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Samantha Bomotti, Rupert Wolfgang Strauss, Hendrik P Scholl, Robert Wojciechowski, ProgStar Study Group; ABCA4 variants in Stargardt disease: Preliminary results from the ProgStar study. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2862.
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Stargardt disease type 1 (OMIM 248200) is the most common juvenile macular dystrophy. It follows an autosomal recessive mode of inheritance. There is currently no cure and Stargardt remains difficult to diagnose due to its high allelic and phenotypic heterogeneity. We are compiling phenotypic data and genetic variant information at the ABCA4 gene in Stargardt patients at nine clinical centers across the United States and Europe. The data will be used to establish genotype-phenotype relationships for ABCA4 mutations, and to identify the effects of variants of unknown clinical significance.
To date, genetic and clinical data have been collected from 244 Stargardt patients. A variety of biological assays have been employed to identify the ABCA4 variants, depending on the technologies in use at the time of diagnosis (from 2008 or earlier to present). We report on the distribution of ABCA4 variants in this selected Stargardt population. These preliminary analyses are being conducted as the ProgStar study nears enrollment completion, at which point complete data will be available for in-depth analysis.
Among the 244 Stargardt individuals for whom we have genotype information thus far, the majority (86.9%) were heterozygous for ABCA4 mutations. In 26 cases (10.7%), only one ABCA4 mutation was identified, suggesting incomplete coverage of the functional regions of ABCA4 or locus heterogeneity. The most common variant was c.5882G>A, found in 67 (27.5%) participants. Three (4.5%) of these individuals were homozygous for this variant. The second most common mutation, c.2588G>C, was observed in one copy in 28 (11.5%) individuals. These variants are among the most commonly found in previously published data. Thirty-three individuals (13.5%) had three putatively pathogenic ABCA4 variants and three (1.2%) had four variants.
Initial mutation analyses in the ProgStar study confirm the high allelic heterogeneity of Stargardt disease. These data will shed new light on variant effects on the progression of Stargardt disease. It should be noted that testing protocols varied considerably across testing laboratories that contributed data to ProgStar. Most assays were based on mutations known at the time of testing, and favored screening of more common mutations. High-throughput sequencing technologies will allow for an unbiased ascertainment of pathogenic ABCA4 mutations in Stargardt disease.
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