Laura Kuehlewein 1 2, Ditta Zobor 1, Sten Olof Andreasson 3, Carmen Ayuso 4 5, Sandro Banfi 6, Beatrice Bocquet 7 8, Antje S Bernd 2, Saskia Biskup 9, Camiel J F Boon 10 11, Susan M Downes 12, M Dominik Fischer 1 2, Frank G Holz 13, Ulrich Kellner 14 15, Bart P Leroy 16 17 18 19, Isabelle Meunier 7 8, Fadi Nasser 1, Thomas Rosenberg 20, Günther Rudolph 21, Katarina Stingl 2, Alberta A H J Thiadens 22, Barbara Wilhelm 23, Bernd Wissinger 24, Eberhart Zrenner 1 25, Susanne Kohl 24, Nicole Weisschuh 24, RD-CURE Consortium
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  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.
Conflict of interest statement
Conflict of Interest Disclosures: Dr Downes reported grants from Clinical Research Network NIHR Thames Valley during the conduct of the study; involvement with a commercial study on age-related macular degeneration with Allergan and Novartis; personal fees from Allergan, Circadian Therapeutics, and Boehringer Ingelheim; grants from Retina UK RP Genome outside the submitted work; and service as the chair of the medical advisory board for Retina UK. Dr Fischer reported being a director of Fischer Consulting Limited. Dr Kellner reported study support from Medspace/GTScope, Samsung, Bayer Vital, and Novartis and personal fees from Roche outside the submitted work. Dr Leroy reported grants and personal fees from GenSight Therapeutic, ProQR Therapeutics, and Novartis Pharma; personal fees from IVERIC Bio, Spark Therapeutics, REGENXBio, Biogen, and Vedere Bio; and grants from MeiraGTx outside the submitted work. Dr Stingl reported grants from Kerstan Foundation during the conduct of the study and grants from Retina Implant and personal fees from ProQR and Novartis outside the submitted work. Dr Leroy reports being a senior clinical investigator of the Research Foundation–Flanders (Belgium). Drs Wilhelm, Wissinger, Zrenner, Kohl, Kuehlewein, Weisschuh, and Zobor reported grants from Tistou and Charlotte Kerstan Foundation during the conduct of the study. No other disclosures were reported.
- Institute for Ophthalmic Research, Centre for Ophthalmology, Eberhard Karls University Tübingen, Germany.
- University Eye Hospital, Centre for Ophthalmology, Eberhard Karls University Tübingen, Germany.
- Lund University, Skane University Hospital, Department of Ophthalmology, Lund, Sweden.
- Department of Genetics, IIS-Fundación Jiménez Díaz-University Hospital; Universidad Autónoma de Madrid, Madrid, Spain.
- Centre for Biomedical Research on Rare Diseases, Madrid, Spain.
- Telethon Institute of Genetics and Medicine, Pozzuoli (NA) and Medical Genetics, Department of Precision Medicine, University of Campania “Luigi Vanvitelli,” Naples, Italy.
- Institute for Neurosciences of Montpellier Unité 1051, University of Montpellier, Montpellier, France.
- National Center for Rare Diseases, Genetics of Sensory Diseases, University Hospital, Montpellier, France.
- Praxis für Humangenetik Tübingen, Tübingen, Germany.
- Department of Ophthalmology, Leiden University Medical Center, Leiden University, Leiden, the Netherlands.
- Department of Ophthalmology, Amsterdam University Medical Centers, Amsterdam, the Netherlands.
- Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, United Kingdom.
- Department of Ophthalmology, University of Bonn, Germany.
- Rare Retinal Disease Center, AugenZentrum Siegburg, MVZ Augenärztliches Diagnostik- und Therapiecentrum GmbH, Siegburg, Germany.
- RetinaScience, Bonn, Germany.
- Department of Ophthalmology Ghent University Hospital, Ghent, Belgium.
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
- Division of Ophthalmology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.
- Center for Cellular & Molecular Therapeutics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.
- Department of Ophthalmology, Kennedy Center, Rigshospitalet, Copenhagen, Denmark.
- Ophthalmogenetik, Augenklinik, Klinikum der Universität München, Munich, Germany.
- Department Ophthalmology, Erasmus MC, Rotterdam, the Netherlands..
- STZ Eyetrial, Centre for Ophthalmology, Eberhard Karls University Tübingen, Tübingen, Germany.
- Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, Eberhard Karls University Tübingen, Tübingen, Germany.
- Werner Reichardt Centre for Integrative Neuroscience, Eberhard Karls University Tübingen, Tübingen, Germany.