Abstract
Purpose: To clarify the mutation spectrum and frequency of ABCA4 in a Chinese cohort with Stargardt disease (STGD1). Methods: A total of 153 subjects, comprising 25 families (25 probands and their family members) and 71 sporadic cases, were recruited for the analysis of ABCA4 variants. All probands with STGD1 underwent a comprehensive ophthalmologic examination. Overall, 792 genes involved in common inherited eye diseases were screened for variants by panel-based next-generation sequencing (NGS). Variants were filtered and analyzed to evaluate possible pathogenicity. Results: The total variant detection rate of at least one ABCA4 mutant allele was 84.3% (129/153): two or three disease-associated variants in 86 subjects (56.2%), one mutant allele in 43 subjects (28.1%), and no variants in 24 subjects (15.7%). Ninety-six variants were identified in the total cohort, which included 62 missense (64%), 15 splicing (16%), 11 frameshift (12%), 6 nonsense (6%), and 2 small insertion or deletion (2%) variants. Thirty-seven novel variants were found, including a de novo variant, c.4561delA. The most prevalent variant was c.101_106delCTTTAT (10.5%), followed by c.2894A > G (6.5%) and c.6563T > C (4.6%), in STGD1 patients from eastern China. Conclusion: Thirty-seven novel variants were detected using panel-based NGS, including one de novo variant, further extending the mutation spectrum of ABCA4. The common variants in a population from eastern China with STGD1 were also identified.
Highlights
Stargardt disease (STGD1, OMIM 248200), known as juvenile macular degeneration, is a hereditary macular dystrophy characterized by bilateral or sequential central visual loss in early adolescence (North et al, 2014; Tanna et al, 2017)
The variant detection rate for ATP-binding cassette subfamily A member 4 (ABCA4) in STGD1 patients from European and American countries is basically around 80%, while the variant detection rate in the Chinese population can reach more than 90%
The results showed that 37 novel variants were distributed in 19 exons and 7 introns of ABCA4
Summary
Stargardt disease (STGD1, OMIM 248200), known as juvenile macular degeneration, is a hereditary macular dystrophy characterized by bilateral or sequential central visual loss in early adolescence (North et al, 2014; Tanna et al, 2017). The fundus of STGD1 patients commonly presents with yellow-white flecks, bull’s eye maculopathy, a beaten bronze appearance of the macula, and atrophy of retinal pigment epithelium (RPE). It is caused by the massive deposition of lipofuscin in RPE, followed by photoreceptor cell death and eventually loss of vision (Aaberg and Han, 1987; Anderson et al, 1995; Fishman et al, 1999; Lewis et al, 1999). The disease-causing ABCA4 variants are extremely heterogeneous, previous studies have confirmed frequent ABCA4 variants with ethnic specificity, such as c.2588G > C in the Western European population (Maugeri et al, 1999), p.Y808* in Chinese patients (Jiang et al, 2016), c.5714+5G > A in a Greek cohort (Smaragda et al, 2018), p.N965S in Denmark (Rosenberg et al, 2007), p.A1773V in Mexico (Chacon-Camacho et al, 2013), p.R1129L in Spain (Riveiro-Alvarez et al, 2013), and p.R2107H in African American patients (Zernant et al, 2014a)
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