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Genotype-Phenotype Correlations in a Spanish Cohort of 506 Families With Biallelic ABCA4 Pathogenic Variants

Del Pozo-Valero, Marta and Riveiro-Alvarez, Rosa and Blanco-Kelly, Fiona and Aguirre-Lamban, Jana and Martin-Merida, Inmaculada and Iancu, Ionut-Florin and Swafiri, Saoud and Lorda-Sanchez, Isabel and Rodriguez-Pinilla, Elvira and Trujillo-Tiebas, Maria José and Jimenez-Rolando, Belen and Carreño, Ester and Mahillo-Fernandez, Ignacio and Rivolta, Carlo and Corton, Marta and Avila-Fernandez, Almudena and Garcia-Sandoval, Blanca and Ayuso, Carmen. (2020) Genotype-Phenotype Correlations in a Spanish Cohort of 506 Families With Biallelic ABCA4 Pathogenic Variants. American journal of ophthalmology, 219. pp. 195-204.

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Abstract

To define genotype-phenotype correlations in the largest cohort study worldwide of patients with biallelic ABCA4 variants, including 434 patients with Stargardt disease (STGD1) and 72 with cone-rod dystrophy (CRD).; Cohort study.; We characterized 506 patients with ABCA4 variants using conventional genetic tools and next-generation sequencing technologies. Medical history and ophthalmologic data were obtained from 372 patients. Genotype-phenotype correlation studies were carried out for the following variables: variant type, age at symptom onset (AO), and clinical phenotype.; A total of 228 different pathogenic variants were identified in 506 ABCA4 patients, 50 of which were novel. Genotype-phenotype correlations showed that most of the patients with biallelic truncating variants presented with CRD and that these cases had a significantly earlier AO than patients with STGD1. Three missense variants are associated with CRD for the first time (c.1804C>T; p.[Arg602Trp], c.3056C>T; p.[Thr1019Met], and c.6320G>C; p.[Arg2107Pro]). Analysis of the most prevalent ABCA4 variant in Spain, c.3386G>T; p.(Arg1129Leu), revealed that is correlated to STGD1, later AO, and foveal sparing.; Our study, conducted in the largest ABCA4-associated disease cohort reported to date, updates the genotype-phenotype model established for ABCA4 variants and broadens the mutational spectrum of the gene. According to our observations, patients with ABCA4 presenting with 2 truncating variants may first present features of STGD1 but eventually develop rod dysfunction, and specific missense variants may be associated with a different phenotype, underscoring the importance of an accurate genetic diagnosis. Also, it is a prerequisite for enrollment in clinical trials, and to date, no other treatment has been approved for STGD1.
Faculties and Departments:03 Faculty of Medicine
09 Associated Institutions > Institute of Molecular and Clinical Ophthalmology Basel (IOB)
09 Associated Institutions > Institute of Molecular and Clinical Ophthalmology Basel (IOB) > Research Group Rivolta IOB
UniBasel Contributors:Rivolta, Carlo
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Elsevier
ISSN:0002-9394
e-ISSN:1879-1891
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:22 Jan 2021 08:53
Deposited On:23 Dec 2020 10:20

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