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Original Investigation
October 15, 2020

Clinical Phenotype and Course of PDE6A-Associated Retinitis Pigmentosa Disease, Characterized in Preparation for a Gene Supplementation Trial

Author Affiliations
  • 1Institute for Ophthalmic Research, Centre for Ophthalmology, Eberhard Karls University Tübingen, Germany
  • 2University Eye Hospital, Centre for Ophthalmology, Eberhard Karls University Tübingen, Germany
  • 3Lund University, Skane University Hospital, Department of Ophthalmology, Lund, Sweden
  • 4Department of Genetics, IIS–Fundación Jiménez Díaz–University Hospital; Universidad Autónoma de Madrid, Madrid, Spain
  • 5Centre for Biomedical Research on Rare Diseases, Madrid, Spain
  • 6Telethon Institute of Genetics and Medicine, Pozzuoli (NA) and Medical Genetics, Department of Precision Medicine, University of Campania “Luigi Vanvitelli,” Naples, Italy
  • 7Institute for Neurosciences of Montpellier Unité 1051, University of Montpellier, Montpellier, France
  • 8National Center for Rare Diseases, Genetics of Sensory Diseases, University Hospital, Montpellier, France
  • 9Praxis für Humangenetik Tübingen, Tübingen, Germany
  • 10Department of Ophthalmology, Leiden University Medical Center, Leiden University, Leiden, the Netherlands
  • 11Department of Ophthalmology, Amsterdam University Medical Centers, Amsterdam, the Netherlands
  • 12Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, United Kingdom
  • 13Department of Ophthalmology, University of Bonn, Germany
  • 14Rare Retinal Disease Center, AugenZentrum Siegburg, MVZ Augenärztliches Diagnostik- und Therapiecentrum GmbH, Siegburg, Germany
  • 15RetinaScience, Bonn, Germany
  • 16Department of Ophthalmology Ghent University Hospital, Ghent, Belgium
  • 17Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
  • 18Division of Ophthalmology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
  • 19Center for Cellular & Molecular Therapeutics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
  • 20Department of Ophthalmology, Kennedy Center, Rigshospitalet, Copenhagen, Denmark
  • 21Ophthalmogenetik, Augenklinik, Klinikum der Universität München, Munich, Germany
  • 22Department Ophthalmology, Erasmus MC, Rotterdam, the Netherlands
  • 23STZ Eyetrial, Centre for Ophthalmology, Eberhard Karls University Tübingen, Tübingen, Germany
  • 24Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, Eberhard Karls University Tübingen, Tübingen, Germany
  • 25Werner Reichardt Centre for Integrative Neuroscience, Eberhard Karls University Tübingen, Tübingen, Germany
JAMA Ophthalmol. Published online October 15, 2020. doi:10.1001/jamaophthalmol.2020.4206
Key Points

Question  What are the clinical features and course of retinitis pigmentosa associated with biallelic sequence variations in the PDE6A gene?

Findings  In this longitudinal cohort study of 57 adults, 17 of the PDE6A variants appeared to be novel. Disease was highly symmetrical between right and left eyes, and visual impairment was mild or moderate in 90% of patients.

Meaning  These data suggest that PDE6A–retinitis pigmentosa may be amenable to gene therapy.

Abstract

Importance  Treatment trials require sound knowledge on the natural course of disease.

Objective  To assess clinical features, genetic findings, and genotype-phenotype correlations in patients with retinitis pigmentosa (RP) associated with biallelic sequence variations in the PDE6A gene in preparation for a gene supplementation trial.

Design, Setting, and Participants  This prospective, longitudinal, observational cohort study was conducted from January 2001 to December 2019 in a single center (Centre for Ophthalmology of the University of Tübingen, Germany) with patients recruited multinationally from 12 collaborating European tertiary referral centers. Patients with retinitis pigmentosa, sequence variants in PDE6A, and the ability to provide informed consent were included.

Exposures  Comprehensive ophthalmological examinations; validation of compound heterozygosity and biallelism by familial segregation analysis, allelic cloning, or assessment of next-generation sequencing–read data, where possible.

Main Outcomes and Measures  Genetic findings and clinical features describing the entire cohort and comparing patients harboring the 2 most common disease-causing variants in a homozygous state (c.304C>A;p.(R102S) and c.998 + 1G>A;p.?).

Results  Fifty-seven patients (32 female patients [56%]; mean [SD], 40 [14] years) from 44 families were included. All patients completed the study. Thirty patients were homozygous for disease-causing alleles. Twenty-seven patients were heterozygous for 2 different PDE6A variants each. The most frequently observed alleles were c.304C>A;p.(R102S), c.998 + 1G>A;p.?, and c.2053G>A;p.(V685M). The mean (SD) best-corrected visual acuity was 0.43 (0.48) logMAR (Snellen equivalent, 20/50). The median visual field area with object III4e was 660 square degrees (5th and 95th percentiles, 76 and 11 019 square degrees; 25th and 75th percentiles, 255 and 3923 square degrees). Dark-adapted and light-adapted full-field electroretinography showed no responses in 88 of 108 eyes (81.5%). Sixty-nine of 108 eyes (62.9%) showed additional findings on optical coherence tomography imaging (eg, cystoid macular edema or macular atrophy). The variant c.998 + 1G>A;p.? led to a more severe phenotype when compared with the variant c.304C>A;p.(R102S).

Conclusions and Relevance  Seventeen of the PDE6A variants found in these patients appeared to be novel. Regarding the clinical findings, disease was highly symmetrical between the right and left eyes and visual impairment was mild or moderate in 90% of patients, providing a window of opportunity for gene therapy.

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