Structural and Genetic Assessment of the<i>ABCA4</i>-Associated Optical Gap Phenotype

Nõupuu, Kalev; Lee, Winston; Zernant, Jana; Tsang, Stephen H.; Allikmets, Rando

doi:10.1167/iovs.14-14674

Cited by 32 publications

(34 citation statements)

References 35 publications

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“…In this way, laser injury on OCT can phenocopy a number of other genetic conditions that also feature a foveal gap, including rod monochromatism, Stargardt disease (G1961E allele of ABCA4 ), and occult macular dystrophy (RP1L1 mutation). 9–10 Yet even in the absence of a clear history or distinctive lesions, laser injury can be differentiated from genetic diseases without the need for expensive genetic screens, as follow-up OCT images in cases of laser injury will show substantial recovery and decrease suspicion of a genetic diagnosis. Other causes of an optical gap—including solar/photic retinopathy, abuse of alkyl nitrite compounds (poppers’ maculopathy), and iatrogenic maculopathy during surgery—are also easily differentiated from laser injury by history.…”

Section: Discussionmentioning

confidence: 99%

Laser-Induced Photic Injury Phenocopies Macular Dystrophy

Zhang

Zheng

Nie

et al. 2016

Ophthalmic Genetics

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Objective To describe the phenotypes associated with laser-induced retinal damage in children. Methods Five patients with maculopathy and reduced visual acuity associated with laser pointer use were evaluated. Best-corrected visual acuity, retinal structure, and function were monitored with color fundus, infrared (IR), and red-free images, fundus autofluorescence (AF), spectral domain-optical coherence tomography (SD-OCT), and full-field electroretinography (ERG). Results All five laser pointer injury patients had retinal lesions resembling a macular dystrophy (1 bilateral and 4 unilateral). These lesions were irregular in shape but all had a characteristic dendritic appearance with linear streaks radiating from the lesion. Photoreceptor damage was present in all patients, but serial OCT monitoring showed that subsequent photoreceptor recovery occurred over time in the eyes of at least 4 patients. 1 patient also had bilateral pigment epithelial detachments (PED). Both hyper- and hypoautofluorecence were observed in the laser damage area. Conclusions In general, OCT and IR images are quite useful to diagnose laser damage, but AF is not as sensitive. Laser pointer damage in children can occasionally be misdiagnosed as a macular dystrophy disease, but the distinctive lesions and OCT features are helpful for differentiating laser damage from other conditions.

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Section: Discussionmentioning

confidence: 99%

Laser-Induced Photic Injury Phenocopies Macular Dystrophy

Zhang

Zheng

Nie

et al. 2016

Ophthalmic Genetics

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“…Similarly, phenotypes caused by ABCA4 mutant alleles have also been extensively studied and found to be notable for a high degree of variability of expression (Fujinami et al 2014; Fujinami et al 2015; Mullins et al 2012; Noupuu et al 2014; Zahid et al 2013). Genetic analyses are challenging due to the size of the gene and the extensive genetic heterogeneity.…”

Section: Discussionmentioning

confidence: 99%

Complex inheritance of ABCA4 disease: four mutations in a family with multiple macular phenotypes

et al. 2015

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Over 800 mutations in the ABCA4 gene cause autosomal recessive Stargardt disease. Due to extensive genetic heterogeneity, observed variant-associated phenotypes can manifest tremendous variability of expression. Furthermore, the high carrier frequency of pathogenic ABCA4 alleles in the general population (~1:20) often results in pseudo-dominant inheritance patterns further complicating the diagnosis and characterization of affected individuals. This study describes a genotype/phenotype analysis of an unusual family with multiple macular disease phenotypes spanning across two generations and segregating four distinct ABCA4 mutant alleles. Complete sequencing of ABCA4 discovered two known missense mutations, p.C54Y and p.G1961E. Array comparative genomic hybridization revealed a large novel deletion combined with a small insertion, c.6148-698_c.6670del/insTGTGCACCTCCCTAG, and complete sequencing of the entire ABCA4 genomic locus uncovered a new deep intronic variant, c.302+68C>T. Patients with the p.G1961E mutation had the mildest, confined maculopathy phenotype with peripheral flecks while those with all other mutant allele combinations exhibited a more advanced stage of generalized retinal and choriocapillaris atrophy. This family epitomizes the clinical and genetic complexity of ABCA4-associated diseases. It contained variants from all classes of mutations, in the coding region, deep intronic, both single nucleotide variants (SNV) and copy number variants (CNV) that accounted for varying phenotypes segregating in an apparent dominant fashion. Unequivocally defining disease-associated alleles in the ABCA4 locus requires a multifaceted approach that includes advanced mutation detection methods and a thorough analysis of clinical phenotypes.

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“…1 Since its discovery as the causative gene in 1997, 2 more than 800 disease-causing mutations within the coding (50 exons) and noncoding regions of the ATP Binding Cassette Subfamily A Member 4 ( ABCA4 , Mendelian Inheritance in Man #601691) gene have been reported, 3 giving rise to a large heterogeneous group of retinal dystrophies. As a result, the clinical variation of ABCA4 diseases is extensive and spans a wide spectrum of phenotypes, including occult maculopathy, 4 bull’s eye maculopathy, 5,6 cone-rod dystrophy, 7,8 generalized choriocapillaris dystrophy, 9 and severe retinitis pigmentosa-like retinopathies. 7,10 The diagnostic criteria for ABCA4-associated disease encompasses several distinct features that are generally ubiquitous among affected patients.…”

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The Rapid-Onset Chorioretinopathy Phenotype of ABCA4 Disease

et al. 2018

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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.

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Structural and Genetic Assessment of theABCA4-Associated Optical Gap Phenotype

Cited by 32 publications

References 35 publications

Laser-Induced Photic Injury Phenocopies Macular Dystrophy

Laser-Induced Photic Injury Phenocopies Macular Dystrophy

Complex inheritance of ABCA4 disease: four mutations in a family with multiple macular phenotypes

The Rapid-Onset Chorioretinopathy Phenotype of ABCA4 Disease

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