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Genetic spectrum, retinal phenotype, and peripapillary RNFL thickness in RPGR heterozygotes

  • Genetics
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Abstract

Purpose

Phenotypic heterogeneity with variable severity has been reported in female carriers of retinitis pigmentosa GTPase regulator (RPGR) mutations, including a male-type phenotype. A phenomenon not fully understood is peripapillary retinal nerve fiber layer (pRNFL) thickening in male patients with RPGR-associated X-linked retinitis pigmentosa, especially in the temporal sector. We aim to describe the genetic spectrum, retinal phenotypes, and pRNFL thickness in a cohort of Caucasian RPGR-mutation heterozygotes.

Methods

A cross-sectional study was conducted at an inherited retinal degeneration (IRD) reference center in Portugal. Female patients heterozygous for clinically significant RPGR variants were identified using the IRD-PT registry. A complete ophthalmologic examination was performed, complemented by macular and peripapillary spectral domain optical coherence tomography (SD-OCT), ultra-widefield color fundus photography (UW-CFP), and ultra-widefield fundus autofluorescence (UW-FAF). The retinal phenotypes were graded according to previously described classifications. The pRNFL thickness across the superior, inferior, nasal, and temporal quadrants was compared to the Spectralis® RNFL age-adjusted reference database.

Results

Forty-eight eyes from 24 females (10 families) were included in the study. Genetic analysis yielded 8 distinct clinically significant frameshift variants in RPGR gene, 3 of which herein reported for the first time. No association was found between mutation location and best-corrected visual acuity (BCVA) or retinal phenotype. Age was associated with worse BCVA and more advanced phenotypes on SD-OCT, UW-CFP, and UW-FAF. Seven women (29.17%) presented a male-type phenotype on UW-FAF in at least one eye. An association was found between UW-FAF and pRNFL thickness in the temporal sector (p = 0.003), with the most advanced fundus autofluorescence phenotypes showing increased pRNFL thickness in this sector.

Conclusion

This study expands the genetic landscape of RPGR-associated disease by reporting 3 novel clinically significant variants. We have shown that clinically severe phenotypes are not uncommon among female carriers. Furthermore, we provide novel insights into pRNFL changes observed in RPGR heterozygotes that mimic what has been reported in male patients.

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Data availability

This work and its original data have not been previously published.

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Author information

Author notes

  1. João Pedro Marques and Rosa Pinheiro contributed equally.

Authors and Affiliations

  1. Ophthalmology Unit, Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal

    João Pedro Marques, Rosa Pinheiro, Miguel Raimundo, Mário Soares, Pedro Melo, Joaquim Murta & Rufino Silva

  2. Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal

    João Pedro Marques, Ana Luísa Carvalho, Miguel Raimundo, Joaquim Murta, Jorge Saraiva & Rufino Silva

  3. University Clinic of Ophthalmology, Faculty of Medicine, University of Coimbra (FMUC), Coimbra, Portugal

    João Pedro Marques, Miguel Raimundo, Joaquim Murta & Rufino Silva

  4. Centro de Responsabilidade Integrado de Oftalmologia (CRIO), Centro Hospitalar e Universitário de Coimbra (CHUC), Praceta Prof. Mota Pinto, 3000-075, Coimbra, Portugal

    João Pedro Marques

  5. Medical Genetics Unit, Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal

    Ana Luísa Carvalho

  6. University Clinic of Medical Genetics, Faculty of Medicine, University of Coimbra (FMUC), Coimbra, Portugal

    Ana Luísa Carvalho & Jorge Saraiva

  7. University Clinic of Pediatrics, Faculty of Medicine, University of Coimbra (FMUC), Coimbra, Portugal

    Jorge Saraiva

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  1. João Pedro Marques
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Corresponding author

Correspondence to João Pedro Marques.

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Ethics approval and consent to participate

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Human Research Ethics Committee (HREC) of Centro Hospitalar e Universitário de Coimbra (CHUC) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

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The authors declare no competing interests.

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Supplementary information

Supplemental Fig. 1

Top Graphical representation depicting the positive correlation between logMAR best-corrected visual acuity (BCVA) and age (R2 = 0.123, p = 0.016). Bottom Graphical representation depicting the negative correlation between logMAR BCVA and spherical equivalent (R2 = 0.535, p < 0.001). (PNG 79 kb)

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Marques, J.P., Pinheiro, R., Carvalho, A.L. et al. Genetic spectrum, retinal phenotype, and peripapillary RNFL thickness in RPGR heterozygotes. Graefes Arch Clin Exp Ophthalmol 261, 867–878 (2023). https://doi.org/10.1007/s00417-022-05809-0

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  • DOI: https://doi.org/10.1007/s00417-022-05809-0

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