AMD Patients Carrying Rare Gene Variants Predisposed to GA

A more severe drusen phenotype and larger drusen size, together with other characteristics associated with carriership of rare variants in CFH and CFI—such as an early age of onset and a positive family history of AMD—could help eye doctors identify AMD patients that are more likely to carry a rare variant in CFH or CFI, this group of researchers suggested in a recent paper. Photo: Jay Haynie, OD. Click image to enlarge. It’s been reported that several genetic variants, including ones affecting the complement factor H (CFH) and complement factor I (CFI) genes, may have an important role in AMD pathogenesis. In a recent study, researchers described the phenotype of AMD patients carrying these variants: more severe drusen as well as reticular pseudodrusen (RPD) and a higher frequency of intermediate AMD and GA. The findings were reported in Ophthalmology Science.Genetic data of 234 AMD patients carrying rare variants in CFH (n=134) and CFI (n=100) as well as 234 AMD noncarriers from a European database were filtered for rare coding and splice-site variants in CFH and CFI. For each carrier, an age-matched AMD patient without the gene variants was selected. Fundus characteristics were graded according to the Rotterdam Classification and compared between carriers and noncarriers.AMD patients carrying the gene variants presented with a more severe drusen phenotype and a higher prevalence of GA, particularly those carrying rare pathogenic variants in CFH. Subgroup analysis showed distinct findings unique to each of the two gene variants.In a previous study, multiple fundus features, including a drusen area larger than 375μm and drusen type (soft indistinct and RPD) were reported to be strongly associated with risk for progression to GA, which may explain the higher prevalence of GA in the rare variant carriers, where they observed a more severe drusen phenotype.A possible explanation for the more severe drusen phenotype in the rare variant carriers might be related to the stronger dysregulation of the complement system in these patients. “Complement components, such as C3 and C5, are one of the components of conventional drusen,” the authors explained in their findings in their Ophthalmology Science paper. “Also, RPD contain immune cells, photoreceptor outer segments and are rich in vitronectin. This latter component interacts with complement proteins and inhibits the terminal cytolytic part of the complement pathway.” One might argue that in patients carrying rare genetic variants in complement related genes, such as CFH and CFI, accumulation of complement components may be more severe or may even occur at an earlier age, they added.Identifying these distinct phenotypic features, along with early age of onset and positive family history, may help ophthalmologists identify patients more likely to carry rare CFH or CFI variants. Additionally, because individuals with CFH variants are often younger, they face a longer burden of potential vision loss, making them promising targets for early intervention trials and may be more likely to benefit from complement-inhibiting therapies, the authors concluded in their paper.Click here for the journal source. De Breuk A, de Jong S, Bakker B, et al. Geographic atrophy in patients with age-related macular degeneration is associated with rare variants in complement factor H and complement factor I. Ophthalmol Sci. March 17, 2026. [Epub ahead of print.]  This article was developed by the editorial staff in conjunction with experts in the field. In the process, AI may have been among the editorial tools used to meet the goals of human editors, who approved all content.