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

The contribution of common population variants to hypomorphic oculocutaneous albinism phenotypes: a novel tri-allelic TYR genotype
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.
5784
Norman, Chelsea Sarah
f21381a8-b83c-456d-afb2-b7a3aecd3e19
O'Gorman, Luke
6127468d-0693-4a05-b2d0-2f1c2ddc84ff
Gibson, Jane
855033a6-38f3-4853-8f60-d7d4561226ae
Pengelly, Reuben J.
af97c0c1-b568-415c-9f59-1823b65be76d
Baralle, Diana
faac16e5-7928-4801-9811-8b3a9ea4bb91
Ratnayaka, J. Arjuna
002499b8-1a9f-45b6-9539-5ac145799dfd
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Self, James E.
0f6efc58-ae24-4667-b8d6-6fafa849e389
Norman, Chelsea Sarah
f21381a8-b83c-456d-afb2-b7a3aecd3e19
O'Gorman, Luke
6127468d-0693-4a05-b2d0-2f1c2ddc84ff
Gibson, Jane
855033a6-38f3-4853-8f60-d7d4561226ae
Pengelly, Reuben J.
af97c0c1-b568-415c-9f59-1823b65be76d
Baralle, Diana
faac16e5-7928-4801-9811-8b3a9ea4bb91
Ratnayaka, J. Arjuna
002499b8-1a9f-45b6-9539-5ac145799dfd
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Self, James E.
0f6efc58-ae24-4667-b8d6-6fafa849e389

Norman, Chelsea Sarah, O'Gorman, Luke, Gibson, Jane, Pengelly, Reuben J., Baralle, Diana, Ratnayaka, J. Arjuna, Ennis, Sarah and Self, James E. (2018) The contribution of common population variants to hypomorphic oculocutaneous albinism phenotypes: a novel tri-allelic TYR genotype. Investigative Ophthamology & Visual Science, 59 (9), 5784.

Record type: Meeting abstract

Abstract

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.

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More information

Published date: 1 July 2018

Identifiers

Local EPrints ID: 423101
URI: http://eprints.soton.ac.uk/id/eprint/423101
PURE UUID: 3aa3179e-d9ae-4385-ac72-ea81be25f960
ORCID for Jane Gibson: ORCID iD orcid.org/0000-0002-0973-8285
ORCID for Reuben J. Pengelly: ORCID iD orcid.org/0000-0001-7022-645X
ORCID for Diana Baralle: ORCID iD orcid.org/0000-0003-3217-4833
ORCID for J. Arjuna Ratnayaka: ORCID iD orcid.org/0000-0002-1027-6938
ORCID for Sarah Ennis: ORCID iD orcid.org/0000-0003-2648-0869
ORCID for James E. Self: ORCID iD orcid.org/0000-0002-1030-9963

Catalogue record

Date deposited: 14 Aug 2018 16:30
Last modified: 10 Nov 2021 03:34

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Contributors

Author: Chelsea Sarah Norman
Author: Luke O'Gorman
Author: Jane Gibson ORCID iD
Author: Diana Baralle ORCID iD
Author: Sarah Ennis ORCID iD
Author: James E. Self ORCID iD

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