Genotype-Phenotype Correlation Model for the Spectrum of TYR-Associated Albinism

Abstract

We present two children aged 3 and 5 years who share identical TYR genotype, yet exhibit contrasting phenotypic manifestations in terms of eye, skin, and hair coloration. The patients are heterozygous for TYR c.1A>G, p. (Met1?), which is pathogenic, and homozygous for TYR c.1205G>A, p. (Arg402Gln), which is classified as a risk factor. The children manifested diminished visual acuity, nystagmus, and foveal hypoplasia. The first patient presented with hypopigmentation of the skin, hair, and ocular tissues, while the second patient presented with hypopigmentation of the skin, hair, retinal pigment epithelium, and choroid with dark brown irises. Furthermore, the brown-eyed subject presented astigmatic refractive error and both global and local stereopsis capabilities, contrasting with the presentation of hypermetropia, strabismus, and the absence of stereopsis in the blue-eyed individual. Herein, we propose a genotype-phenotype correlation model to elucidate the diverse clinical presentations stemming from biallelic and triallelic pathogenic variants in TYR, establishing a link between the residual tyrosinase activity and resultant phenotypes. According to our proposed model, the severity of TYR variants correlates with distinct albino phenotypes. Our findings propose the potential association between reduced pigmentation levels in ocular tissues and binocular functions, suggesting pigmentation as a possible independent variable influencing the onset of strabismus-an association unreported until now in the existing literature.

Keywords: albinism; depth perception; genotype; optical coherence tomography; phenotype; pigmentation.

Figure 1

Ultra-widefield imaging depicted brightly pigmented retina on both eyes, consistent with grade 1 fundi (top row). Fundus autofluorescence image of the both eyes was isoautofluorescent (bottom row).

Figure 2

Optical coherence tomography (OCT) imaging showing the right (A) and left (B) macular area of the first patient and the right (C) and left (D) macular area of the second patient. Foveal hypoplasia grade 4 according to the Leicester Grading System was evident.

Figure 3

Ultra-widefield imaging showing pronounced light pigmented retina consistent with grade 2 fundi and absent macular reflexes on both eyes (top row). Fundus autofluorescence image showing isoautofluorescent signal on both eyes (bottom row).