Identification of the RPGR Gene Pathogenic Variants in a Cohort of Polish Male Patients with Retinitis Pigmentosa Phenotype

Abstract

The goal of the study was to explore the spectrum of pathogenic variants in the RPGR gene in a group of male Polish patients with a retinitis pigmentosa (RP) phenotype. A total of 45 male index patients, including twins, being members of 44 families, were screened for pathogenic variants in the RPGR gene via the direct sequencing of PCR-amplified genomic DNA and underwent a comprehensive ophthalmological examination in one center located in Poland. A total of two pathogenic and five likely pathogenic variants in eight patients (18%) were detected in the studied cohort. Of these, five variants were novel, and five disease-causing variants (71%) were identified within the ORF15 mutational hotspot of the RPGR gene. The median age of onset of the disease was 10 years (range 6–14 years), the median age during the examination was 30 years (range 20–47 years), and the median visual acuity was 0.4 (range 0.01–0.7). The majority of patients had middle constriction of the visual field and thinning of the central foveal thickness. Dizygotic twins bearing the same hemizygous mutation showed a different retinal phenotype in regard to the severity of the symptoms. This is the first RPGR mutation screening in Poland showing a prevalence of 18% of RPGR pathogenic mutations and likely pathogenic variants in the studied cohort of male patients with an RP phenotype.

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

“…Two novel variants—one in CRB1 (NM_201253.3:c.1342C>T) and in DNAJC30 (NM_032317.3:c.293A>G)—have been recently published as a part of a description of a small group of patients with distinct clinical symptoms [ 29 , 32 ]. Additionally, our study allowed us to repeatedly identify rare variants (without any record in gnomAD v2.1.1 and ClinVar), apparently more frequent in the Polish population—in RPGR ORF15 (NM_001034853.2:c.3142_3143dup) [ 27 , 30 ] and in EYS (NM_001142800.2:c.1836_1837del) [ 24 ], uncovering some specific genetic traits of the Polish population.…”

“…Results of several studies for groups or small cohorts of Polish IRD patients were published, including those for Stargardt disease [23,24] and RP [25][26][27]. Those studies used mostly targeted approaches such as Sanger sequencing of selected genes [27], singlenucleotide polymorphism microarrays or small NGS panels (in Leber congenital amaurosis [28,29]; in CRD [30]) or more comprehensive NGS panels (108 genes, [23,24]), while, in several studies, the WES approach was applied [25,26,30,31]. Sanger sequencing and SNP arrays, as well as an NGS panel, were used to search for the molecular diagnosis in a large group of patients with LHON/LHONAR [32].…”