Comprehensive variant spectrum of the CNGA3 gene in patients affected by achromatopsia

Maria Solaki; Britta Baumann; Peggy Reuter; Sten Andreasson; Isabelle Audo; Carmen Ayuso; Ghassan Balousha; Francesco Benedicenti; David Birch; Pierre Bitoun; Delphine Blain; Beatrice Bocquet; Kari Branham; Jaume Català-Mora; Elfride de Baere; Helene Dollfus; Mohammed Falana; Roberto Giorda; Irina Golovleva; Irene Gottlob; John R. Heckenlively; Samuel G. Jacobson; Kaylie Jones; Herbert Jägle; Andreas R. Janecke; Ulrich Kellner; Petra Liskova; Birgit Lorenz; Loreto Martorell-Sampol; André Messias; Isabelle Meunier; Fernanda Belga Ottoni Porto; Eleni Papageorgiou; Astrid S. Plomp; Thomy J. L. de Ravel; Charlotte M. Reiff; Agnes B. Renner; Thomas Rosenberg; G. nther Rudolph; Roberto Salati; E. Cumhur Sener; Paul A. Sieving; Franco Stanzial; Elias I. Traboulsi; Stephen H. Tsang; Balázs Varsanyi; Richard G. Weleber; Ditta Zobor; Katarina Stingl; Bernd Wissinger; Susanne Kohl

doi:https://doi.org/10.1002/humu.24371

Comprehensive variant spectrum of the CNGA3 gene in patients affected by achromatopsia

Maria Solaki, Britta Baumann, Peggy Reuter, Sten Andreasson, Isabelle Audo, Carmen Ayuso, Ghassan Balousha, Francesco Benedicenti, David Birch, Pierre Bitoun, Delphine Blain, Beatrice Bocquet, Kari Branham, Jaume Català-Mora, Elfride de Baere, Helene Dollfus, Mohammed Falana, Roberto Giorda, Irina Golovleva, Irene GottlobJohn R. Heckenlively, Samuel G. Jacobson, Kaylie Jones, Herbert Jägle, Andreas R. Janecke, Ulrich Kellner, Petra Liskova, Birgit Lorenz, Loreto Martorell-Sampol, André Messias, Isabelle Meunier, Fernanda Belga Ottoni Porto, Eleni Papageorgiou, Astrid S. Plomp, Thomy J. L. de Ravel, Charlotte M. Reiff, Agnes B. Renner, Thomas Rosenberg, G. nther Rudolph, Roberto Salati, E. Cumhur Sener, Paul A. Sieving, Franco Stanzial, Elias I. Traboulsi, Stephen H. Tsang, Balázs Varsanyi, Richard G. Weleber, Ditta Zobor, Katarina Stingl, Bernd Wissinger, Susanne Kohl

Research output: Contribution to journal › Article › Academic › peer-review

9 Citations (Scopus)

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.

Original language	English
Pages (from-to)	832-858
Number of pages	27
Journal	Human mutation
Volume	43
Issue number	7
Early online date	2022
DOIs	https://doi.org/10.1002/humu.24371
Publication status	Published - Jul 2022

Keywords

CNGA3
achromatopsia
cyclic nucleotide-gated ion channel
in silico analysis
variant classification
variant spectrum

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https://doi.org/10.1002/humu.24371

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Solaki, M., Baumann, B., Reuter, P., Andreasson, S., Audo, I., Ayuso, C., Balousha, G., Benedicenti, F., Birch, D., Bitoun, P., Blain, D., Bocquet, B., Branham, K., Català-Mora, J., de Baere, E., Dollfus, H., Falana, M., Giorda, R., Golovleva, I., ... Kohl, S. (2022). Comprehensive variant spectrum of the CNGA3 gene in patients affected by achromatopsia. Human mutation, 43(7), 832-858. https://doi.org/10.1002/humu.24371

