Genotype-Phenotype Correlation in Italian Families with Stargardt Disease

Abstract

Autosomal recessive Stargardt disease (STGD) has been associated with substantial genetic and phenotypic heterogeneity. By systematic clinical analyses of STGD patients with complete genetic data (i.e. identified mutations on both alleles of the ABCA4 gene), we set out to determine phenotypic subtypes and to correlate these with specific ABCA4 alleles. Twenty-eight patients from 18 families with STGD/fundus flavimaculatus were investigated. All patients were submitted to complete ophthalmologic examination, electrophysiology, fluorescein angiography and ABCA4 gene chip analysis. Two main clinical phenotypes were observed among the examined patients. The severe phenotype was characterized by the onset of the disease <20 years and reduced ERG response, whereas the mild phenotype presented with later onset of the disease and a normal ERG response. Genetic analysis of the ABCA4 gene revealed, in the severe group, more frequently deletions, stop codons and insertions as compared to the mild phenotype group (p = 0.0113 by Fisher’s exact test). Moreover, the compound heterozygous mutations G1961E/5018 + 2T → C found in 7 patients from 3 unrelated STGD families were associated with a mild phenotype in all subjects, except 1. This study documented variability of the clinical expression of STGD in relation to the age of onset of the disease, fundus appearance and the ERG response and allowed to subdivide patients into a severe and a mild phenotype group. These findings suggest that an extensive and comprehensive genetic analysis of STGD patients combined with thorough clinical evaluation, including the careful recording of the age of onset of the disease, would allow a more precise prognostic evaluation.

Novel mutations in of the ABCR gene in italian patients with Stargardt disease

“…Therefore, it can be speculated that its clinical expression depends on the mutation severity on the fellow allele, as suggested by earlier genotype/ phenotype studies. 17,21 Still, although the A1038V mutation is commonly reported in the literature, 9,13,27 in our series, it was detected in only two patients (1.4% of the patients, 0.7% of the alleles) within the L541P-A1038V complex allele. Moreover, in the Italian studies, this mutation was reported in 4.1 10 and 5.5% 11 of the alleles.…”

“…11 In addition, another study on an Italian sample considered only patients with biallelic disease mutations for a genotype-phenotype correlation. 17 In this study, the mutation spectrum of the ABCR gene was determined in another group of Italian patients affected with autosomal recessive STGD. Our series consisted of 62 families, originating for the most part from the central Italy.…”

Retinal Phenotypes in Patients Homozygous for the G1961E Mutation in theABCA4Gene

“…22 The heterozygous G1961E mutation, in combination with a different ABCA4 allele on the other chromosome, has been associated with a localized disease process that is confined to the posterior pole, normal full-field electroretinogram (ffERG), absence of the ''dark choroid'' sign on fluorescein angiography (FA), and BEM on fundus autofluorescence (FAF). 19,[23][24][25] Despite all these data, there still is debate as to whether this mutation causes retinal pathology in homozygosity. We studied patients homozygous for the G1961E allele to demonstrate the pathogenicity of the mutation in homozygosity and to describe further the variation in retinal phenotypes associated with it.…”

Retinal Phenotypes in Patients Homozygous for the G1961E Mutation in theABCA4Gene

“…The phenotype for the heterozygous cases is similar to that reported by Simonelli and colleagues. 3 Collectively, these reports suggest that there may not be a meaningful difference in the phenotype and specifically the age of onset between homozygous and heterozygous carriers of the G1961E mutation. …”