic Database for the Polish Population.

Matczynska E, Szymanczak R, Stradomska K, Lyszkiewicz P, Jedrzejowska M, Kaminska K Genes (Basel). 2024; 15(8).

PMID: 39202371 PMC: 11353931. DOI: 10.3390/genes15081011.

Optimised, Broad NGS Panel for Inherited Eye Diseases to Diagnose 1000 Patients in Poland.

Matczynska E, Bec-Gajowniczek M, Sivitskaya L, Gregorczyk E, Lyszkiewicz P, Szymanczak R Biomedicines. 2024; 12(6).

PMID: 38927562 PMC: 11202224. DOI: 10.3390/biomedicines12061355.

Clinical and analytical validation of an 82-gene comprehensive genome-profiling panel for identifying and interpreting variants responsible for inherited retinal dystrophies.

Chan J, Holdstock J, Shovelton J, Reid J, Speight G, Molha D PLoS One. 2024; 19(6):e0305422.

PMID: 38870140 PMC: 11175448. DOI: 10.1371/journal.pone.0305422.

Disease modeling and pharmacological rescue of autosomal dominant retinitis pigmentosa associated with copy number variation.

Kandoi S, Martinez C, Chen K, Mehine M, Reddy L, Mansfield B Elife. 2024; 12.

PMID: 38661530 PMC: 11045220. DOI: 10.7554/eLife.90575.

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