@article{f0bfeb0151bc4671923ab84549bb431d,

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 Rudolph, {G. nther} 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 = "https://doi.org/10.1002/humu.24371",

language = "English",

volume = "43",

pages = "832--858",

journal = "Human mutation",

issn = "1059-7794",

publisher = "Wiley-Liss Inc.",

number = "7",

}

Solaki, M, Baumann, B, Reuter, P, Andreasson, S, Audo, I, Ayuso, C, Balousha, G, Benedicenti, F, Birch, D, Bitoun, P, Blain, D, Bocquet, B, Branham, K, Català-Mora, J, de Baere, E, Dollfus, H, Falana, M, Giorda, R, Golovleva, I, Gottlob, I, Heckenlively, JR, Jacobson, SG, Jones, K, Jägle, H, Janecke, AR, Kellner, U, Liskova, P, Lorenz, B, Martorell-Sampol, L, Messias, A, Meunier, I, Belga Ottoni Porto, F, Papageorgiou, E, Plomp, AS, de Ravel, TJL, Reiff, CM, Renner, AB, Rosenberg, T, Rudolph, GN, Salati, R, Sener, EC, Sieving, PA, Stanzial, F, Traboulsi, EI, Tsang, SH, Varsanyi, B, Weleber, RG, Zobor, D, Stingl, K, Wissinger, B & Kohl, S 2022, 'Comprehensive variant spectrum of the CNGA3 gene in patients affected by achromatopsia', Human mutation, vol. 43, no. 7, pp. 832-858. https://doi.org/10.1002/humu.24371

TY - JOUR

T1 - Comprehensive variant spectrum of the CNGA3 gene in patients affected by achromatopsia

AU - Solaki, Maria

AU - Baumann, Britta

AU - Reuter, Peggy

AU - Andreasson, Sten

AU - Audo, Isabelle

AU - Ayuso, Carmen

AU - Balousha, Ghassan

AU - Benedicenti, Francesco

AU - Birch, David

AU - Bitoun, Pierre

AU - Blain, Delphine

AU - Bocquet, Beatrice

AU - Branham, Kari

AU - Català-Mora, Jaume

AU - de Baere, Elfride

AU - Dollfus, Helene

AU - Falana, Mohammed

AU - Giorda, Roberto

AU - Golovleva, Irina

AU - Gottlob, Irene

AU - Heckenlively, John R.

AU - Jacobson, Samuel G.

AU - Jones, Kaylie

AU - Jägle, Herbert

AU - Janecke, Andreas R.

AU - Kellner, Ulrich

AU - Liskova, Petra

AU - Lorenz, Birgit

AU - Martorell-Sampol, Loreto

AU - Messias, André

AU - Meunier, Isabelle

AU - Belga Ottoni Porto, Fernanda

AU - Papageorgiou, Eleni

AU - Plomp, Astrid S.

AU - de Ravel, Thomy J. L.

AU - Reiff, Charlotte M.

AU - Renner, Agnes B.

AU - Rosenberg, Thomas

AU - Rudolph, G. nther

AU - Salati, Roberto

AU - Sener, E. Cumhur

AU - Sieving, Paul A.

AU - Stanzial, Franco

AU - Traboulsi, Elias I.

AU - Tsang, Stephen H.

AU - Varsanyi, Balázs

AU - Weleber, Richard G.

AU - Zobor, Ditta

AU - Stingl, Katarina

AU - Wissinger, Bernd

AU - Kohl, Susanne

N1 - 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 Moravíková 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 Moravíková 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: © 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.

PY - 2022/7

Y1 - 2022/7

N2 - 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.

AB - 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.

KW - CNGA3

KW - achromatopsia

KW - cyclic nucleotide-gated ion channel

KW - in silico analysis

KW - variant classification

KW - variant spectrum

UR - http://www.scopus.com/inward/record.url?scp=85129080727&partnerID=8YFLogxK

U2 - https://doi.org/10.1002/humu.24371

DO - https://doi.org/10.1002/humu.24371

M3 - Article

C2 - 35332618

SN - 1059-7794

VL - 43

SP - 832

EP - 858

JO - Human mutation

JF - Human mutation

IS - 7

ER -

Comprehensive variant spectrum of the CNGA3 gene in patients affected by achromatopsia

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