Study Details Genetic Basis of Iris Freckles, Nevi

Iris freckles and nevi are associated with uveal melanoma, age-related macular degeneration and solar damage. This analysis of genetic markers associated with these lesions may help identify patients at an elevated risk of developing these conditions. These images from the study show examples of the different pigmentary elements found in six participants: (a) freckles with pigmented collarette, (b) nevi, (c, d) freckles (orange arrows) and nevus (black arrow), (e) a multitude of iris freckles on a green eye and (f) an extremely rare case of an iris with a very large amount of nevi. Photo: Boldu-Roig J, et al. Invest Ophthalmol Vis Sci. 2025;66(4):62. Click image to enlarge. Iris freckles and nevi are present in 40% to 70% and 4% to 6% of adults, respectively. These pigmented spots can alter the perception of overall eye color, which, in forensic science, is often based on DNA samples; therefore, it’s important to understand how genetics influence iris surface pigmented spots to improve the accuracy of eye color predictive models. Furthermore, given the increased prevalence of certain cancers and ophthalmic diseases like AMD in patients with these lesions, delineating their genetic markers could help stratify disease risk. Seeking to provide further insight, researchers conducted a new study that identified significant associations between iris freckles, nevi, gender, age and specific genes like IRF4, HERC2 and OCA2.The investigation involved a cohort of 1,014 Spanish individuals who underwent comprehensive ophthalmological exams, including iris photography and genetic analysis. Rigorous exclusion criteria ensured the reliability of the data, focusing only on participants without relevant ocular pathologies or prior related treatments.The results underscored a predominant occurrence of iris freckles and nevi with aging, particularly in women. The authors noted in their paper for Investigative Ophthalmology & Vision Science that “this is the first study that describes a clear positive association between iris freckles or nevi and female sex,” though prior research “has already described positive female sex biases in human pigmentation, including skin pigmentation, cutaneous freckling and eye color.”Iris freckles and nevi were most common in green eyes and those with pigmented collarettes. Moreover, both iris lesions were positively correlated with facial freckles and cutaneous nevi. Genetic analyses revealed that the presence of these pigmented spots is strongly correlated with specific genetic markers. For example, iris freckles were positively associated with variants in the following genes: IRF4, HERC2, OCA2 and SLC45A2, though the latter only showed an association in female patients. Among patients with iris nevi, genetic variants were identified in IRF4 and HERC2, as well as in TYR, though only in brown-eyed individuals.The IRF4 gene—a vital human pigmentation gene and the second most important for freckle development in the skin—was identified as the major contributor to iris freckles and nevi, which researchers note marks “the first reported association between IRF4 and iris nevi.” Interestingly, they noted, “both rs12203592 in IRF4 and rs12913832 in HERC2, the two most important genetic determinants of iris freckles and nevi found in this work, have also been recently identified as risk factors for developing uveal melanoma.”In summary, the researchers concluded, “These findings contribute to our understanding of iris pigmented benign lesions and their potential implications in conditions such as uveal melanoma, age-related macular degeneration or solar damage.” Click here for the journal source.  Boldu-Roig J, Sorli-Clemente E, Kuljuh-Causevic A, et al. Iris pigmented lesions: unraveling the genetic basis of iris freckles and nevi. Invest Ophthalmol Vis Sci. 2025;66(4):62.