RPGR : Deep Phenotyping and Genetic Characterization With Findings Specific to the 3′-end of ORF15

Abstract

Purpose To describe a group of patients with retinitis pigmentosa GTPase regulator ( RPGR )-related retinopathy with a tapetal-like retinal sheen and corresponding changes in the reflectivity of the ellipsoid zone on optical coherence tomography (OCT) imaging. Methods A retrospective case series of 66 patients with a disease-causing variant in RPGR was performed. An expert examiner, masked to patient demographics, clinical evaluations, and specific RPGR variant, analyzed color fundus photographs for the presence of a tapetal-like retinal sheen and assessed OCT images for the presence of an abnormally broad hyper-reflective band in the outer retina. Longitudinal reflectivity profiles were generated and compared with healthy controls. Results Twelve patients (18.2%) had a retinal sheen on color images that cosegregated with an abnormally broad hyper-reflective ellipsoid zone band on OCT imaging. Three-fourths of these patients were male, had a cone–rod dystrophy, and had pathogenic RPGR variants located toward the 3′-end of ORF15. This group had a different longitudinal reflectivity profile signature compared with controls. After a period of prolonged dark adaptation, the abnormal hyper-reflective band on OCT became less apparent, and the outer retinal layers adopted a more normal appearance. Conclusions RPGR -related retinopathy should be considered for males presenting with retinal sheen, abnormal ellipsoid zone hyper-reflectivity, and cone or cone–rod dysfunction on ERG, and pursued with molecular testing. Our results have implications for understanding the role of the C-terminal domain encoded by RPGR ORF15 in the phototransduction cascade. Further, the findings may be important to incorporate into both inclusion criteria and outcome measure developments in future RPGR -related cone or cone–rod dystrophy clinical trials.

Phenotypic Manifestations in Female Carriers of RPGR ORF15 Variants Causing X-Linked Cone Dystrophy

“…Multimodal structural imaging of the retina revealed a distinct topographic distribution. Subtle abnormalities were confined to the macula and posterior pole, and resembled early disease seen in male individuals with RPGR -related cone dystrophy . This consisted of an en face tapetal-like sheen, most sensitively detected with green (518-nm wavelength) reflectance imaging, that colocalized with the hyperreflective space between the retinal pigment epithelium and ellipsoid zone on spectral-domain optical coherence tomography (Figure 2).…”

“…This study identified some degree of abnormal reflex or sheen in all participating female carriers of both phenotype categories with varying severity using reflectance imaging. Various techniques have previously been used to image this reflex, namely green light fundus autofluorescence imaging, 488-nm reflectance imaging (red free with a green filter) and widefield Optos 532-nm imaging . In this study, the abnormal en face sheen was resolved sharpest using green (518-nm) wavelength reflectance imaging.…”

“…Various techniques have previously been used to image this reflex, namely green light fundus autofluorescence imaging, 488-nm reflectance imaging (red free with a green filter) and widefield Optos 532-nm imaging. 9,11,13 In this study, the abnormal en face sheen was resolved sharpest using green (518-nm) wavelength reflectance imaging.…”

Phenotypic Manifestations in Female Carriers of RPGR ORF15 Variants Causing X-Linked Cone Dystrophy

“…Multimodal structural imaging of the retina revealed a distinct topographic distribution. Subtle abnormalities were confined to the macula and posterior pole, and resembled early disease seen in male individuals with RPGR -related cone dystrophy . This consisted of an en face tapetal-like sheen, most sensitively detected with green (518-nm wavelength) reflectance imaging, that colocalized with the hyperreflective space between the retinal pigment epithelium and ellipsoid zone on spectral-domain optical coherence tomography (Figure 2).…”

“…This study identified some degree of abnormal reflex or sheen in all participating female carriers of both phenotype categories with varying severity using reflectance imaging. Various techniques have previously been used to image this reflex, namely green light fundus autofluorescence imaging, 488-nm reflectance imaging (red free with a green filter) and widefield Optos 532-nm imaging . In this study, the abnormal en face sheen was resolved sharpest using green (518-nm) wavelength reflectance imaging.…”

“…Various techniques have previously been used to image this reflex, namely green light fundus autofluorescence imaging, 488-nm reflectance imaging (red free with a green filter) and widefield Optos 532-nm imaging. 9,11,13 In this study, the abnormal en face sheen was resolved sharpest using green (518-nm) wavelength reflectance imaging.…”

Retinitis Pigmentosa GTPase regulator–Associated Retinal Degeneration: Integrating Patient-Reported Outcomes, Genetic, and Structural Biomarkers

“… 2 , 3 The RPGR ORF15 isoform has been identified as a mutational hotspot and plays an important role in retinal ciliary transport. 4 This glycine- and glutamate-rich domain is a challenging but critical area for genetic diagnosis, accounting for up to 80% of all RPGR cases. 3 , 5 , 6 …”

