Comprehensive variant spectrum of the
            <i>CNGA3</i>
            gene in patients affected by achromatopsia

Solaki, Maria; Baumann, Britta; Reuter, Peggy; Andréasson, Sten; Audo, Isabelle; Ayuso, Carmen; Balousha, Ghassan; Benedicenti, Francesco; Birch, David G.; Bitoun, Pierre; Blain, Delphine; Bocquet, Béatrice; Branham, Kari; Català‐Mora, Jaume; Baere, Elfride De; Dollfus, Hélène; Falana, Mohammed; Giorda, Roberto; Golovleva, Irina; Gottlob, Irène; Heckenlively, John R.; Jacobson, Samuel G.; Webb‐Jones, Kaylie; Jägle, Herbert; Janecke, Andreas R.; Kellner, Ulrich; Lišková, Petra; Lorenz, Birgit; Martorell, Loreto; Messias, André; Meunier, Isabelle; Porto, Fernanda Belga Ottoni; Papageorgiou, Eleni; Plomp, Astrid S.; Ravel, Thomy J.L.; Reiff, Charlotte; Renner, Agnes B.; Rosenberg, Thomas; Rudolph, Günther; Salati, R.; Şener, Emin Cumhur; Sieving, Paul A.; Stanzial, Franco; Traboulsi, Elias I.; Tsang, Stephen H.; Varsányi, Balázs; Weleber, Richard G.; Zobor, Ditta; Štingl, Katarína; Wissinger, Bernd; Kohl, Susanne

doi:10.1002/humu.24371

Cited by 11 publications

(14 citation statements)

References 130 publications

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“…Variants in CNGA3 were the second most frequent cause of ACHM in our cohort and were most predominantly missense variants resulting from single base pair substitutions, and have all been previously published [ 13 , 24 , 38 , 39 , 40 , 41 , 42 ].…”

Section: Resultsmentioning

confidence: 72%

Genetic and Clinical Characterization of Danish Achromatopsia Patients

Andersen

Bertelsen

Grønskov

et al. 2023

Genes

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Achromatopsia is a rare congenital condition with cone photoreceptor dysfunction causing color blindness, reduced vision, nystagmus and photophobia. New treatments are being developed, but the current evidence is still conflicting regarding possible progression over time, and there is no clear genotype-phenotype correlation. This natural history study aimed to further explore the course of disease and potential clinical differences between various genotypes. The retrospective design allowed for the study of a large cohort with a long follow-up. Patients were identified from the Danish national registries. If not already available, genetic analysis was offered to the patient. Clinical data from 1945–2022 were retrieved from medical records and included best-corrected visual acuity (BCVA), color vision, refractive error, nystagmus, visual fields and fundoscopic findings. We identified variants believed to be disease causing in five of the known achromatopsia genes: CNGA3; CNGB3; GNAT2; PDE6C and PDE6H; and novel variants were identified in CNGB3 and PDE6C. Progressive deterioration of BCVA only attributable to achromatopsia was found in three of 58 patients. Progressive phenotype was seen with variants in CNGB3 and PDE6C. The results indicate that myopia could be more frequently occurring with variants in GNAT2, PDE6C and PDE6H and support the evidence that achromatopsia is a predominantly stationary condition with respect to BCVA. Although a clear genotype-phenotype correlation can still not be concluded, there may be differences in phenotypical characteristics with variants in different genes.

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Section: Resultsmentioning

confidence: 72%

Genetic and Clinical Characterization of Danish Achromatopsia Patients

Andersen

Bertelsen

Grønskov

et al. 2023

Genes

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“…1 ). The variants were either identified in our cohort of achromatopsia patients 9 , or reported as disease-associated in HGMD 8 , ClinVar 10 , and LOVD 11 . Note that we have not included variants with a minor allele frequency > 0.05 in the population database gnomAD ( https://gnomad.broadinstitute.org/ ) and that we have not considered variants deep in introns that were not predicted to create or strengthen a cryptic splice site.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, it is very likely that CNGA3-ACHM patients with a splice variant on one allele have a missense variant on the other allele. The majority of variants were previously classified according to ACMG guidelines 2 , 9 , with two variants classified as benign, two as likely benign, eight as VUS, six as likely pathogenic, and two as pathogenic. We reclassified the variants considering the results of our minigene assays by applying the BS3 criterion for variants not affecting splicing and the PS3 criterion for variants that induced missplicing in the minigene assay.…”

