Novel Complex <i>ABCA4</i> Alleles in Brazilian Patients With Stargardt Disease: Genotype–Phenotype Correlation

Salles, Mariana Vallim; Motta, Fabiana Louise; Silva, Elton Dias da; Varela, Patrícia Siqueira; Costa, Kassandra Silva Falcão; Filippelli-Silva, Rafael; Martin, Renan Paulo; Chiang, John; Pesquero, João Bosco; Sallum, Juliana Maria Ferraz

doi:10.1167/iovs.17-22398

Cited by 11 publications

(11 citation statements)

References 37 publications

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“…Indeed, the most prevalent mutation in the Mexican population p.(Ala1773Val) (Chacón-Camacho et al, 2013) was utterly absent in our cohort; moreover, p.(Arg602Trp), the most prevalent mutation in Brazilian patients (Salles et al, 2018) was only found in one allele (0.6%). Besides, we found that only ∼14% of our probands harbored complex alleles in ABCA4 compared to 30% reported in Brazilian patients (Salles et al, 2017). These findings can be explained by Argentina's differential ancestral admixture compared to Brazil and Mexico (Muzzio et al, 2018).…”

Section: Discussioncontrasting

confidence: 57%

Clinical and Genetic Spectrum of Stargardt Disease in Argentinean Patients

et al. 2021

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PurposeTo describe the clinical and molecular spectrum of Stargardt disease (STGD) in a cohort of Argentinean patients.MethodsThis 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.ResultsWe 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.ConclusionThis 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.

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Section: Discussioncontrasting

confidence: 57%

Clinical and Genetic Spectrum of Stargardt Disease in Argentinean Patients

et al. 2021

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“…Among the maculopathies, STGD was the predominant disease, with ABCA4 mutations the most common. About one-third of patients with pathogenic variants in the ABCA4 gene had complex alleles 33 , which reinforce the need for familiar segregation analysis to determine if both alleles have at least one pathogenic variant. In the current study, the PROM1 gene caused STGD with autosomal dominant and recessive traits, and this pattern already was reported 34 .…”

Section: Discussionmentioning

confidence: 99%

Relative frequency of inherited retinal dystrophies in Brazil

Motta

Martin

Filippelli-Silva

et al. 2018

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Among the Brazilian population, the frequency rates of inherited retinal dystrophies and their causative genes are underreported. To increase the knowledge about these dystrophies in our population, we retrospectively studied the medical records of 1,246 Brazilian patients with hereditary retinopathies during 20 years of specialized outpatient clinic care. Of these patients, 559 had undergone at least one genetic test. In this cohort, the most prevalent dystrophies were non-syndromic retinitis pigmentosa (35%), Stargardt disease (21%), Leber congenital amaurosis (9%), and syndromic inherited retinal dystrophies (12%). Most patients had never undergone genetic testing (55%), and among the individuals with molecular test results, 28.4% had negative or inconclusive results compared to 71.6% with a conclusive molecular diagnosis. ABCA4 was the most frequent disease-causing gene, accounting for 20% of the positive cases. Pathogenic variants also occurred frequently in the CEP290, USH2A, CRB1, RPGR, and CHM genes. The relative frequency rates of different inherited retinal dystrophies in Brazil are similar to those found globally. Although mutations in more than 250 genes lead to hereditary retinopathies, only 66 genes were responsible for 70% of the cases, which indicated that smaller and cheaper gene panels can be just as effective and provide more affordable solutions for implementation by the Brazilian public health system.

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“…The sole application of microarray was enough to solve 76 cases, which were not further investigated with Sanger technique. Indeed, this may have led to an underestimation of the prevalence of novel additional mutations and/or complex alleles in this cohort [28,58]. The relatively high number of unsolved cases may be related to a combination of different factors: (1) The clinical overlap of distinct genetic entities could have led to uncertainties in patients’ selection.…”

Section: Discussionmentioning

confidence: 99%

“…This phenomenon may be partially explained by the ethnic variability of the studied populations [12]. Therefore the need to screen large populations and to identify novel variants is still relevant [27,28] and can help not only to explore the genetic architecture of ABCA4 pathology, but also the genotype/phenotype correlation. Much effort today is directed towards a more specific correlation tailored on single variants [24,28,29,30,31], even though their low frequency makes it challenging.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore the need to screen large populations and to identify novel variants is still relevant [27,28] and can help not only to explore the genetic architecture of ABCA4 pathology, but also the genotype/phenotype correlation. Much effort today is directed towards a more specific correlation tailored on single variants [24,28,29,30,31], even though their low frequency makes it challenging. Reporting ABCA4 novel variants with a clear and definite correlation with STGD1 would also help the proper selection of patients for therapeutic clinical trials reaching a higher degree of confidence with molecular diagnosis [32,33].…”

Section: Introductionmentioning

confidence: 99%

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Expanding the Mutation Spectrum in ABCA4: Sixty Novel Disease Causing Variants and Their Associated Phenotype in a Large French Stargardt Cohort

Nassisi

Mohand‐Saïd

Dhaenens

et al. 2018

IJMS

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Here we report novel mutations in ABCA4 with the underlying phenotype in a large French cohort with autosomal recessive Stargardt disease. The DNA samples of 397 index subjects were analyzed in exons and flanking intronic regions of ABCA4 (NM_000350.2) by microarray analysis and direct Sanger sequencing. At the end of the screening, at least two likely pathogenic mutations were found in 302 patients (76.1%) while 95 remained unsolved: 40 (10.1%) with no variants identified, 52 (13.1%) with one heterozygous mutation, and 3 (0.7%) with at least one variant of uncertain significance (VUS). Sixty-three novel variants were identified in the cohort. Three of them were variants of uncertain significance. The other 60 mutations were classified as likely pathogenic or pathogenic, and were identified in 61 patients (15.4%). The majority of those were missense (55%) followed by frameshift and nonsense (30%), intronic (11.7%) variants, and in-frame deletions (3.3%). Only patients with variants never reported in literature were further analyzed herein. Recruited subjects underwent complete ophthalmic examination including best corrected visual acuity, kinetic and static perimetry, color vision test, full-field and multifocal electroretinography, color fundus photography, short-wavelength and near-infrared fundus autofluorescence imaging, and spectral domain optical coherence tomography. Clinical evaluation of each subject confirms the tendency that truncating mutations lead to a more severe phenotype with electroretinogram (ERG) impairment (p = 0.002) and an earlier age of onset (p = 0.037). Our study further expands the mutation spectrum in the exonic and flanking regions of ABCA4 underlying Stargardt disease.

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Novel Complex ABCA4 Alleles in Brazilian Patients With Stargardt Disease: Genotype–Phenotype Correlation

Abstract: Segregation analysis is important in order to confirm the molecular diagnosis of patients with Stargardt disease, given the frequency of complex alleles in the ABCA4 gene. The various pathogenic variation combinations observed in this study were associated with different phenotypes.

Cited by 11 publications

References 37 publications

Clinical and Genetic Spectrum of Stargardt Disease in Argentinean Patients

Clinical and Genetic Spectrum of Stargardt Disease in Argentinean Patients

Relative frequency of inherited retinal dystrophies in Brazil

Expanding the Mutation Spectrum in ABCA4: Sixty Novel Disease Causing Variants and Their Associated Phenotype in a Large French Stargardt Cohort

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