The contribution of common population variants to hypomorphic oculocutaneous albinism phenotypes: a novel tri-allelic TYR genotype

Purpose : Oculocutaneous albinism type 1 (OCA1) is the most common cause of albinism in European populations and is inherited through autosomal recessive mutations in the Tyrosinase (TYR) gene. The high level of reported missing heritability in OCA1 can obstruct confident diagnoses. We have used next generation sequencing techniques to interrogate the genotype for a cohort of patients with hypomorphic albinism and examined the hypothesis that common population variants can contribute to the hypomorphic albinism phenotype.Methods : We have interrogated the genetic cause of albinism in a well phenotyped, hypomorphic albinism cohort of 18 patients. Hypomorphic phenotypes were diagnosed as those with at least two, but not all features of albinism. DNA was sequenced on the TruSight One ‘clinical exome’ panel to search for causal variants in all OCA genes, as well as being analysed through multiple ligation dependent probe amplification (MLPA) to determine the presence of any large deletions in the TYR or OCA2 gene. Further analysis of OCA1 genotypes was carried out through segregation studies in phenotyped family members. Probands and family members were sequenced for TYR rare variants as well as the common variants S192Y and R402Q, both of which have a population frequency greater than 20%.Results : Of eighteen probands we confidently diagnose one with ocular albinism, two with OCA type 2, 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, figure 1. The predicted frequency of p.[S192Y;R402Q] in cis is 1.1%, however a cis versus trans distinction cannot be made in all cases.Conclusions : Our segregation results suggest that a combination of R402Q and S192Y with a deleterious mutation in a ‘tri-allelic genotype’ can account for missing heritability in a substantial number of hypomorphic OCA1B albinism phenotypes. The work also describes subtle phenotypic features that could be missed when a patient presents with nystagmus, thus leading to improvements in the overall diagnosis of congenital nystagmus