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. 2025 Apr 1;66(4):62.
doi: 10.1167/iovs.66.4.62.

Iris Pigmented Lesions: Unraveling the Genetic Basis of Iris Freckles and Nevi

Julia Boldu-Roig  1 , Elena Sorli-Clemente  2 , Aida Kuljuh-Causevic  3 , Alba Loras  3 , Alfonso Anton  1 , Conrado Martinez-Cadenas  3
Affiliations

Iris Pigmented Lesions: Unraveling the Genetic Basis of Iris Freckles and Nevi

Julia Boldu-Roig et al. Invest Ophthalmol Vis Sci. .

Abstract

Purpose: To investigate the diversity of pigmented benign lesions in the human iris, aiming to provide insights for forensic, biomedical, and ophthalmological research.

Methods: A cohort of 1014 individuals of Spanish descent was analyzed. Digital slit-lamp photographs were used to evaluate iris pigmentation traits, including iris freckles, iris nevi, iris color, and the presence of a pigmented collarette. A candidate gene association study was performed on these pigmentation traits.

Results: Both iris freckles and nevi were associated with increased age, female sex, pigmented collarette, and eye color (mainly green). Additionally, higher freckle and nevus counts were observed in participants with more facial freckles and cutaneous nevi and were positively associated with each other. After adjustment, a positive significant association was identified between the presence of iris freckles and genetic variants in the IRF4, HERC2, and OCA2 genes, as well as SLC45A2, although only in females. The prevalence of iris nevi was significantly lower compared to freckles. The presence of iris nevi also showed positive associations with genetic variants in IRF4 and HERC2, plus TYR in brown-eyed individuals only. No association was identified between MC1R, the major cutaneous freckle gene, and the presence of iris freckles or nevi.

Conclusions: The genetic basis of iris freckles and nevi reveals associations with well-known pigmentation genes (particularly IRF4), as well as eye color, sex, and age. 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.

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Conflict of interest statement

Disclosure: J. Boldu-Roig, None; E. Sorli-Clemente, None; A. Kuljuh-Causevic, None; A. Loras, None; A. Anton, None; C. Martinez-Cadenas, None

Figures

Figure 1.
Figure 1.
Digital images with examples of the different pigmentary elements found in the iris from six participants. (A) Freckles on a green eye with pigmented collarette. (B) Nevi on a brown eye. (C) Freckles (orange arrows) and nevus (black arrow) on a blue eye. (D) Freckles (orange arrows) and nevus (black arrow) on a green eye. (E) Multitude of iris freckles on a green eye. (F) An extremely rare case of an iris with a very large amount of nevi.
Figure 2.
Figure 2.
Graphical representation of a left eye showing the topographic distribution of the percentages of the different pigmentary spots in the iris by quadrants. (A) Iris freckles. (B) Iris nevi. The lacrimal point corresponds to the nasal meridian, and the opposite corresponds to the temporal meridian.
See this image and copyright information in PMC

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