Clinical Phenotype of PDE6B-Associated Retinitis Pigmentosa

Authors

Laura Kuehlewein^{1 2}, Ditta Zobor¹, Katarina Stingl^{2 3}, Melanie Kempf^{2 3} , Fadi Nasser¹, Antje Bernd², Saskia Biskup⁴, Frans P M Cremers^{5 6}, Muhammad Imran Khan^{5 6}, Pascale Mazzola⁷, Karin Schäferhoff⁷, Tilman Heinrich^{7 8}, Tobias B Haack^{7 8}, Bernd Wissinger⁹, Eberhart Zrenner^{1 10}, Nicole Weisschuh⁹, Susanne Kohl⁹

Institute for Ophthalmic Research, Centre for Ophthalmology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
University Eye Hospital, Centre for Ophthalmology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
Center for Rare Eye Diseases, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
CeGaT GmbH, 72076 Tuebingen, Germany.
Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands.
Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 AJ Nijmegen, The Netherlands.
Institute for Medical Genetics and Applied Genomics, University Hospital, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
Centre for Rare Diseases, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
Werner Reichardt Centre for Integrative Neuroscience (CIN), Eberhard Karls University Tübingen, 72076 Tübingen, Germany.

Abstract

In this retrospective, longitudinal, observational cohort study, we investigated the phenotypic and genotypic features of retinitis pigmentosa associated with variants in the PDE6B gene. Patients underwent clinical examination and genetic testing at a single tertiary referral center, including best-corrected visual acuity (BCVA), kinetic visual field (VF), full-field electroretinography, full-field stimulus threshold, spectral domain optical coherence tomography, and fundus autofluorescence imaging. The genetic testing comprised candidate gene sequencing, inherited retinal disease gene panel sequencing, whole-genome sequencing, and testing for familial variants by Sanger sequencing. Twenty-four patients with mutations in PDE6B from 21 families were included in the study (mean age at the first visit: 32.1 ± 13.5 years). The majority of variants were putative splicing defects (8/23) and missense (7/23) mutations. Seventy-nine percent (38/48) of eyes had no visual acuity impairment at the first visit. Visual acuity impairment was mild in 4% (2/48), moderate in 13% (6/48), and severe in 4% (2/48). BCVA was symmetrical in the right and left eyes. The kinetic VF measurements were highly symmetrical in the right and left eyes, as was the horizontal ellipsoid zone (EZ) width. Regarding the genetic findings, 43% of the PDE6B variants found in our patients were novel. Thus, this study contributed substantially to the PDE6B mutation spectrum. The visual acuity impairment was mild in 83% of eyes, providing a window of opportunity for investigational new drugs. The EZ width was reduced in all patients and was highly symmetric between the eyes, making it a promising outcome measure. We expect these findings to have implications on the design of future PDE6B-related retinitis pigmentosa (RP) clinical trials.

Keywords: phosphodiesterase 6; retinitis pigmentosa.

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