A Subgroup of Age-Related Macular Degeneration is Associated With Mono-Allelic Sequence Variants in theABCA4Gene

Abstract

PURPOSE. Age-related macular degeneration (AMD) is a heterogeneous condition of high prevalence and complex etiology involving genetic as well as environmental factors. By fundus autofluorescence (FAF) imaging, AMD can be classified into several distinct phenotypes, with one subgroup characterized by fine granular pattern with peripheral punctate spots (GPS [+]). Some features of GPS[+] overlap with Stargardt disease (STGD1), a recessive macular dystrophy caused by biallelic sequence variants in the ATP-binding cassette transporter 4 (ABCA4) gene. The aim of this study was to investigate the role of ABCA4 in GPS [+].METHODS. The ABCA4 gene was sequenced in 25 patients with the GPS[+] phenotype and 29 with geographic atrophy (GA)-AMD but no signs of GPS (GPS [-]). In addition, frequencies of risk-increasing alleles at three known AMD susceptibility loci, including complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), and complement component 3 (C3), were evaluated. RESULTS.We demonstrate that GPS[+] is associated significantly with monoallelic ABCA4 sequence variants. Moreover, frequencies of AMD risk-increasing alleles at CFH, ARMS2, and C3 are similar in GPS[+] and STGD1 patients, with risk allele frequencies in both subcategories comparable to populationbased control individuals estimated from 3,510 individuals from the NHLBI Exome Sequencing Project.CONCLUSIONS. Our data suggest that the GPS[+] phenotype is accounted for by monoallelic variants in ABCA4 and unlikely by the well-established AMD risk-increasing alleles at CFH, ARMS2, and C3. These findings provide support for a complex role of ABCA4 in the etiology of a minor proportion of patients with AMD. (Invest Ophthalmol Vis Sci.

Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family

“…35 Interestingly, our STGD1 patients carried the sequence variant ABCA4 p.N1868I that was predicted to be possibly damaging, as well as acting as a risk-increasing factor in AMD. 36 In our study, this variant was detected in almost 14% of the healthy controls, which is higher compared with the maximal frequency of 7.5% reported in a Finnish population in the 1000 Genomes project. 36 It is worth mentioning that ABCA4 c.2588G4C (p.G863A), the most frequent autosomal recessive mutation in the European population, is disease causative only in combination with a severe ABCA4 mutation, 32 and does not result in a STGD1 phenotype when present bi-allelic or in combination with a mild ABCA4 mutation.…”

“…36 In our study, this variant was detected in almost 14% of the healthy controls, which is higher compared with the maximal frequency of 7.5% reported in a Finnish population in the 1000 Genomes project. 36 It is worth mentioning that ABCA4 c.2588G4C (p.G863A), the most frequent autosomal recessive mutation in the European population, is disease causative only in combination with a severe ABCA4 mutation, 32 and does not result in a STGD1 phenotype when present bi-allelic or in combination with a mild ABCA4 mutation. Maugeri et al 32 hypothesised the possibility of a carrier advantage due to the high carrier frequency of the 2588C allele in Sweden (1 out of 18), 37 although the incidence of STGD1 is not higher in our country than in the rest of Europe.…”

“…While the manuscript was in preparation, this variant was also reported in one AMD patient. 36 This variant was not detected in 3510 controls of European American descent, 36 and in our study only one carrier of 113 tested was found. The effect of the c.4773 þ 3A4G mutation can be tested using RNA splicing analysis.…”

Personalized genomic disease risk of volunteers

“…The childhood brittle corneal syndrome type 1 occurred in a volunteer who had undergone successful corneal transplant and carried a putative compound heterozygosity in ZNF469 (37). One volunteer was under care for macular dystrophy and carried an ABCA4 allele (38). One sterile male volunteer was found to have an insertion in gene USP26 (known to be responsible for infertility in men) (39).…”

Bisretinoid-mediated Complement Activation on Retinal Pigment Epithelial Cells Is Dependent on Complement Factor H Haplotype

“…Inflammation, oxidative stress, high-fat diets, light exposure, and genetic factors all contribute to the pathogenesis of AMD (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Among the genetic determinants for AMD, the gene for complement factor H (CFH) is a strong susceptibility locus (4 -7).…”