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Ta-Ching Chen, Pei-Lung Chen, Chao-Wen Lin, Ding-Siang Huang, Hsueh-Min Hsu, Chang-Hao Yang, Chung-May Yang, Fung-Rong Hu; Genetic Diagnosis and detection of novel variants in ABCA4-related Stargradt disease in East Asia. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2945. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
The ABCA4 protein is active following phototransduction to remove potentially toxic substances N-retinylidene-PE from photoreceptor cells. Mutation of ABCA4 gene is the main cause of Stargradt disease. Here, we reported our experiences of genetic diagnosis and identifing novel variants in ABCA4 that would cause retinal degeneration.
The reported cases were recruited in the TIP (Taiwan Inherited retinal diseases Project) program. The blood sample was collected and the genomic DNA was sequenced by panel-based next-generation sequencing (NGS) with 215 genes associated with inherited retinal degenerations. NGS data were processed and pathogenicity of retained variants was predicted by algorithm analysis such as SIFT, PolyPhen-2, and database such as GnomAD. The criteria of classifying pathogenic variants were based on the ACMG standard and guideline.
In our first 100 probands recruited in TIP program, 12 families were identified having ABCA4 genetic defects as causative variants. Among them, 4 novel variants were identified. All these novel variants were identified “likely pathogenic” based on the ACMG standard. Here we also present the clinical pictures of two cases. In patient 1, compound heterozygous nonsense mutations c.1804C>T (p.Arg602Trp) and another novel variantc.6113G>A (p.Arg2038Gln)were identified in ABCA4 gene. In patient 2, compound heterozygous nonsense mutations c.6190G>A (p.Ala2064Thr) and a novel variant c.3287C>T (p.Ser1096Leu) were identified in ABCA4 gene. They both showed typical phenotype of central macular degeneration and decreasing visual acuity from late teens, corresponding to Stargradt disease.
Here we report our experiences in genetic diagnosis using panel-based NGS for inherited retinal degenerations (IRDs) in east Asia as well as report novel variants in ABCA4-related Stargradt disease. These findings confirm the value of NGS technique for IRDs as well as broaden the spectrum of ABCA4 mutations and might be useful for genetic consultation and diagnosis in the future.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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