|Gene (OMIM no.)|
|Function of gene/protein|
|Clinical phenotype (with OMIM phenotype no.)|
|Ocular features||The ocular phenotype and visual function are highly variable among individuals affected by OCA1. They may have some/all of the following features:|
|Systemic features||Key investigations||Molecular diagnosis||Next generation sequencing||Management||Therapies under research||Further information|
Pathogenic mutations in the TYR gene are associated with the oculocutaneous albinism type 1 (OCA1) phenotype. OCA1 is the most common OCA subtype among Caucasians, with an estimated prevalence of 1 in 40,000. OCA1 can be further divided into two groups depending on the residual activity of the tyrosinase enzyme. Those with complete lack of tyrosinase activity due to production of an inactive enzyme are classified as OCA1A, while those with reduced tyrosinase activity are known to have OCA1B (partial albinism).
The associated ocular and cutaneous phenotypes can be highly variable, where ocular features are more penetrant compared to cutaneous changes. In multiple large cohort studies with confirmed molecular diagnoses, features such as foveal hypoplasia, chiasmal misrouting on VEP, nystagmus and ocular hypopigmentation (iris transillumination and fundal hypopigmentation) are frequently detected but all of these features may not be present in the same patient. Comparatively, skin and/or hair hypopigmentation are variable and can be difficult to ascertain in individuals from fair-skinned ethnicities.[9–12]
Patients harbouring both loss-of-function variants usually display the full complement of OCA features while patients with OCA1B tend to be more subtle. Recently, the haplotype c.[575 C > A; 1205 G > A] p.[(Ser192Tyr);(Arg402Gln)] has been proven to cause OCA1B when segregated in trans with a pathogenic TYR variant, resolving up to 25% of previously genetically unsolved OCA cases where only one pathogenic or likely pathogenic TYR variant was found. (Southampton group, 2022) Patients who are homozygous of this haplotype seem to display very mild features of OCA (foveal hypoplasia +/- mild iris transillumination) with good visual function and no pigmentation changes, which can be easily missed without complete phenotyping. Hence, ophthalmic investigations such as OCT scans and VEP testing are key in diagnosing OCA clinically, which can be further refined using established diagnostic criteria such as the one proposed by Krujit et al. Crucially, patients should be offered genetic testing as it can help direct further management, counselling and research participation. Patients harbouring variants in genes associated with syndromic OCA can be referred earlier to the relevant specialties to improve quality of life and survival. Moreover, it can also help differentiate OCA from other clinically similar conditions such as PAX6-oculopathy, GPR143 X-linked ocular albinism, FRMD7 X-linked infantile idiopathic nystagmus and SLC38A8-associated FHONDA (foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis).
Waardenburg syndrome (WS) is a clinically and genetically heterogeneous condition characterised by deafness and pigmentary anomalies of the hair (white forelock/premature greying), skin and eyes. WS can be divided into four subtypes based on specific clinical findings and molecular aetiology. WS1 and WS2 have similar features but WS2 is distinguished by the lack of dystopia canthorum (telecanthus). WS2 can be caused by heterozygous mutations in the MITF gene but a digenic interaction between MITF and the TYR p.Arg402Gln allele has been demonstrated in a family with WS2 and ocular albinism. However, it is important to note that the p.Arg402Gln polymorphism is common in the general population, particularly among Caucasians. Thus, the reported TYR polymorphism in this family may be unrelated to the phenotype.
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- Lin S, Sanchez-Bretaño A, Leslie JS, et al. Evidence that the Ser192Tyr/Arg402Gln in cis Tyrosinase gene haplotype is a disease-causing allele in oculocutaneous albinism type 1B (OCA1B). NPJ Genom Med. 2022;7(1):2.
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