CNGB3 mutations cause severe rod dysfunction

Maguire, John F.; McKibbin, Martin; Khan, Kamron; Kohl, Susanne; Ali, Manir; McKeefry, Declan J.

doi:10.1080/13816810.2017.1368087

Cited by 11 publications

(7 citation statements)

References 38 publications

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“…Achromatopsia (ACHM) presents from birth or early infancy, with poor visual acuity, pendular nystagmus, photophobia, and color vision loss in all three axes 1,2. Absent cone electroretinogram responses is the hallmark of disease, with normal rod function or uncommonly mildly reduced rod responses 3–5. ACHM is an autosomal recessive disorder with a heterogeneous genetic background.…”

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confidence: 99%

Adaptive Optics Retinal Imaging inCNGA3-Associated Achromatopsia: Retinal Characterization, Interocular Symmetry, and Intrafamilial Variability

Georgiou

Litts

Kalitzeos

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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Citation: Georgiou M, Litts KM, Kalitzeos A, et al. Adaptive optics retinal imaging in CNGA3-associated achromatopsia: retinal characterization, interocular symmetry, and intrafamilial variability. Invest Ophthalmol Vis Sci. 2019;60:383-396. https://doi.org/ 10.1167/iovs.18-25880 PURPOSE. To investigate retinal structure in subjects with CNGA3-associated achromatopsia and evaluate disease symmetry and intrafamilial variability.METHODS. Thirty-eight molecularly confirmed subjects underwent ocular examination, optical coherence tomography (OCT), and nonconfocal split-detection adaptive optics scanning light ophthalmoscopy (AOSLO). OCT scans were used for evaluating foveal hypoplasia, grading foveal ellipsoid zone (EZ) disruption, and measuring outer nuclear layer (ONL) thickness. AOSLO images were used to quantify peak foveal cone density, intercell distance (ICD), and the coefficient of variation (CV) of ICD.RESULTS. Mean (6SD) age was 25.9 (613.1) years. Mean (6 SD) best corrected visual acuity (BCVA) was 0.87 (60.14) logarithm of the minimum angle of resolution. Examination with OCT showed variable disruption or loss of the EZ. Seven subjects were evaluated for disease symmetry, with peak foveal cone density, ICD, CV, ONL thickness, and BCVA not differing significantly between eyes. A cross-sectional evaluation of AOSLO imaging showed a mean (6SD) peak foveal cone density of 19,844 (613,046) cones/mm 2 . There was a weak negative association between age and peak foveal cone density (r ¼ À0.397, P ¼ 0.102), as well as between EZ grade and age (P ¼ 0.086).CONCLUSIONS. The remnant cone mosaics were irregular and variably disrupted, with significantly lower peak foveal cone density than unaffected individuals. Variability was also seen among subjects with identical mutations. Therefore, subjects should be considered on an individual basis for stratification in clinical trials. Interocular symmetry suggests that both eyes have comparable therapeutic potential and the fellow eye can serve as a valid control. Longitudinal studies are needed, to further examine the weak negative association between age and foveal cone structure observed here.

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confidence: 99%

Adaptive Optics Retinal Imaging inCNGA3-Associated Achromatopsia: Retinal Characterization, Interocular Symmetry, and Intrafamilial Variability

Georgiou

Litts

Kalitzeos

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…Both the GEDi testing and WES identified a single rare variant in the CNGB3 gene (c.1148delC, p.Thr383IlefsTer13) which has been reported to be pathogenic 66–68 , but a second rare variant in CNGB3 was not identified, nor were other potential causative genetic variants forthcoming for the two affected members of the family. CNGB3 mutations are among the most common causes of cone dysfunction syndrome, but to the best of our knowledge, Chiari malformations have not been reported as an accompanying symptom in CNGB3 patients 69, 70 . Moreover, the 1.75e -3 gnomAD allele frequency of the p.Thr383IlefsTer13 variant is higher than expected for recessive pathogenic variants and two homozygous individuals are reported in the gnomAD database.…”

Section: Resultsmentioning

confidence: 77%

A combined RNA-seq and whole genome sequencing approach for identification of non-coding pathogenic variants in single families

Bronstein

Capowski

Mehrotra

et al. 2019

Preprint

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Inherited retinal degenerations (IRDs) are at the focus of current genetic therapeutic advancements. For a genetic treatment such as gene therapy to be successful an accurate genetic diagnostic is required. Genetic diagnostics relies on the assessment of the probability that a given DNA variant is pathogenic. Non-coding variants present a unique challenge for such assessments as compared to coding variants. For one, non-coding variants are present at much higher number in the genome than coding variants. In addition, our understanding of the rules that govern the non-coding regions of the genome is less complete than our understanding of the coding regions. Methods that allow for both the identification of candidate non-coding pathogenic variants and their functional validation may help overcome these caveats allowing for a greater number of patients to benefit from advancements in genetic therapeutics. We present here an unbiased approach combining whole genome sequencing (WGS) with patient induced pluripotent stem cell (iPSC) derived retinal organoids (ROs) transcriptome analysis. With this approach we identified and functionally validated a novel pathogenic non-coding variant in a small family with a previously unresolved genetic diagnosis.

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“…Both the GEDi testing and WES identified a single rare variant in the CNGB3 gene (c.1148delC, p.Thr383IlefsTer13) which has been reported to be pathogenic [66][67][68] , but a second rare variant in CNGB3 was not identified, nor were other potential causative genetic variants forthcoming for the two affected members of the family. CNGB3 mutations are among the most common causes of cone dysfunction syndrome, but to the best of our knowledge, Chiari malformations have not been reported as an accompanying symptom in CNGB3 patients 69,70 .…”

Section: Unresolved Genetic Analysis Of Family Ogi-081mentioning

confidence: 78%

A combined RNA-seq and whole genome sequencing approach for identification of non-coding pathogenic variants in single families

Bronstein

Capowski

Mehrotra

et al. 2020

Human Molecular Genetics

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Inherited retinal degenerations (IRDs) are at the focus of current genetic therapeutic advancements. For a genetic treatment such as gene therapy to be successful, an accurate genetic diagnostic is required. Genetic diagnostics relies on the assessment of the probability that a given DNA variant is pathogenic. Non-coding variants present a unique challenge for such assessments as compared to coding variants. For one, non-coding variants are present at much higher number in the genome than coding variants. In addition, our understanding of the rules that govern the non-coding regions of the genome is less complete than our understanding of the coding regions. Methods that allow for both the identification of candidate non-coding pathogenic variants and their functional validation may help overcome these caveats allowing for a greater number of patients to benefit from advancements in genetic therapeutics. We present here an unbiased approach combining whole genome sequencing (WGS) with patient-induced pluripotent stem cell (iPSC)-derived retinal organoids (ROs) transcriptome analysis. With this approach, we identified and functionally validated a novel pathogenic non-coding variant in a small family with a previously unresolved genetic diagnosis.

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CNGB3 mutations cause severe rod dysfunction

Cited by 11 publications

References 38 publications

Adaptive Optics Retinal Imaging inCNGA3-Associated Achromatopsia: Retinal Characterization, Interocular Symmetry, and Intrafamilial Variability

Adaptive Optics Retinal Imaging inCNGA3-Associated Achromatopsia: Retinal Characterization, Interocular Symmetry, and Intrafamilial Variability

A combined RNA-seq and whole genome sequencing approach for identification of non-coding pathogenic variants in single families

A combined RNA-seq and whole genome sequencing approach for identification of non-coding pathogenic variants in single families

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