Analysis of RPGR gene mutations in 41 Chinese families affected by X-linked inherited retinal dystrophy

Xiaozhen Liu; Ruixuan Jia; Xiang Meng; Likun Wang; Liping Yang

doi:10.3389/fgene.2022.999695

Analysis of RPGR gene mutations in 41 Chinese families affected by X-linked inherited retinal dystrophy

Front Genet. 2022 Oct 6:13:999695. doi: 10.3389/fgene.2022.999695. eCollection 2022.

Authors

Xiaozhen Liu^{1

2}, Ruixuan Jia^{1

2}, Xiang Meng^{1

2}, Likun Wang³, Liping Yang^{1

2}

Affiliations

¹ Department of Ophthalmology, Peking University Third Hospital, Beijing, China.
² Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Peking University Third Hospital, Beijing, China.
³ Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking-Tsinghua Center of Life Sciences, Peking University Health Science Center, Beijing, China.

Abstract

Background: This study analyzed the phenotypes and genotypes of 41 Chinese families with inherited retinal dystrophy (IRD) and RPGR gene mutations. Methods: This retrospective analysis evaluated a cohort of 41 patients who were subjected to a specific Hereditary Eye Disease Enrichment Panel (HEDEP) analysis. All (likely) pathogenic variants were determined by Sanger sequencing, and co-segregation analyses were performed on the available family members. All cases were subjected to Sanger sequencing for RPGR open reading frame 15 (ORF15) mutations. Results: A total of 41 probands from different families with a clinical diagnosis of retinitis pigmentosa (RP; 34 cases) and cone-rod dystrophy (CORD; 7 cases) were included in this cohort. According to clinical information, 2, 18, and 21 cases were first assigned as autosomal dominant (AD), sporadic, and X-linked (XL) inheritance, respectively. Several cases of affected females who presented with a male phenotype have been described, posing challenges at diagnosis related to the apparent family history of AD. Mutations were located in RPGR exons or introns 1-14 and in ORF15 of 12 of 41 (29.3%) and 29 of 41 (70.7%) subjects, respectively. Thirty-four (likely) pathogenic mutations were identified. Frameshifts were the most frequently observed variants, followed by nonsense, splice, and missense mutations. Herein, a detailed description of four RP patients carrying RPGR intronic mutations is reported, and in vitro splice assays were performed to confirm the pathogenicity of these intronic mutations. Conclusion: Our findings provide useful insights for the genetic and clinical counseling of patients with XL IRD, which will be useful for ongoing and future gene therapy trials.

Keywords: RPGR gene; female carriers; hereditary eye disease enrichment panel; in vitro splice assay; inherited retinal dystrophies.