Abstract
Individuals who have ocular features of albinism and skin pigmentation in keeping with their familial background present a considerable diagnostic challenge. Timely diagnosis through genomic testing can help avert diagnostic odysseys and facilitates accurate genetic counselling and tailored specialist management. Here, we report the clinical and gene panel testing findings in 12 children with presumed ocular albinism. A definitive molecular diagnosis was made in 8/12 probands (67%) and a possible molecular diagnosis was identified in a further 3/12 probands (25%). TYR was the most commonly mutated gene in this cohort (75% of patients, 9/12). A disease-causing TYR haplotype comprised of two common, functional polymorphisms, TYR c.[575 C > A;1205 G > A] p.[(Ser192Tyr);(Arg402Gln)], was found to be particularly prevalent. One participant had GPR143-associated X-linked ocular albinism and another proband had biallelic variants in SLC38A8, a glutamine transporter gene associated with foveal hypoplasia and optic nerve misrouting without pigmentation defects. Intriguingly, 2/12 individuals had a single, rare, likely pathogenic variant in each of TYR and OCA2 – a significant enrichment compared to a control cohort of 4046 individuals from the 100,000 genomes project pilot dataset. Overall, our findings highlight that panel-based genetic testing is a clinically useful test with a high diagnostic yield in children with partial/ocular albinism.
Highlights
Individuals who have ocular features of albinism and skin pigmentation in keeping with their familial background present a considerable diagnostic challenge
We identified 12 children with nystagmus, at least one other ocular feature of albinism, and no apparent skin hypopigmentation in the context of their family
Possible electrophysiological evidence of optic nerve misrouting was identified at some point in the life of 9/10 patients tested; 3 of these 9 children were tested more than once and there was variability in the visual evoked potential (VEP) findings between visits (Table 1)
Summary
Individuals who have ocular features of albinism and skin pigmentation in keeping with their familial background present a considerable diagnostic challenge. Ocular features are present in all albinism patients and are characteristic of the condition; these may include nystagmus, foveal hypoplasia, fundal hypopigmentation, iris transillumination and optic nerve misrouting. Skin pigmentation abnormalities can often be difficult to evaluate, especially in people with light-skinned familial backgrounds In such cases, there is significant phenotypic overlap with a range of other ophthalmic conditions including X-linked idiopathic congenital nystagmus [MIM: 310700]5, SLC38A8-associated foveal hypoplasia ( known as FHONDA [MIM: 609218], a condition including optic nerve decussation defects and, in some cases, anterior segment dysgenesis)[6], and dominant PAX6-related oculopathy [MIM: 136520]7. The current diagnostic pathway for these individuals is often prolonged, cumbersome and frequently unsuccessful Investigations such as slit lamp examination, macular optical coherence tomography and visual electrophysiology can be helpful and are typically used to formally diagnose iris transillumination, foveal hypoplasia and optic nerve misrouting respectively. Multiple clinic visits over years and several investigations may be needed to reach a formal diagnosis
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