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

被引：15

作者：

Solaki, Maria ^{[1
]}

Baumann, Britta ^{[1
]}

Reuter, Peggy ^{[1
]}

Andreasson, Sten ^{[2
]}

Audo, Isabelle ^{[3
,4
,5
]}

Ayuso, Carmen ^{[6
,7
]}

Balousha, Ghassan ^{[8
]}

Benedicenti, Francesco ^{[9
,10
]}

Birch, David ^{[11
]}

Bitoun, Pierre ^{[12
]}

Blain, Delphine ^{[13
]}

Bocquet, Beatrice ^{[14
]}

Branham, Kari ^{[15
]}

Catala-Mora, Jaume ^{[16
]}

De Baere, Elfride ^{[17
,18
]}

Dollfus, Helene ^{[19
,20
]}

Falana, Mohammed

Giorda, Roberto ^{[21
]}

Golovleva, Irina ^{[22
]}

Gottlob, Irene ^{[23
]}

Heckenlively, John R.

Jacobson, Samuel G. ^{[24
]}

Jones, Kaylie

Jaegle, Herbert ^{[25
]}

Janecke, Andreas R. ^{[26
]}

Kellner, Ulrich ^{[27
,28
]}

Liskova, Petra ^{[29
,30
,31
,32
]}

Lorenz, Birgit ^{[33
,34
]}

Martorell-Sampol, Loreto ^{[35
]}

Messias, Andre ^{[36
]}

Meunier, Isabelle ^{[37
,38
]}

Belga Ottoni Porto, Fernanda ^{[39
]}

Papageorgiou, Eleni ^{[40
]}

Plomp, Astrid S. ^{[41
]}

de Ravel, Thomy J. L.

Reiff, Charlotte M. ^{[42
]}

Renner, Agnes B. ^{[43
]}

Rosenberg, Thomas ^{[44
]}

Rudolph, Guenther ^{[45
]}

Salati, Roberto ^{[46
]}

Sener, E. Cumhur ^{[47
]}

Sieving, Paul A. ^{[48
]}

Stanzial, Franco ^{[10
]}

Traboulsi, Elias, I ^{[49
]}

Tsang, Stephen H. ^{[50
]}

Varsanyi, Balazs ^{[51
,52
]}

Weleber, Richard G. ^{[53
]}

Zobor, Ditta ^{[54
,55
]}

Stingl, Katarina ^{[56
]}

Wissinger, Bernd ^{[1
]}

机构：

[1] Univ Tubingen, Inst Ophthalm Res, Ctr Ophthalmol, Tubingen, Germany

[2] Univ Hosp Lund, Dept Ophthalmol, Lund, Sweden

[3] Sorbonne Univ, Inst Vis, INSERM, CNRS, Paris, France

[4] CHNO Quinze Vingts, Ctr Reference Malad Rares, REFERET, Paris, France

[5] CHNO Quinze Vingts, INSERM DGOS CIC 1423, Paris, France

[6] Univ Autonoma Madrid IISFJD UAM, Fdn Jimenez Diaz Univ Hosp, Inst Invest Sanitaria, Dept Genet & Gen, Madrid, Spain

[7] ISCIII, Ctr Biomed Network Res Rare Dis CIBERER, Madrid, Spain

[8] Al Quds Univ, Fac Med, Dept Pathol & Histol, Eastern Jerusalem, Palestine

[9] Reg Hosp Bolzano, Clin Genet Serv, Bolzano, Italy

[10] Reg Hosp Bolzano, South Tyrol Coordinat Ctr Rare Dis, Dept Pediat, Bolzano, Italy

[11] Retina Fdn SW, Dallas, TX USA

[12] CHU Paris Nord, Hop Jean Verdier, Genet Med, Bondy, France

[13] Natl Eye Inst NEI, Bethesda, MD USA

[14] Univ Montpellier, Inst Neurosci Montpellier INM, Natl Reference Ctr Inherited Sensory Dis, INSERM, Montpellier, France

[15] Univ Michigan, Kellogg Eye Ctr, Dept Ophthalmol & Visual Sci, Ann Arbor, MI USA

