Abstract
We investigated the prevalence of reported deep-intronic variants in a French cohort of 70 patients with Stargardt disease harboring a monoallelic pathogenic variant on the exonic regions of ABCA4. Direct Sanger sequencing of selected intronic regions of ABCA4 was conducted. Complete phenotypic analysis and correlation with the genotype was performed in case a known intronic pathogenic variant was identified. All other variants found on the analyzed sequences were queried for minor allele frequency and possible pathogenicity by in silico predictions. The second mutated allele was found in 14 (20%) subjects. The three known deep-intronic variants found were c.5196+1137G>A in intron 36 (6 subjects), c.4539+2064C>T in intron 30 (4 subjects) and c.4253+43G>A in intron 28 (4 subjects). Even though the phenotype depends on the compound effect of the biallelic variants, a genotype-phenotype correlation suggests that the c.5196+1137G>A was mostly associated with a mild phenotype and the c.4539+2064C>T with a more severe one. A variable effect was instead associated with the variant c.4253+43G>A. In addition, two novel variants, c.768+508A>G and c.859-245_859-243delinsTGA never associated with Stargardt disease before, were identified and a possible splice defect was predicted in silico. Our study calls for a larger cohort analysis including targeted locus sequencing and 3D protein modeling to better understand phenotype-genotype correlations associated with deep-intronic changes and patients’ selection for clinical trials.
Highlights
Stargardt disease (STGD1; MIM #248200) is the most common juvenile macular dystrophy, with a prevalence of 1 over 8.000–10.000 [1]
There is mounting evidence that the heterogeneity of the phenotype is related to the severity of the genetic variants on ABCA4, with a loss of function leading to an earlier onset and a faster progression, while later onset with foveal sparing are usually associated with milder variants [3,4]
The initial screening on the exonic parts of ABCA4 started in 2007 and was performed with methods available at our institution at that time, including microarray analysis and Sanger sequencing. This led to the identification of seventy index patients carrying only one pathogenic variant. These subjects and their siblings were screened for the presence of the 24 known ABCA4 deep-intronic variants included from the review of the literature (Table S1)
Summary
Stargardt disease (STGD1; MIM #248200) is the most common juvenile macular dystrophy, with a prevalence of 1 over 8.000–10.000 [1] It is an autosomal recessive disease, associated with mutations in ABCA4 (MIM #601691) [2]. This disease affects only the retina and leads to a progressive loss of retinal structure and function. There is mounting evidence that the heterogeneity of the phenotype is related to the severity of the genetic variants on ABCA4, with a loss of function leading to an earlier onset and a faster progression, while later onset with foveal sparing are usually associated with milder variants [3,4]. Since an important phenotypic variability between and within families has been described, it was suggested that other factors, including genetic and environmental factors, can influence the phenotype [5]
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