This report reviews the experience of the Ocular Genetics Service at Cleveland Clinic Abu Dhabi with clinically diagnosed ABCA4-related retinopathy in Emirati patients who underwent genetic testing.
Initial testing involved eight patients with central retinal disease (Stargardt disease, STGD) and eight with peripheral retinal disease (retinitis pigmentosa, RP), who were examined using fMRI and MP (Nidek MP-1).
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 <i>ABCA4</i>-associated retinal diseases (<i>ABCA4-</i>RD).
Noncoding pathogenic variants, novel structural variants, and a common hypomorphic allele of the ABCA4 gene explain the majority of unsolved cases with ABCA4-associated disease, rendering this retinopathy a model for missing heritability in autosomal recessive disorders.
ABCA4 modeled structure provides a molecular basis on which to analyze protein sequence mutations related to genetic retinal disease in order to predict the risk of retinal disease across all possible ABCA4 mutations.
In a further 5.9% of patients (n = 5), a single heterozygous ABCA4 variant was identified; all these participants had a spectrum of clinical features consistent with ABCA4retinopathy.
Nevertheless, all-trans-retinal dimer (atRAL dimer) was found to be much more abundant than that of A2E in eyes of Abca4-/-Rdh8-/- double-knockout (DKO) mice, a rodent model showing the typical characteristics of retinopathies in AMD patients.
Identification of ABCA4retinopathies provides a specific molecular diagnosis and justifies a prompt introduction of simple precautions that may slow disease progression.
In contrast, we report a statistically significant association of common variants in the ABCA4 gene with retinal disease, assessed by a score-based variance-component test (PSKAT = 0.0055).
Disease in 11 patients was explained by mutations outside ABCA4, underlining the need to genotype all retinal disease genes to maximize genetic diagnostic rates.
One parent with ABCA4-related retinopathy and increased qAF carried an additional ABCA4 mutation, explaining the phenotype under a recessive disease model (pseudodominance).
To identify retinal-disease-associated genes, we performed exome sequencing in 28 individuals with "cone-first" retinal disease and clinical features atypical for ABCA4retinopathy.
The presence of 2 distinct phenotypes of Stargardt disease (foveal sparing and foveal atrophy) suggests that there may be more than 1 disease mechanism in ABCA4retinopathy.
Eighteen affected individuals from 13 families ascertained from a total cohort of 214 families with ABCA4-related retinal disease presenting to a single center.
A commercial diagnostic array-based assay has been developed targeting known mutations, however a conclusive genetic diagnosis must rely on a comprehensive genetic screening as the mutation spectrum of ABCA4-related retinopathies continues to expand.
Since the discovery of the ABCA4 gene as the cause of autosomal recessive Stargardt disease/fundus flavimaculatus much has been written of the phenotypic variability in ABCA4retinopathy.