RESUMO

The purpose of this study was to analyze and molecularly describe the largest group of patients with ABCA4-associated retinal degeneration in Latin America. Pathogenic variants in ABCA4, a member of the ATP Binding Cassette (ABC) transporters superfamily, is one of the most common causes of inherited visual deficiency in humans. Retinal phenotypes associated with genetic defects in ABCA4 are collectively known as ABCA4-associated retinal degenerations (ABCA4R), a group of recessively inherited disorders associated with a high allelic heterogeneity. While large groups of Caucasian and Asiatic individuals suffering from ABCA4R have been well characterized, molecular information from certain ethnic groups is limited or unavailable, precluding a more realistic knowledge of ABCA4-related mutational profile worldwide. In this study, we describe the molecular findings of a large group of 211 ABCA4R index cases from Mexico. Genotyping was performed using either next generation sequencing (NGS) of a retinal dystrophy genes panel or exome. ABCA4 targeted mutation testing was applied to a subgroup of subjects in whom founder mutations were suspected. A total of 128 different ABCA4 pathogenic variants were identified, including 22 previously unpublished variants. The most common type of genetic variation was single nucleotide substitutions which occurred in 92.7% (408/440 alleles). According to the predicted protein effect, the most frequent variant type was missense, occurring in 83.5% of disease-causing alleles (368/440). Mutations such as p.Ala1773Val are fully demonstrated as a founder effect in native inhabitants of certain regions of Mexico. This study also gives us certain indications of other founder effects that need to be further studied in the near future. This is the largest molecularly characterized ABCA4R Latin American cohort, and our results supports the value of conducting genetic screening in underrepresented populations for a better knowledge of the mutational profile leading to monogenic diseases.

Assuntos

Transportadores de Cassetes de Ligação de ATP , Genótipo , Degeneração Retiniana , Humanos , Transportadores de Cassetes de Ligação de ATP/genética , México , Masculino , Feminino , Degeneração Retiniana/genética , Criança , Mutação , Adulto , Adolescente , Pessoa de Meia-Idade , Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Fenótipo , Pré-Escolar , Adulto Jovem , Linhagem

RESUMO

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.

RESUMO

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.

RESUMO

Background: Inherited ocular conditions are a frequent cause of blindness. Gene therapy has encouraged the development of genetic testing, currently able to detect up to 80% of mutations in contrast to the 5% sensitivity achieved a few decades ago.Materials and methods: One hundred sixty-three patients with suspected genetic ocular disorders who were referred to a single clinician between August 2014 and August 2019 underwent a thorough ophthalmologic examination. Those diagnosed with congenital cataract, retinoblastoma, anterior segment dysgenesis, autoimmune retinal disease, posterior microphthalmia, or cobalamin C deficiency were excluded, along with patients who opted against genetic testing. Included probands were classified into a diagnostic clinical category and offered genetic testing. Blood samples were sent to foreign accredited diagnostic laboratories, followed by clinical interpretation of the results.Results: Of the 163 patients referred, 104 were enrolled in the study. Median age at disease onset was 2 years (range, 0 to 43 years). A molecular diagnosis was established at a median age of 10 years (range, 0.4 to 50 years). Disease-causing genotypes were identified in 82 of the probands, indicating a mutation detection rate of 78.8%. Mutations were identified in 38 genes, ABCA4 being the most commonly affected (23% of mutations), followed by CRB1 (13% of mutations). Whole-exome sequencing was performed in 6 patients, resulting in a definite diagnosis in 3 (50%).Conclusions: Molecular testing for inherited ocular conditions is feasible in developing countries by sending samples to certified foreign laboratories, with a mutation detection rate comparable to published values in developed countries. Further studies to identify more disease-causing genes may improve the overall sensitivity.

Assuntos

Proteínas do Olho/genética , Testes Genéticos/métodos , Mutação , Doenças Retinianas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Países em Desenvolvimento , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fenótipo , Doenças Retinianas/diagnóstico , Adulto Jovem

RESUMO

BACKGROUND: Stargardt disease (STGD) is the most common juvenile hereditary macular dystrophy. In the majority of cases, the diagnosis is made prior to 20 years of age and usually leads to loss of central vision. Late-onset STGD affects a smaller number of patients. Identifying genetic changes which could be associated with clinically important differences in severity or presentation of the disease is important for understanding the mechanisms of visual loss and for planning future therapeutic approaches. METHODS: We report a patient with the classic phenotype of STGD with late-onset mild disease exhibiting a slow clinical progression over 14 months of follow-up. RESULTS: A 37-year-old man presented with STGD and good vision of 6/24 in the right eye and of 6/6 in the left eye as well as typical electrophysiology findings. Objective and subjective visual deterioration was not noted over a period of 14 months. Macular genetic testing revealed a novel missense mutation in ABCA4 (Thr829Met) combined with Gly1961Glu, a classic STGD mutation usually associated with a moderately severe phenotype. CONCLUSIONS: It is suggested that the Thr829Met mutation could give rise to a hypomorphic allele of the ABC transporter with a resultant phenotype of comparatively mild STGD.