Prospective Study of the Phenotypic and Mutational Spectrum of Ocular Albinism and Oculocutaneous Albinism

Abstract

Albinism encompasses a group of hereditary disorders characterized by reduced or absent ocular pigment and variable skin and/or hair involvement, with syndromic forms such as Hermansky-Pudlak syndrome and Chédiak-Higashi syndrome. Autosomal recessive oculocutaneous albinism (OCA) is phenotypically and genetically heterogenous (associated with seven genes). X-linked ocular albinism (OA) is associated with only one gene, GPR143. We report the clinical and genetic outcomes of 44 patients, from 40 unrelated families of diverse ethnicities, with query albinism presenting to the ocular genetics service at Moorfields Eye Hospital NHS Foundation Trust between November 2017 and October 2019. Thirty-six were children (≤ 16 years) with a median age of 31 months (range 2-186), and eight adults with a median age of 33 years (range 17-39); 52.3% (n = 23) were male. Genetic testing using whole genome sequencing (WGS, n = 9) or a targeted gene panel (n = 31) gave an overall diagnostic rate of 42.5% (44.4% (4/9) with WGS and 41.9% (13/31) with panel testing). Seventeen families had confirmed mutations in TYR (n = 9), OCA2, (n = 4), HPS1 (n = 1), HPS3 (n = 1), HPS6 (n = 1), and GPR143 (n = 1). Molecular diagnosis of albinism remains challenging due to factors such as missing heritability. Differential diagnoses must include SLC38A8-associated foveal hypoplasia and syndromic forms of albinism.

Keywords: Hermansky–Pudlak syndrome; albinism; chiasmal misrouting; foveal hypoplasia; nystagmus; ocular albinism; oculocutaneous albinism.

Figure 1

Best corrected visual acuity (BCVA) changes in albinism patients. (A) Correlation between the change in BCVA at baseline and most recent follow up. The black dashed line represents a ‘no change’ scenario, while the grey correlation line illustrates the subtle change seen in patients. (B) Demonstrates the change in BCVA of each paediatric patient at baseline and most recent vision as a function of age. The black dashed line represents the point at which more accurate visual acuity testing can be achieved in children 3 years old and upwards.

Figure 2

Overview of the phenotypic spectrum of 44 suspected albinism patients presenting to the ocular genetics service. For chiasmal misrouting, n = 37, 7 declined electrophysiology visual evoked potential (VEP) testing.

Figure 3

(A) Proportion of families who underwent whole genome sequencing (WGS) and targeted gene panel testing seen through the ocular genetics service between November 2017 and September 2019 at MEH (Moorfields Eye Hospital NHS Foundation Trust). (B) Mutational spectrum of families with positive molecular findings. (C) Molecular diagnostic outcomes for WGS and targeted panel sequencing for the entire cohort. NPF = no primary findings.

Figure 4

Iris and multimodal retinal imaging (right and left eye) of a patient (27079) with homozygous TYR mutation. (A,B) Iris transillumination defects with visualization of nasal lens equator; (C,D) ultra-widefield (UWF) pseudocolor showing hypopigmented fundi and prominent choroidal vessels; (E,F) UWF fundus autofluorescence (FAF) illustrating the absence of hypoautofluoresence at the fovea due to decreased luteal pigments, crossing of retinal vessels at the fovea, and prominent choroidal vessels can be appreciated; (G,H) grade 4 foveal hypoplasia on spectral-domain optical coherence tomography (SDOCT).

Figure 5

Pattern appearance VEPs (PVEP) from a patient (27079) with TYR mutation. PVEP responses on stimulating the right eye are displayed on the top row and those on stimulating the left eye are on the bottom row. Column 1 and 2 are responses from the right hemisphere, column 4 and 5 are responses from the left hemisphere, and column 3 is the combined midline response. PVEP shows contralateral predominance (turquoise arrow) when the opposite eye (dotted red arrow) is stimulated.