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Multi-platform imaging in ABCA4-Associated Disease.

ABSTRACT: Fundus autofluorescence (FAF) imaging is crucial to the diagnosis and monitoring of recessive Stargardt disease (STGD1). In a retrospective cohort study of 34 patients, we compared FAF imaging platforms varying in field size (30° and 55°: blue/SW-AF and NIR-AF; 200°: ultrawide-field, UWF-AF), excitation wavelength (488?nm, blue/SW-AF; 532?nm, UWF-AF and 787?nm, NIR-AF) and image processing. Due to reduced absorption of 532?nm and 787?nm light by macular pigment, foveal sparing was more readily demonstrable by green/UWF-AF and NIR-AF imaging. Prominent in green/UWF-AF images is a central zone of relatively elevated AF that is continuous inferonasal with a demarcation line bordering lower AF nasally and higher AF temporally. This zone and border are more visible in STGD1 than in healthy eyes and more visible with green/UWF-AF. With the development of AF flecks, inferonasal retina is initially spared. Central atrophic areas were larger in NIR-AF images than in blue/SW-AF and green/UWF-AF images and the presence of a contiguous hyperAF ring varied with imaging modality. Flecks visible as hyperAF foci in blue/SW-AF images were also visible in green/UWF-AF but were often hypoAF in NIR-AF. Since disease in STGD1 often extends beyond the 30° and 55° fields, green/UWF-AF has advantages including for pediatric patients. The imaging platforms examined provided complementary information.

SUBMITTER: Chen L

PROVIDER: S-EPMC6478712 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Multi-platform imaging in ABCA4-Associated Disease.

Chen Lijuan L Lee Winston W de Carvalho Jose Ronaldo Lima JRL Chang Stanley S Tsang Stephen H SH Allikmets Rando R Sparrow Janet R JR

Scientific reports 20190423 1

Fundus autofluorescence (FAF) imaging is crucial to the diagnosis and monitoring of recessive Stargardt disease (STGD1). In a retrospective cohort study of 34 patients, we compared FAF imaging platforms varying in field size (30° and 55°: blue/SW-AF and NIR-AF; 200°: ultrawide-field, UWF-AF), excitation wavelength (488 nm, blue/SW-AF; 532 nm, UWF-AF and 787 nm, NIR-AF) and image processing. Due to reduced absorption of 532 nm and 787 nm light by macular pigment, foveal sparing was more readily d ...[more]

PMID: 31015497

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Project description:PurposeQuantitative fundus autofluorescence (qAF) and spectral-domain optical coherence tomography (SD OCT) were performed in patients with bull's-eye maculopathy (BEM) to identify phenotypic markers that can aid in the differentiation of ABCA4-associated and non-ABCA4-associated disease.DesignProspective cross-sectional study at an academic referral center.SubjectsThirty-seven BEM patients (age range, 8-60 years) were studied. All patients exhibited a localized macular lesion exhibiting a smooth contour and qualitatively normal-appearing surrounding retina without flecks. Control values consisted of previously published data from 277 healthy subjects (374 eyes; age range, 5-60 years) without a family history of retinal dystrophy.MethodsAutofluorescence (AF) images (30°, 488-nm excitation) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference to account for variable laser power and detector sensitivity. The grey levels (GLs) from 8 circularly arranged segments positioned at an eccentricity of approximately 7° to 9° in each image were calibrated to the reference (0 GL), magnification, and normative optical media density to yield qAF. In addition, horizontal SD OCT images through the fovea were obtained. All patients were screened for ABCA4 mutations using the ABCR600 microarray, next-generation sequencing, or both.Main outcome measuresQuantitative AF, correlations between AF and SD OCT, and genotyping for ABCA4 variants.ResultsABCA4 mutations were identified in 22 patients, who tended to be younger (mean age, 21.9±8.3 years) than patients without ABCA4 mutations (mean age, 42.1±14.9 years). Whereas phenotypic differences were not obvious on the basis of qualitative fundus AF and SD OCT imaging, with qAF, the 2 groups of patients were clearly distinguishable. In the ABCA4-positive group, 37 of 41 eyes (19 of 22 patients) had qAF8 of more than the 95% confidence interval for age. Conversely, in the ABCA4-negative group, 22 of 26 eyes (13 of 15 patients) had qAF8 within the normal range.ConclusionsThe qAF method can differentiate between ABCA4-associated and non-ABCA4-associated BEM and may guide clinical diagnosis and genetic testing.

Project description:Introduction: Inherited retinal dystrophies (IRDs) can be caused by variants in more than 280 genes. The ATP-binding cassette transporter type A4 (ABCA4) gene is one of these genes and has been linked to Stargardt disease type 1 (STGD1), fundus flavimaculatus, cone-rod dystrophy (CRD), and pan-retinal CRD. Approximately 25% of the reported ABCA4 variants affect RNA splicing. In most cases, it is necessary to perform a functional assay to determine the effect of these variants. Methods: Whole genome sequencing (WGS) was performed in one Spanish proband with Stargardt disease. The putative pathogenicity of c.6480-35A>G on splicing was investigated both in silico and in vitro. The in silico approach was based on the deep-learning tool SpliceAI. For the in vitro approach we used a midigene splice assay in HEK293T cells, based on a previously established wild-type midigene (BA29) containing ABCA4 exons 46 to 48. Results: Through the analysis of WGS data, we identified two candidate variants in ABCA4 in one proband: a previously described deletion, c.699_768+342del (p.(Gln234Phefs*5)), and a novel branchpoint variant, c.6480-35A>G. Segregation analysis confirmed that the variants were in trans. For the branchpoint variant, SpliceAI predicted an acceptor gain with a high score (0.47) at position c.6480-47. A midigene splice assay in HEK293T cells revealed the inclusion of the last 47 nucleotides of intron 47 creating a premature stop codon and allowed to categorize the variant as moderately severe. Subsequent analysis revealed the presence of this variant as a second allele besides c.1958G>A p.(Arg653His) in an additional Spanish proband in a large cohort of IRD cases. Conclusion: A splice-altering effect of the branchpoint variant, confirmed by the midigene splice assay, along with the identification of this variant in a second unrelated individual affected with STGD, provides sufficient evidence to classify the variant as likely pathogenic. In addition, this research highlights the importance of studying non-coding regions and performing functional assays to provide a conclusive molecular diagnosis.

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Multi-platform imaging in ABCA4-Associated Disease.

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Multi-platform imaging in ABCA4-Associated Disease.

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