Clinical phenotype and course of PDE6A-associated retinitis pigmentosa disease, characterized in preparation for a gene supplementation trial

Laura Kuehlewein, Ditta Zobor, Sten Olof Andreasson, Carmen Ayuso, Sandro Banfi, Beatrice Bocquet, Antje S. Bernd, Saskia Biskup, Camiel J.F. Boon, Susan M. Downes, M. Dominik Fischer, Frank G. Holz, Ulrich Kellner, Bart P. Leroy, Isabelle Meunier, Fadi Nasser, Thomas Rosenberg, Günther Rudolph, Katarina Stingl, Alberta A.H.J. ThiadensBarbara Wilhelm, Bernd Wissinger, Eberhart Zrenner, Susanne Kohl, Nicole Weisschuh, Karl Ulrich Bartz-Schmidt, Sylvia Bolz, Regine Mühlfriedel, Jonas Neubauer, Alex Ochakovski, Francois Paquet-Durand, Mathias Seeliger, Vithiyanjali Sothilingam, Marius Ueffing, Fabian Wozar, Ahmad Zhour, Martin Biel, Stylianos Michalakis, Christian Schön, Nadine Kahle, Tobias Peters, Stephen H. Tsang, Christian Johannes Glöckner, RD-CURE Consortium

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskriftPeer review

6 Citeringar (SciVal)


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.

Sidor (från-till)1241-1250
Antal sidor10
TidskriftJAMA Ophthalmology
Tidigt onlinedatum2020
StatusPublished - 2020 dec.

Ämnesklassifikation (UKÄ)

  • Oftalmologi


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