Retinal Phenotypes in Patients Homozygous for the G1961E Mutation in the<i>ABCA4</i>Gene

Burton, David S M; Ali, Manir; McKibbin, Martin

doi:10.1167/iovs.12-11472

Cited by 4 publications

(4 citation statements)

References 3 publications

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“…A striking feature is that the standardized coefficients are similar for each ERG parameter (average r = 0.82), indicating consistency across the different stimulus responses for a given variant. The results are also highly consistent with what is already known about specific milder variants, such as c.5882G>A p.(Gly1961Glu), 18 , 19 c.5603A>T p.(Asn1868Ile), 20 and c.4253+43G>A, 21 and nonsense and frameshift variants, including c.5461-10T>C, 22 , 23 supporting the accuracy of this novel approach.…”

Section: Discussionsupporting

confidence: 88%

“…Figure 6 displays the standardized β-coefficient values for the 47 most common genetic variants in the cohort. Regression analysis showed higher coefficient values are associated with the typically milder variants c.5882G>A p.(Gly1961Glu), 18 , 19 c.5603A>T p.(Asn1868Ile), 20 and intronic variant c.4253+43G>A, 21 while lower coefficient values were associated with known nonsense and frameshift variants, as well as known null-like intronic variant c.5461-10T>C. 22 , 23 Several missense mutations also displayed more negative coefficients, suggesting a more deleterious effect on ABCA4 protein function. Supplementary Table S4 contains the standardized β-coefficients for the 101 variants occurring in two or more patients.…”

Section: Resultsmentioning

confidence: 99%

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Phenotyping of ABCA4 Retinopathy by Machine Learning Analysis of Full-Field Electroretinography

Glinton

Calcagni

Lilaonitkul

et al. 2022

Trans. Vis. Sci. Tech.

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Purpose Biallelic pathogenic variants in ABCA4 are the commonest cause of monogenic retinal disease. The full-field electroretinogram (ERG) quantifies severity of retinal dysfunction. We explored application of machine learning in ERG interpretation and in genotype–phenotype correlations. Methods International standard ERGs in 597 cases of ABCA4 retinopathy were classified into three functional phenotypes by human experts: macular dysfunction alone (group 1), or with additional generalized cone dysfunction (group 2), or both cone and rod dysfunction (group 3). Algorithms were developed for automatic selection and measurement of ERG components and for classification of ERG phenotype. Elastic-net regression was used to quantify severity of specific ABCA4 variants based on effect on retinal function. Results Of the cohort, 57.6%, 7.4%, and 35.0% fell into groups 1, 2, and 3 respectively. Compared with human experts, automated classification showed overall accuracy of 91.8% (SE, 0.169), and 96.7%, 39.3%, and 93.8% for groups 1, 2, and 3. When groups 2 and 3 were combined, the average holdout group accuracy was 93.6% (SE, 0.142). A regression model yielded phenotypic severity scores for the 47 commonest ABCA4 variants. Conclusions This study quantifies prevalence of phenotypic groups based on retinal function in a uniquely large single-center cohort of patients with electrophysiologically characterized ABCA4 retinopathy and shows applicability of machine learning. Novel regression-based analyses of ABCA4 variant severity could identify individuals predisposed to severe disease. Translational Relevance Machine learning can yield meaningful classifications of ERG data, and data-driven scoring of genetic variants can identify patients likely to benefit most from future therapies.

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Section: Discussionsupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Phenotyping of ABCA4 Retinopathy by Machine Learning Analysis of Full-Field Electroretinography

Glinton

Calcagni

Lilaonitkul

et al. 2022

Trans. Vis. Sci. Tech.

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“…We appreciate the interest and comments of Burton et al 1 relating to our recent publication ''Retinal phenotypes in patients homozygous for the G1961E mutation in the ABCA4 gene.'' 2 In our report of 12 patients homozygous for the G1961E mutation, six patients had ''milder'' and six had more ''severe'' retinal disease phenotypes (as suggested by the extent of retinal changes present).…”

mentioning

confidence: 94%

Author Response: Retinal Phenotypes in Patients Homozygous for the G1961E Mutation in theABCA4Gene

Burke

Allikmets

2013

Invest. Ophthalmol. Vis. Sci.

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“…ATP-binding cassette, sub-family A, member 4 (ABCA4) belongs to the transmembrane protein superfamily [9], which is located on chromosome 1p22.1 [10,11]. The ABCA4 is an ATP-binding cassette transporter that is particularly expressed in the rod and cone photoreceptor cells of the vertebrate retina [9][10][11] and is associated with various ocular diseases [12]. A systematic review reported the significant presence of ocular abnormalities in patients with NSCL/P [13].…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms of ATP-binding cassette, sub-family A, member 4 (rs560426 and rs481931) and non-syndromic cleft lip/palate: A systematic review and meta-analysis

Imani¹,

Safaei²,

López‐Jornet³

et al. 2019

Preprint

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Background A number of gene loci are closely associated with the incidence of non-syndromic cleft lip/palate (NSCL/P). Herein, this meta-analysis assessed the association between ATP-binding cassette, sub-family A, member 4 (ABCA4) polymorphisms (rs560426 and rs481931) and the risk of NSCL/P by reviewing case-control studies.Methods Four databases including Scopus, Cochrane Library, Web of Science, and PubMed were searched for articles published up to December 2018. The Review Manager 5.3 software was used to calculate the crude odds ratio (OR) and 95% confidence interval (CI).Results Of 82 retrieved studies, 12 were analyzed in this meta-analysis (2,859 NSCL/P patients and 3,792 controls for ABCA4 rs560426 polymorphism and 1,333 NSCL/P patients and 1,884 controls for ABCA4 rs481931 polymorphism). There was no significant association between the polymorphisms and the risk of NSCL/P, with the exception of the allelic model (OR=1.13; 95% CI: 1.01, 1.27; p=0.03), the homozygote model (OR=1.53; 95% CI: 1.01, 2.31; p=0.04), and the recessive model (OR=1.30; 95% CI: 1.03, 1.63; p=0.03) in the Asian ethnicity for rs560426 polymorphism.Conclusion The findings confirmed that G allele and GG genotype of rs560426 polymorphism were significantly associated with the risk of NSCL/P in the Asian population, but not for rs481931polymorphism. Also, there was no association between both polymorphisms (rs560426 and rs481931) with the risk of NSCL/P in the Caucasian and the mixed ethnicities, as well as the source of controls. Therefore, ethnicity may play a significant role in this association.

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Retinal Phenotypes in Patients Homozygous for the G1961E Mutation in theABCA4Gene

Cited by 4 publications

References 3 publications

Phenotyping of ABCA4 Retinopathy by Machine Learning Analysis of Full-Field Electroretinography

Phenotyping of ABCA4 Retinopathy by Machine Learning Analysis of Full-Field Electroretinography

Author Response: Retinal Phenotypes in Patients Homozygous for the G1961E Mutation in theABCA4Gene

Polymorphisms of ATP-binding cassette, sub-family A, member 4 (rs560426 and rs481931) and non-syndromic cleft lip/palate: A systematic review and meta-analysis

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