@article{2e18ab4789ab4c76b14849e207dbfaf8,
title = "Comprehensive variant spectrum of the CNGA3 gene in patients affected by achromatopsia",
abstract = "Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by impaired color discrimination, low visual acuity, photosensitivity, and nystagmus. To date, six genes have been associated with ACHM (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6), the majority of these being implicated in the cone phototransduction cascade. CNGA3 encodes the CNGA3 subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors and is one of the major disease-associated genes for ACHM. Herein, we provide a comprehensive overview of the CNGA3 variant spectrum in a cohort of 1060 genetically confirmed ACHM patients, 385 (36.3%) of these carrying “likely disease-causing” variants in CNGA3. Compiling our own genetic data with those reported in the literature and in public databases, we further extend the CNGA3 variant spectrum to a total of 316 variants, 244 of which we interpreted as “likely disease-causing” according to ACMG/AMP criteria. We report 48 novel “likely disease-causing” variants, 24 of which are missense substitutions underlining the predominant role of this mutation class in the CNGA3 variant spectrum. In addition, we provide extensive in silico analyses and summarize reported functional data of previously analyzed missense, nonsense and splicing variants to further advance the pathogenicity assessment of the identified variants.",
keywords = "CNGA3, achromatopsia, cyclic nucleotide-gated ion channel, in silico analysis, variant classification, variant spectrum",
author = "Maria Solaki and Britta Baumann and Peggy Reuter and Sten Andreasson and Isabelle Audo and Carmen Ayuso and Ghassan Balousha and Francesco Benedicenti and David Birch and Pierre Bitoun and Delphine Blain and Beatrice Bocquet and Kari Branham and Jaume Catal{\`a}-Mora and {De Baere}, Elfride and Helene Dollfus and Mohammed Falana and Roberto Giorda and Irina Golovleva and Irene Gottlob and Heckenlively, {John R.} and Jacobson, {Samuel G.} and Kaylie Jones and Herbert J{\"a}gle and Janecke, {Andreas R.} and Ulrich Kellner and Petra Liskova and Birgit Lorenz and Loreto Martorell-Sampol and Andr{\'e} Messias and Isabelle Meunier and {Belga Ottoni Porto}, Fernanda and Eleni Papageorgiou and Plomp, {Astrid S.} and {de Ravel}, {Thomy J.L.} and Reiff, {Charlotte M.} and Renner, {Agnes B.} and Thomas Rosenberg and G{\"u}nther Rudolph and Roberto Salati and Sener, {E. Cumhur} and Sieving, {Paul A.} and Franco Stanzial and Traboulsi, {Elias I.} and Tsang, {Stephen H.} and Bal{\'a}zs Varsanyi and Weleber, {Richard G.} and Ditta Zobor and Katarina Stingl and Bernd Wissinger and Susanne Kohl",
note = "Funding Information: The authors would like to thank all patients and their families for participating in this study. We would also like to acknowledge the contributions of Agnes Farkas (Budapest, Hungary) and the deceased Christian Hamel (Montpellier, France). Jana Morav{\'i}kov{\'a} performed segregation analysis in samples of Czech origin. This study was funded by the Deutsche Forschungsgemeinschaft as part of the SPP 2127: Gene and cell-based therapies to counteract neuroretinal degeneration, project numbers: KO 2176/3-1, 398539671 to S. Kohl and STI 727/1-1, 399487883 to K. Stingl. In addition, S. Kohl has received reimbursement for CNGA3 variant deposition at the LOVD, which is supported by a Research Core Award of the Foundation Fighting Blindness Inc. (award number BR-GE-0120-0775-LUMC) to J. T. den Dunnen, F. P. M. Cremers, I. F. A. C. Fokkema, and S. Roosing. S. Kohl, K. Stingl, I. Audo, I. Meunier, H. Dollfus, E. De Baere, P. Liskova, and B. Lorenz are members of ERN-EYE. This study was supported by the Instituto de Salud Carlos III (ISCIII) of the Spanish Ministry of Health (FIS PI19/00321). I. Audo was supported by LabEx LifeSenses, IHU FOReSIGHT, and Foundation Fighting Blindness grant (BR-GE-0619-0761-INSERM). Samples from I. Audo originate from NeuroSensCol, a biobank for research in neuroscience (PI: J. A. Sahel, coPI I. Audo, partner with Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM, and CNRS). The authors are thankful to the patients and family members participating in the study and clinical staff from the Centre d'Investigation Clinique CIC1438. P. L. was supported by the Ministry of Health of the Czech Republic (AZV NU20-07-00182 research grant). Open access funding enabled and organized by Projekt DEAL. Funding Information: The authors would like to thank all patients and their families for participating in this study. We would also like to acknowledge the contributions of Agnes Farkas (Budapest, Hungary) and the deceased Christian Hamel (Montpellier, France). Jana Morav{\'i}kov{\'a} performed segregation analysis in samples of Czech origin. This study was funded by the Deutsche Forschungsgemeinschaft as part of the SPP 2127: Gene and cell‐based therapies to counteract neuroretinal degeneration, project numbers: KO 2176/3‐1, 398539671 to S. Kohl and STI 727/1‐1, 399487883 to K. Stingl. In addition, S. Kohl has received reimbursement for CNGA3 variant deposition at the LOVD, which is supported by a Research Core Award of the Foundation Fighting Blindness Inc. (award number BR‐GE‐0120‐0775‐LUMC) to J. T. den Dunnen, F. P. M. Cremers, I. F. A. C. Fokkema, and S. Roosing. S. Kohl, K. Stingl, I. Audo, I. Meunier, H. Dollfus, E. De Baere, P. Liskova, and B. Lorenz are members of ERN‐EYE. This study was supported by the Instituto de Salud Carlos III (ISCIII) of the Spanish Ministry of Health (FIS PI19/00321). I. Audo was supported by LabEx LifeSenses, IHU FOReSIGHT, and Foundation Fighting Blindness grant (BR‐GE‐0619‐0761‐INSERM). Samples from I. Audo originate from NeuroSensCol, a biobank for research in neuroscience (PI: J. A. Sahel, coPI I. Audo, partner with Centre Hospitalier National d'Ophtalmologie des Quinze‐Vingts, INSERM, and CNRS). The authors are thankful to the patients and family members participating in the study and clinical staff from the Centre d'Investigation Clinique CIC1438. P. L. was supported by the Ministry of Health of the Czech Republic (AZV NU20‐07‐00182 research grant). Open access funding enabled and organized by Projekt DEAL. Funding Information: S. H. Tsang is salaried by the National Institute of Health 5P30CA013696, U01 EY030580, R01EY033770, R01EY018213, R01EY024698, R24EY028758, R24EY027285, 5P30EY019007, U54OD020351, and R21AG050437. S. H. Tsang receives grant support from Abeona Therapeutics, Inc and Emendo. He is also the founder of Rejuvitas and is on the scientific and clinical advisory board for Nanoscope Therapeutics. The other authors declared no conflict of interest. Publisher Copyright: {\textcopyright} 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.",
year = "2022",
month = jul,
doi = "10.1002/humu.24371",
language = "English (US)",
volume = "43",
pages = "832--858",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "Wiley-Liss Inc.",
number = "7",
}