Dataset Information

Genotypic profile and phenotype correlations of ABCA4-associated retinopathy in Koreans.

ABSTRACT: Purpose:This study was conducted to analyze the clinical features associated with the pathogenic variants of ABCA4 in Korean patients with inherited retinal dystrophies (IRDs). Methods:We enrolled patients with IRDs who visited a tertiary referral hospital and identified the pathogenic variants of ABCA4 through targeted gene panel sequencing and whole exome sequencing. We analyzed the clinical characteristics and phenotypic spectrum according to genotype. Results:Eleven patients (from nine families) with IRDs and pathogenic variants in ABCA4 were included. Eight patients (from seven families) with Stargardt disease (STGD), two (from one family) with cone-rod dystrophy (CRD), and one with early-onset retinitis pigmentosa (RP) were included. Two heterozygous mutations were identified in eight families, and one variant was found in a patient with fundus flavimaculatus. Two variants, p.Gln294Ter and p.Gln636Lys, were associated with severe phenotypes, such as early-onset RP and CRD. Four novel pathogenic variants, p.Gln636Lys, p.Ile1114del, p.Thr1117Ala, and p.Asn1588Tyr, were identified. p.Gln294Ter, p.Leu1157Ter, and p.Lys2049ArgfsTer12 were repeatedly detected in Koreans with ABCA4-associated retinal diseases (ABCA4-RD). Conclusions:Various pathogenic variants of ABCA4, including four novel variants, were identified, and ABCA4-RD exhibited various phenotypes and disease severities in a Korean IRD cohort. These findings will be useful for understanding the clinical features of ABCA4-RD and ethnicity-specific variants in East Asians.

SUBMITTER: Joo K

PROVIDER: S-EPMC6857773 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Genotypic profile and phenotype correlations of <i>ABCA4</i>-associated retinopathy in Koreans.

Joo Kwangsic K Seong Moon-Woo MW Park Kyu Hyung KH Park Sung Sup SS Woo Se Joon SJ

Molecular vision 20191114

<h4>Purpose</h4>This study was conducted to analyze the clinical features associated with the pathogenic variants of <i>ABCA4</i> in Korean patients with inherited retinal dystrophies (IRDs).<h4>Methods</h4>We enrolled patients with IRDs who visited a tertiary referral hospital and identified the pathogenic variants of <i>ABCA4</i> through targeted gene panel sequencing and whole exome sequencing. We analyzed the clinical characteristics and phenotypic spectrum according to genotype.<h4>Results< ...[more]

PMID: 31814693

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Project description:PurposeTo describe the earliest features of ABCA4-associated retinopathy.DesignCase series.ParticipantsChildren with a clinical and molecular diagnosis of ABCA4-associated retinopathy without evidence of macular atrophy.MethodsThe retinal phenotype was characterized by color fundus photography, OCT, fundus autofluorescence (FAF) imaging, electroretinography, and in 2 patients, adaptive optics scanning laser ophthalmoscopy (AOSLO). Sequencing of the ABCA4 gene was performed in all patients.Main outcome measuresVisual acuity, OCT, FAF, electroretinography, and AOSLO results.ResultsEight children with ABCA4-associated retinopathy without macular atrophy were identified. Biallelic variants in ABCA4 were identified in all patients. Four children were asymptomatic, and 4 reported loss of VA. Patients were young (median age, 8.5 years; interquartile range, 6.8 years) with good visual acuity (median, 0.155 logarithm of the minimum angle of resolution [logMAR]; interquartile range, 0.29 logMAR). At presentation, the macula appeared normal (n = 3), had a subtly altered foveal reflex (n = 4), or demonstrated manifest fine yellow dots (n = 1). Fundus autofluorescence identified hyperautofluorescent dots in the central macula in 3 patients, 2 of whom showed a normal fundus appearance. Only 1 child had widespread hyperautofluorescent retinal flecks at presentation. OCT imaging identified hyperreflectivity at the base of the outer nuclear layer in all 8 patients. Where loss of outer nuclear volume was evident, this appeared to occur preferentially at a perifoveal locus. Longitudinal split-detector AOSLO imaging in 2 individuals confirmed that the greatest change in cone spacing occurred in the perifoveal, and not foveolar, photoreceptors. Electroretinography showed a reduced B-wave-to-A-wave ratio in 3 of 5 patients tested; in 2 children, recordings clearly showed electronegative results.ConclusionsIn childhood-onset ABCA4-associated retinopathy, the earliest stages of macular atrophy involve the parafovea and spare the foveola. In some cases, these changes are predated by tiny, foveal, yellow, hyperautofluorescent dots. Hyperreflectivity at the base of the outer nuclear layer, previously described as thickening of the external limiting membrane, is likely to represent a structural change at the level of the foveal cone nuclei. Electroretinography suggests that the initial site of retinal dysfunction may occur after phototransduction.

