Abstract
Oculocutaneous albinism (OCA) and ocular albinism (OA) are inherited disorders of melanin biosynthesis, resulting in loss of pigment and severe visual deficits. OCA encompasses a range of subtypes with overlapping, often hypomorphic phenotypes. OCA1 is the most common cause of albinism in European populations and is inherited through autosomal recessive mutations in the Tyrosinase (TYR) gene. However, there is a high level of reported missing heritability, where only a single heterozygous mutation is found in TYR. This is also the case for other OCA subtypes including OCA2 caused by mutations in the OCA2 gene. Here we have interrogated the genetic cause of albinism in a well phenotyped, hypomorphic albinism population by sequencing a broad gene panel and performing segregation studies on phenotyped family members. Of eighteen probands we can confidently diagnose three with OA and OCA2, and one with a PAX6 mutation. Of six probands with only a single heterozygous mutation in TYR, all were found to have the two common variants S192Y and R402Q. Our results suggest that a combination of R402Q and S192Y with a deleterious mutation in a ‘tri-allelic genotype’ can account for missing heritability in some hypomorphic OCA1 albinism phenotypes.
Highlights
Oculocutaneous albinism (OCA) and X-linked ocular albinism (OA) are inherited disorders of melanin biosynthesis which result in varied levels of hypopigmentation of skin, hair, and ocular tissues[1]
Six genes involved in melanin biosynthesis pathway are known to cause forms of OCA and OA: TYR, OCA2, TYRP1, SLC45A2, SLC24A5, and C10orf[11] accounting for OCA subtypes 1–4 and 6–7 respectively, and GPR143 accounting for OA16, see Table 1
Phenotypes of partial OCA overlap with those seen in patients with dominant mutations in the PAX6 gene, which is involved in ocular development, where a variety of phenotypes have been described including foveal hypoplasia, iris trans-illumination and nystagmus[9]
Summary
Oculocutaneous albinism (OCA) and X-linked ocular albinism (OA) are inherited disorders of melanin biosynthesis which result in varied levels of hypopigmentation of skin, hair, and ocular tissues[1]. X-linked recessive refractive errors, management of head postures/strabismus and on the importance of effective sun protection. Another important factor in the management albinism is genetic counselling; it is important to confirm a genetic diagnosis for patients. Phenotypes of partial OCA overlap with those seen in patients with dominant mutations in the PAX6 gene, which is involved in ocular development, where a variety of phenotypes have been described including foveal hypoplasia, iris trans-illumination and nystagmus[9]. Ethnic background may play a large role in an individual’s susceptibility to the albinism phenotype, with hypomorphic mutations having a more damaging effect on a less active pigmentary pathway[16, 17]. The quantitative effect of pigmentation has relevance to OCA1B, the notion of autosomal recessive ocular albinism (AROA), an arbitrary characterisation that has been used previously to describe cases with clinically mild OCA1B19, 20
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