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Purpose: To report on a patient with Stargardt disease (STGD1) and with an intronic mutation in the ABCA4 gene. Patients and Methods: A 69-year-old female patient presented to the clinic complaining of progressive vision loss. The ophthalmic evaluation was remarkable for a best corrected visual acuity of counting fingers at 5' in the right eye and 3' in the left eye. Imaging revealed deep extensive atrophy of the central macula, epithelial pigment hyperplasia, and other areas of multifocal atrophy in the right eye. Furthermore, fundus autofluorescence imaging of the macula showed central hypoautofluorescence with bilateral expansion to the periphery in both eyes. A full-field electroretinogram showed a normal rod response, with decreased cone response, bilaterally. Genetic testing was positive for a homozygous intronic mutation in the ABCA4 gene of the variant c.5714+5G>A. Conclusions and Importance: Patients with STGD1 due to presumed mild or moderate mutations in the ABCA4 gene may have a more severe presentation and progression of the disease. Based on this, the first report of a genotype-phenotype correlation in a Puerto Rican patient with STGD1 disease, genotyping all Puerto Rican patients is warranted.
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Inherited retinal diseases (IRDs) represent a spectrum of clinically and genetically heterogeneous disorders. Our study describes an IRD patient carrying ABCA4 and USH2A pathogenic biallelic mutations as a result of paternal uniparental disomy (UPD) in chromosome 1. The proband is a 9-year-old girl born from non-consanguineous parents. Both parents were asymptomatic and denied family history of ocular disease. Clinical history and ophthalmologic examination of the proband were consistent with Stargardt disease. Whispered voice testing disclosed moderate hearing loss. Next-generation sequencing and Sanger sequencing identified pathogenic variants in ABCA4 (c.4926C>G and c.5044_5058del) and USH2A (c.2276G>T). All variants were present homozygously in DNA from the proband and heterozygously in DNA from the father. No variants were found in maternal DNA. Further analysis of single nucleotide polymorphisms confirmed paternal UPD of chromosome 1. This is the first known patient with confirmed UPD for two recessively mutated IRD genes. Our study expands on the genetic heterogeneity of IRDs and highlights the importance of UPD as a mechanism of autosomal recessive disease in non-consanguineous parents. Moreover, a long-term follow-up is essential for the identification of retinal features that may develop as a result of USH2A-related conditions.
RESUMO
PURPOSE: To describe the clinical and molecular spectrum of Stargardt disease (STGD) in a cohort of Argentinean patients. METHODS: This retrospective study included 132 subjects comprising 95 probands clinically diagnosed with STGD and relatives from 16 of them. Targeted next-generation sequencing of the coding and splicing regions of ABCA4 and other phenocopying genes (ELOVL4, PROM1, and CNGB3) was performed in 97 STGD patients. RESULTS: We found two or more disease-causing variants in the ABCA4 gene in 69/95 (73%) probands, a single ABCA4 variant in 9/95 (9.5%) probands, and no ABCA4 variants in 17/95 (18%) probands. The final analysis identified 173 variants in ABCA4. Seventy-nine ABCA4 variants were unique, of which nine were novel. No significant findings were seen in the other evaluated genes. CONCLUSION: This study describes the phenotypic and genetic features of STGD1 in an Argentinean cohort. The mutations p.(Gly1961Glu) and p.(Arg1129Leu) were the most frequent, representing almost 20% of the mutated alleles. We also expanded the ABCA4 mutational spectrum with nine novel disease-causing variants, of which eight might be associated with South American natives.