Identification of a functionally significant tri-allelic genotype in the Tyrosinase gene (TYR) causing hypomorphic oculocutaneous albinism (OCA1B)

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.

Figure 1

OCT images using the Heidelberg Spectralis Diagnostic imaging platform. (a) Normal fovea (Mother of proband 13) (b) Foveal hypoplasia grade 1 (brother of proband 13) (c) Foveal hypoplasia grade 3 (Mother of proband 18). Foveal grading according to the Thomas et al. grading system. Outer nuclear layers (ONL), outer plexiform layers (OPL), inner nuclear layers (INL), inner plexiform layers (IPL), ganglion cell layers (GCL) and retinal nerve fibre layers (RNFL) are labelled.

Figure 2

Pedigree diagrams for six families with a single TYR pathogenic mutation and common polymorphism phenotyping. TYR variants are listed beneath each family. Sanger sequencing was performed on family members as opposed to the full exonic region sequenced in probands. Family number corresponds with proband number.