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Original Investigation
February 2017

Clinical Characterization of CNGB1-Related Autosomal Recessive Retinitis Pigmentosa

Author Affiliations
  • 1Moorfields Eye Hospital, London, England
  • 2University College London Institute of Ophthalmology, London, England
  • 3L’Unità Operativa di Oculistica, Ospedale Sacrocuore-Don Calabria, Negrar, Italy
  • 4Department of Haematology, University of Cambridge, Cambridge, England
  • 5National Institute for Health Research (NIHR) BioResource–Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, England
  • 6Department of Ophthalmology, Great Ormond Street Hospital for Children, London, England
  • 7University College London Genetics Institute, London, England
  • 8Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, England
  • 9Ophthalmology Department, University of California, San Francisco Medical School, San Francisco
JAMA Ophthalmol. 2017;135(2):137-144. doi:10.1001/jamaophthalmol.2016.5213
Key Points

Question  What can a detailed clinical and molecular genetic study of patients with CNGB1-related retinitis pigmentosa reveal about the disease presentation and progression?

Findings  This case series of 10 patients with retinitis pigmentosa identified childhood onset of nyctalopia with preserved visual acuity and central photoreceptors into adulthood.

Meaning  The findings of this case series suggest that retinitis pigmentosa due to variants in CNGB1 is slowly progressive with a long potential treatment window.

Abstract

Importance  There are limited published data on the phenotype of retinitis pigmentosa (RP) related to CNGB1 variants. These data are needed both for prognostic counseling of patients and for understanding potential treatment windows.

Objective  To describe the detailed clinical and molecular genetic findings in a series of patients with RP with likely pathogenic variants in CNGB1.

Design, Setting, and Participants  In this case series, 10 patients from 9 families underwent full ophthalmologic examination. Molecular investigations included whole-exome analysis in 6 patients. The study was conducted from April 17, 2013, to March 3, 2016, with final follow-up completed on March 2, 2016, and data were analyzed from October 27, 2014, to March 29, 2016.

Main Outcomes and Measures  Results of ophthalmologic examination and molecular genetic analysis of CNGB1.

Results  In this case series, 7 women and 3 men from 9 families with a mean (SD) age of 47.4 (13.2) years identified as having CNGB1 variants were included in this study; there was a mean (SD) follow-up length of 3.7 (2.8) years. The first clinical presentation was with nyctalopia in childhood with visual field loss documented later at a mean (SD) age of 33.2 (8.0) years. All patients had preserved best-corrected visual acuity into adulthood, with a mean of 0.1 logMAR (Snellen equivalent, 20/25) in each eye (logMAR range, 0.0 to 0.3 [Snellen 20/20 to 20/40] in the right eye and −0.1 to 0.3 [Snellen 20/16 to 20/40] in the left eye). Fundus examination revealed midperipheral retinal pigment epithelial atrophy and intraretinal pigment migration. Optical coherence tomography of the macula demonstrated complete preservation of the inner segment ellipsoid band in 1 patient, with variable lateral extent in the other patients corresponding to the diameter of a paracentral ring of increased fundus autofluorescence. Electrophysiologic testing in 6 patients confirmed a rod-cone dystrophy phenotype. Molecular investigations identified a previously reported missense variant (p.[N986I]) and 7 variants not previously reported in disease including 4 nonsense (p.[(Q88*], p.[Q222*], p.[Q318*], and p.[R729*]), 2 frameshift (p.[A1048fs*13], p.[L849Afs*3]), and a splice site variant (c.761 + 2T>A).

Conclusions and Relevance  The data from this study suggest that visual acuity and foveal structure in patients with RP are preserved into adult life such that a lengthy window of opportunity should exist for intervention with novel therapies.

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