“… 2 , 3 , 10 , 11 , 16 , 19 This will require the development of additional endpoints, including both structural and functional outcomes that correlate with visual performance and quality of life. 4 , 10 , 11 Incorporating PRO measures in clinical trials and everyday clinics ensures that treatment outcomes align with each patient’s experiences, making them an indispensable component of clinical research. 2 …”

Phenotypic Manifestations in Female Carriers of RPGR ORF15 Variants Causing X-Linked Cone Dystrophy

“…Multimodal structural imaging of the retina revealed a distinct topographic distribution. Subtle abnormalities were confined to the macula and posterior pole, and resembled early disease seen in male individuals with RPGR -related cone dystrophy . This consisted of an en face tapetal-like sheen, most sensitively detected with green (518-nm wavelength) reflectance imaging, that colocalized with the hyperreflective space between the retinal pigment epithelium and ellipsoid zone on spectral-domain optical coherence tomography (Figure 2).…”

“…This study identified some degree of abnormal reflex or sheen in all participating female carriers of both phenotype categories with varying severity using reflectance imaging. Various techniques have previously been used to image this reflex, namely green light fundus autofluorescence imaging, 488-nm reflectance imaging (red free with a green filter) and widefield Optos 532-nm imaging . In this study, the abnormal en face sheen was resolved sharpest using green (518-nm) wavelength reflectance imaging.…”

“…Various techniques have previously been used to image this reflex, namely green light fundus autofluorescence imaging, 488-nm reflectance imaging (red free with a green filter) and widefield Optos 532-nm imaging. 9,11,13 In this study, the abnormal en face sheen was resolved sharpest using green (518-nm) wavelength reflectance imaging.…”

Retinitis Pigmentosa GTPase regulator–Associated Retinal Degeneration: Integrating Patient-Reported Outcomes, Genetic, and Structural Biomarkers

“… 2 , 3 The RPGR ORF15 isoform has been identified as a mutational hotspot and plays an important role in retinal ciliary transport. 4 This glycine- and glutamate-rich domain is a challenging but critical area for genetic diagnosis, accounting for up to 80% of all RPGR cases. 3 , 5 , 6 …”

“… 2 , 3 , 10 , 11 , 16 , 19 This will require the development of additional endpoints, including both structural and functional outcomes that correlate with visual performance and quality of life. 4 , 10 , 11 Incorporating PRO measures in clinical trials and everyday clinics ensures that treatment outcomes align with each patient’s experiences, making them an indispensable component of clinical research. 2 …”

Phenotypic Manifestations in Female Carriers of RPGR ORF15 Variants Causing X-Linked Cone Dystrophy

“…Multimodal structural imaging of the retina revealed a distinct topographic distribution. Subtle abnormalities were confined to the macula and posterior pole, and resembled early disease seen in male individuals with RPGR -related cone dystrophy . This consisted of an en face tapetal-like sheen, most sensitively detected with green (518-nm wavelength) reflectance imaging, that colocalized with the hyperreflective space between the retinal pigment epithelium and ellipsoid zone on spectral-domain optical coherence tomography (Figure 2).…”

“…This study identified some degree of abnormal reflex or sheen in all participating female carriers of both phenotype categories with varying severity using reflectance imaging. Various techniques have previously been used to image this reflex, namely green light fundus autofluorescence imaging, 488-nm reflectance imaging (red free with a green filter) and widefield Optos 532-nm imaging . In this study, the abnormal en face sheen was resolved sharpest using green (518-nm) wavelength reflectance imaging.…”

“…Various techniques have previously been used to image this reflex, namely green light fundus autofluorescence imaging, 488-nm reflectance imaging (red free with a green filter) and widefield Optos 532-nm imaging. 9,11,13 In this study, the abnormal en face sheen was resolved sharpest using green (518-nm) wavelength reflectance imaging.…”

Retinitis Pigmentosa GTPase regulator–Associated Retinal Degeneration: Integrating Patient-Reported Outcomes, Genetic, and Structural Biomarkers

“… 2 , 3 The RPGR ORF15 isoform has been identified as a mutational hotspot and plays an important role in retinal ciliary transport. 4 This glycine- and glutamate-rich domain is a challenging but critical area for genetic diagnosis, accounting for up to 80% of all RPGR cases. 3 , 5 , 6 …”

“… 2 , 3 , 10 , 11 , 16 , 19 This will require the development of additional endpoints, including both structural and functional outcomes that correlate with visual performance and quality of life. 4 , 10 , 11 Incorporating PRO measures in clinical trials and everyday clinics ensures that treatment outcomes align with each patient’s experiences, making them an indispensable component of clinical research. 2 …”