Section: Resultsmentioning

confidence: 99%

“…The mutation spectrum is dominated by nonsense and missense mutations (n = 163) whereas splice mutations are comparably rare (n = 7). We have recently published a mutation overview of our cohort of 889 unrelated achromatopsia patients, 304 of which harbor putatively pathogenic variants in CNGA3 9 . Several patients in that cohort carry splice site variants in CNGA3 classified as VUS.…”

Section: Introductionmentioning

confidence: 99%

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Systematic analysis of CNGA3 splice variants identifies different mechanisms of aberrant splicing

Reuter

Walter

Kohl

et al. 2023

Sci Rep

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Achromatopsia is an autosomal recessive cone photoreceptor disease that is frequently caused by pathogenic variants in the CNGA3 gene. Here, we present a systematic functional analysis of 20 CNGA3 splice site variants detected in our large cohort of achromatopsia patients and/or listed in common variant databases. All variants were analyzed by functional splice assays based on the pSPL3 exon trapping vector. We demonstrated that ten variants, both at canonical and non-canonical splice sites, induced aberrant splicing, including intronic nucleotide retention, exonic nucleotide deletion and exon skipping, resulting in 21 different aberrant transcripts. Of these, eleven were predicted to introduce a premature termination codon. The pathogenicity of all variants was assessed based on established guidelines for variant classification. Incorporation of the results of our functional analyses enabled re-classification of 75% of variants previously classified as variants of uncertain significance into either likely benign or likely pathogenic. Our study is the first in which a systematic characterization of putative CNGA3 splice variants has been performed. We demonstrated the utility of pSPL3 based minigene assays in the effective assessment of putative splice variants. Our findings improve the diagnosis of achromatopsia patients, who may thus benefit from future gene-based therapeutic strategies.

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“…Table 3 resumes variant data, showing the allele count in this cohort and the total allele frequency from all populations in gnomAD. The prevalence of CNGA3 or CNGB3 variants varies globally [9][10][11]. Mayer et al evaluated CNGB3 pathogenic variants in 485 independent families with ACHM, mainly of Western Europe and North America descent [10].…”

Section: Resultsmentioning

confidence: 99%

Molecular and Clinical Characterization of CNGA3 and CNGB3 Genes in Brazilian Patients Affected with Achromatopsia

Amaral

Motta²,

Zin

et al. 2023

Genes

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Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by reduced visual acuity, nystagmus, photophobia, and very poor or absent color vision. Pathogenic variants in six genes encoding proteins composing the cone phototransduction cascade (CNGA3, CNGB3, PDE6C, PDE6H, GNAT2) and of the unfolded protein response (ATF6) have been related to ACHM cases, while CNGA3 and CNGB3 alone are responsible for most cases. Herein, we provide a clinical and molecular overview of 42 Brazilian patients from 38 families affected with ACHM related to biallelic pathogenic variants in the CNGA3 and CNGB3 genes. Patients’ genotype and phenotype were retrospectively evaluated. The majority of CNGA3 variants were missense, and the most prevalent CNGB3 variant was c.1148delC (p.Thr383Ilefs*13), resulting in a frameshift and premature stop codon, which is compatible with previous publications in the literature. A novel variant c.1893T > A (p.Tyr631*) in the CNGB3 gene is reported for the first time in this study. A great variability in morphologic findings was observed in our patients, although no consistent correlation with age and disease stage in OCT foveal morphology was found. The better understanding of the genetic variants landscape in the Brazilian population will help in the diagnosis of this disease.

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

Cited by 11 publications

References 130 publications

Genetic and Clinical Characterization of Danish Achromatopsia Patients

Genetic and Clinical Characterization of Danish Achromatopsia Patients

Systematic analysis of CNGA3 splice variants identifies different mechanisms of aberrant splicing

Molecular and Clinical Characterization of CNGA3 and CNGB3 Genes in Brazilian Patients Affected with Achromatopsia

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