Project description:Purpose:To investigate the interreader and intermodality agreement for grading of retinal pigment epithelium (RPE) atrophy lesion size in ABCA4-related retinopathy using green (GAF) and blue fundus autofluorescence (BAF) imaging. Methods:In this cross-sectional case series, 97 eyes of 49 patients with RPE atrophy secondary to ABCA4-related retinopathy underwent GAF- (518 nm excitation light) and BAF- (488 nm excitation light) imaging using confocal scanning laser ophthalmoscopy (Spectralis HRA, Heidelberg Engineering, Heidelberg, Germany). Lesions with definitely decreased autofluorescence (DDAF) and questionably decreased autofluorescence (QDAF) in GAF and BAF imaging were analyzed separately by five independent readers using semiautomated software (RegionFinder, Heidelberg Engineering). Intermodality and interreader agreements were assessed for the square-root lesion size, lesion perimeter, and circularity. Results:GAF- and BAF-based measurements of DDAF and QDAF showed high intermodality and interreader agreement concerning square-root lesion size, as well as shape descriptive parameters (perimeter and circularity). Interreader agreement of square-root lesion size was slightly, hence not significantly higher for GAF-based grading ([95% coefficients of repeatability, intraclass correlation coefficient] DDAF: 0.215 mm, 0.997; QDAF: 0.712 mm, 0.981) compared to BAF-based grading (DDAF: 0.232 mm, 0.997; QDAF: 0.764 mm, 0.978). However, DDAF-measurements revealed distinctly more reproducible results than QDAF-measurements. Foveal sparing did not interfere with intermodality agreement. Conclusions:Both GAF- and BAF-based quantification of RPE atrophy showed very reliable results with possible superiority of GAF in the context of less energetic excitation light. Translational Relevance:The high interreader agreement qualifies the use of DDAF progression in GAF and BAF imaging as potential morphologic outcome measure for interventional clinical trials and disease monitoring.

Project description:PURPOSE:To characterize patients affected by a uniquely severe, rapid-onset chorioretinopathy (ROC) phenotype of ABCA4 disease. DESIGN:Comparative cohort study. PARTICIPANTS:Sixteen patients were selected from a large clinically diagnosed and genetically confirmed cohort (n = 300) of patients diagnosed with ABCA4 disease. MAIN OUTCOME MEASURES:Phenotypic characteristics were assessed on color fundus photographs, short-wavelength autofluorescence (488-nm), and near-infrared autofluorescence (NIR-AF, 787-nm) images. Subfoveal thickness measurements were obtained from enhanced-depth imaging OCT. Generalized retinal function was determined with full-field electroretinogram (ffERG) testing, and lipofuscin accumulation was assessed by quantitative autofluorescence (qAF). RESULTS:All patients exhibited advanced disease features, including pigment migration in the macula and retinal vessel attenuation at an early age, and reported a symptomatic onset, on average, at 7.4 years (average for ABCA4 disease is 21.9 years, P < 0.0001). Deterioration of the macula was observed to begin with an intense, homogeneous signal on short-wavelength autofluorescence, which corresponds to an attenuated NIR-AF signal and progresses to a patchy, coalescing pattern of chorioretinal atrophy within the subsequent decade. Measurement of choroidal thickness revealed a more rapid thinning of choriocapillaris with age of Sattler's layer compared with the rate in most other patients with ABCA4 disease (P < 0.001). Levels of qAF in the macula before atrophy were above both the 95% confidence intervals for healthy individuals and patients with Stargardt disease (STGD1) (>1000 qAF units). Severe attenuation of cone responses and notable decreases in rod responses were detected by ffERG. Sequencing of the ABCA4 gene revealed exclusively deleterious, null mutations, including stop codons; frameshift deletions; variants in canonical splice sites, which completely abolish splicing; and known deleterious missense alleles. CONCLUSIONS:The ROC phenotype is a unique classification of ABCA4 disease, which is caused by deleterious null biallelic ABCA4 mutations and is characterized by the rapid deterioration of retinal pigment epithelium and photoreceptor layers in the macula and significant choroidal thinning within the first 2 decades of life.

Dataset Information

Genotypic profile and phenotype correlations of ABCA4-associated retinopathy in Koreans.

Publications

Genotypic profile and phenotype correlations of <i>ABCA4</i>-associated retinopathy in Koreans.

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