AUTHORS
Marta Del Pozo-Valero, Rosa Riveiro-Alvarez, Fiona Blanco-Kelly, Jana Aguirre-Lamban, Inmaculada Martin-Merida, Ionut-Florin Iancu, Saoud Swafiri, Isabel Lorda-Sanchez, Elvira Rodriguez-Pinilla, Maria José Trujillo-Tiebas, Belen Jimenez-Rolando, Ester Carreño, Ignacio Mahillo-Fernandez, Carlo Rivolta, Marta Corton, Almudena Avila-Fernandez, Blanca Garcia-Sandoval, Carmen Ayuso
Am J Ophthalmol. 2020 Nov;219:195-204. doi: 10.1016/j.ajo.2020.06.027. Epub 2020 Jun 30.
ABSTRACT
PURPOSE: 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).
DESIGN: Cohort study.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
PMID:32619608 | DOI:10.1016/j.ajo.2020.06.027