[16] Hosp San Juan Dios, Unitat Distrofies Hereditaries Retina, Barcelona, Spain

[17] Univ Ghent, Ctr Med Genet, Dept Biomol Med, Ghent, Belgium

[18] Ghent Univ Hosp, Ghent, Belgium

[19] Hop Univ Strasbourg, CARGO, Strasbourg, France

[20] Univ Strasbourg, Inserm, Fac Med, U 1112, Strasbourg, France

[21] Sci Inst IRCCS E Medea, Mol Biol Lab, Bosisio Parini, Lecco, Italy

[22] Univ Umea, Dept Med Biosci Med & Clin Genet, Umea, Sweden

[23] Univ Leicester, Ulverscroft Eye Unit, Leicester Royal Infirm, Leicester, England

[24] Univ Penn, Scheie Eye Inst, Perelman Sch Med, Dept Ophthalmol, Philadelphia, PA USA

[25] Univ Regensburg, Dept Ophthalmol, Regensburg, Germany

[26] Med Univ Innsbruck, Inst Human Genet, Innsbruck, Austria

[27] MVZ Augenarztliches Diag & Therapiecentrum Siegbu, Augen Zentrum Siegburg, Zentrum Seltene Netzhauterkrankungen, Siegburg, Germany

[28] Retina Sci, D-53192 Bonn, Germany

[29] Charles Univ Prague, Fac Med 1, Dept Paediat & Inherited Metab Disorders, Prague, Czech Republic

[30] Charles Univ Prague, Gen Univ Hosp, Prague, Czech Republic

[31] Charles Univ Prague, Fac Med 1, Dept Ophthalmol, Prague, Czech Republic

[32] Gen Univ Hosp Prague, Prague, Czech Republic

[33] Justus Liebig Univ Giessen, Dept Ophthalmol, Giessen, Germany

[34] Univ Klinikum Bonn, Dept Ophthalmol, Bonn, Germany

[35] Hosp San Juan Dios, Genet Mol Edifici Docent, Barcelona, Spain

[36] Univ Sao Paulo, Dept Ophthalmol Otorhinolaryngol & Head & Neck Su, Sch Med Ribeirao Preto, Ribeirao Preto, Brazil

[37] Univ Montpellier, Montpellier Univ Hosp, Natl Reference Ctr Inherited Sensory Dis, Montpellier, France

[38] Sensgene Care Network, Marseille, France

[39] IEP Santa Casa Belo Horizonte, INRET Clin & Ctr Pesquisa, Belo Horizonte, MG, Brazil

[40] Univ Hosp Larissa, Dept Ophthalmol, Mezourlo, Larissa, Greece

[41] Univ Amsterdam, Dept Human Genet, Amsterdam UMC, Amsterdam, Netherlands

[42] Augenarztpraxis Stadttheater, Freiburg, Germany

[43] Augenarztpraxis Regensburg, Regensburg, Germany

[44] Glostrup Cty Hosp, Dept Ophthalmol, Natl Eye Clin, Glostrup, Denmark

[45] Ludwig Maximilians Univ Munchen, Univ Eye Hosp, Munich, Germany

[46] IRCCS Eugenio Medea, Pediat Ophthalmol Unit, Sci Inst, Bosisio Parini, Lecco, Italy

[47] Strabismus & Pediat Ophthalmol, Ankara, Turkey

[48] Univ Calif Davis, Ctr Ocular Regenerat Therapy, Sch Med, Sacramento, CA USA

[49] Cleveland Clin Fdn, Cole Eye Inst, Ctr Genet Eye Dis, Cleveland Hts, OH USA

[50] Columbia Univ, Columbia Stem Cell Initiat, Coll Phys & Surg, Dept Ophthalmol Pathol & Cell Biol, New York, NY USA

来源：

HUMAN MUTATION | 2022年 / 43卷 / 07期

关键词：

achromatopsia; CNGA3; cyclic nucleotide-gated ion channel; in silico analysis; variant classification; variant spectrum; UNFOLDED PROTEIN RESPONSE; NUCLEOTIDE-GATED CHANNELS; ALPHA-SUBUNIT; PHOTORECEPTOR DEGENERATION; TOTAL COLOURBLINDNESS; FUNCTIONAL-ANALYSIS; MOLECULAR-GENETICS; PAKISTANI FAMILIES; NONSENSE MUTATION; JAPANESE PATIENT;

D O I：

10.1002/humu.24371

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：832 / 858

页数：27

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