TY - JOUR

T1 - Identification of a functionally significant tri-allelic genotype in the Tyrosinase gene (TYR) causing hypomorphic oculocutaneous albinism (OCA1B)

AU - Norman, Chelsea

AU - O'Gorman, Luke

AU - Gibson, Jane

AU - Pengelly, Reuben

AU - Baralle, Diana

AU - Ratnayaka, Arjuna

AU - Griffiths, Helen

AU - Rose-Zerilli, Matthew

AU - Ranger, Megan

AU - Bunyan, David

AU - Lee, Helena

AU - Page, Rhiannon

AU - Newall, Tutte

AU - Shawkat, Fatima

AU - Mattocks, Christopher

AU - Ward, Daniel

AU - Ennis, Sarah

AU - Self, Jay

PY - 2017/6/30

Y1 - 2017/6/30

N2 - 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 asingle 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.

AB - 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 asingle 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.

KW - Eye manifestations

KW - Genetic testing

KW - Genetics research

KW - Hereditary eye disease

KW - Ocular motility disorders

U2 - 10.1038/s41598-017-04401-5

DO - 10.1038/s41598-017-04401-5

M3 - Journal article

VL - 7

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 4415

ER -