Diagnostics 2022, 12, 1851. https://doi.org/10.3390/diagnostics12081851 www.mdpi.com/journal/diagnostics Article Multimodal Study of PRPH2 Gene-Related Retinal Phenotypes Giulio Antonelli 1 , Mariacristina Parravano 1, *, Lucilla Barbano 1 , Eliana Costanzo 1 , Matteo Bertelli 2,3,4 , Maria Chiara Medori 2 , Vincenzo Parisi 1 and Lucia Ziccardi 1 1 IRCCS—Fondazione Bietti, Via Livenza 3, 00198 Rome, Italy; giulio.antonelli@fondazionebietti.it (G.A.); lucilla.barbano@fondazionebietti.it (L.B.); eliana.costanzo@fondazionebietti.it (E.C.); vincenzo.parisi@fondazionebietti.it (V.P.); lucia.ziccardi@fondazionebietti.it (L.Z.) 2 MAGI’S LAB, Via Delle Maioliche 57/D, 38068 Rovereto, Italy; matteo.bertelli@assomagi.org (M.B.); chiara.medori@assomagi.org (M.C.M.) 3 MAGI EUREGIO, Via Maso Delle Pieve 60/A, 39100 Bolzano, Italy 4 MAGISNAT, Atlanta Tech Park, 107 Technology, Parkway, Peachtree Corners, GA 30092, USA * Correspondence: mariacristina.parravano@fondazionebietti.it; Tel.: +39-067-705-2963 Abstract: PRPH2 gene mutations are frequently found in inherited retinal dystrophies (IRD) and are associated with a wide spectrum of clinical phenotypes. We studied 28 subjects affected by IRD carrying pathogenic PRPH2 mutations, belonging to 11 unrelated families. Functional tests (best- corrected visual acuity measurement, chromatic test, visual field, full-field, 30 Hz flicker, and multifocal electroretinogram), morphological retino-choroidal imaging (optical coherence tomography, optical coherence tomography angiography, and fundus autofluorescence), and clinical data were collected and analyzed. Common primary complaints, with onset in their 40s, were visual acuity reduction and abnormal dark adaptation. Visual acuity ranged from light perception to 20/20 Snellen. Visual field peripheral constriction and central scotoma were found. Chromatic sense was reduced in one third of patients. Electrophysiological tests were abnormal in most of the patients. Choroidal neovascular lesions were detected in five patients. Three novel PRPH2 variants were found in four different families. Based on the present multimodal study, we identified seven distinct PRPH2 phenotypes in 11 unrelated families carrying either different mutations or the same mutation, both within the same family or among them. Fundus autofluorescence modality turned out to be the most adequate imaging method for early recognition of this dystrophy, and the optical coherence tomography angiography was highly informative to promptly detect choroidal neovascularization, even in the presence of the extensive chorioretinal atrophy phenotype. Keywords: PRPH2; retinal dystrophy; novel variants; choroidal neovascularization; extensive chorioretinal atrophy; multimodal imaging; electroretinogram 1. Introduction Mutations in the peripherin-2 (PRPH2) gene are frequently found in inherited retinal diseases (IRD) [1,2]. This gene is located on chromosome 6p21.2 and is also known as retinal degeneration slow (RDS) gene. The gene product, the PRPH2 protein, is a member of the tetraspanin family, a transmembrane structural glycoprotein with an integral role in the formation and structure of both rod and cone photoreceptor outer segments [3,4]. The protein, containing four transmembrane domains and an intracellular domain, forms intramolecular disulfide bonds [5–7] and mediates assembly of peripherin-2/retinal outer segment membrane protein 1 (PRHP2/ROM1) tetramers into covalently linked higher-order complexes [7]. The formation of this protein complex is quite important for the functional Citation: Antonelli, G.; Parravano, M.; Barbano, L.; Costanzo, E.; Bertelli, M.; Medori, M.C.; Parisi, V.; Ziccardi, L. Multimodal Study of PRPH2 Gene-Related Retinal Phenotypes. Diagnostics 2022, 12, 1851. https://doi.org/10.3390/diagnostics12 081851 Academic Editor: Antonio Ferreras Received: 6 July 2022 Accepted: 29 July 2022 Published: 31 July 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/license s/by/4.0/).