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A small gene sequencing panel realises a high diagnostic rate in patients with congenital nystagmus following basic phenotyping

A small gene sequencing panel realises a high diagnostic rate in patients with congenital nystagmus following basic phenotyping
A small gene sequencing panel realises a high diagnostic rate in patients with congenital nystagmus following basic phenotyping
Nystagmus is a disorder of uncontrolled eye movement and can occur as an isolated trait (idiopathic INS, IINS) or as part of multisystem disorders such as albinism, significant visual disorders or neurological disease. Eighty-one unrelated patients with nystagmus underwent routine ocular phenotyping using commonly available phenotyping methods and were grouped into four sub-cohorts according to the level of phenotyping information gained and their findings. DNA was extracted and sequenced using a broad utility next generation sequencing (NGS) gene panel. A clinical subpanel of genes for nystagmus/albinism was utilised and likely causal variants were prioritised according to methods currently employed by clinical diagnostic laboratories. We determine the likely underlying genetic cause for 43.2% of participants with similar yields regardless of prior phenotyping. This study demonstrates that a diagnostic workflow combining basic ocular phenotyping and a clinically available targeted NGS panel, can provide a high diagnostic yield for patients with infantile nystagmus, enabling access to disease specific management at a young age and reducing the need for multiple costly, often invasive tests. By describing diagnostic yield for groups of patients with incomplete phenotyping data, it also permits the subsequent design of ‘real-world’ diagnostic workflows and illustrates the changing role of genetic testing in modern diagnostic workflows for heterogeneous ophthalmic disorders.
2045-2322
O'Gorman, Luke
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Norman, Chelsea
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Michaels, Luke
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Newall, Tutte
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Crosby, Andrew H.
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Mattocks, Christopher
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Cree, Angela
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Lotery, Andrew
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Baple, Emma L.
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Ratnayaka, Arjuna
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Baralle, Diana
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Lee, Helena
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Osborne, Daniel
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Shawkat, Fatima
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Gibson, Jane
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Ennis, Sarah
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Self, Jay E.
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O'Gorman, Luke
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Norman, Chelsea
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Michaels, Luke
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Newall, Tutte
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Crosby, Andrew H.
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Mattocks, Christopher
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Cree, Angela
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Lotery, Andrew
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Baple, Emma L.
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Ratnayaka, Arjuna
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Baralle, Diana
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Lee, Helena
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Osborne, Daniel
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Shawkat, Fatima
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Gibson, Jane
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Ennis, Sarah
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Self, Jay E.
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O'Gorman, Luke, Norman, Chelsea, Michaels, Luke, Newall, Tutte, Crosby, Andrew H., Mattocks, Christopher, Cree, Angela, Lotery, Andrew, Baple, Emma L., Ratnayaka, Arjuna, Baralle, Diana, Lee, Helena, Osborne, Daniel, Shawkat, Fatima, Gibson, Jane, Ennis, Sarah and Self, Jay E. (2019) A small gene sequencing panel realises a high diagnostic rate in patients with congenital nystagmus following basic phenotyping. Scientific Reports, 9 (1), [13229]. (doi:10.1038/s41598-019-49368-7).

Record type: Article

Abstract

Nystagmus is a disorder of uncontrolled eye movement and can occur as an isolated trait (idiopathic INS, IINS) or as part of multisystem disorders such as albinism, significant visual disorders or neurological disease. Eighty-one unrelated patients with nystagmus underwent routine ocular phenotyping using commonly available phenotyping methods and were grouped into four sub-cohorts according to the level of phenotyping information gained and their findings. DNA was extracted and sequenced using a broad utility next generation sequencing (NGS) gene panel. A clinical subpanel of genes for nystagmus/albinism was utilised and likely causal variants were prioritised according to methods currently employed by clinical diagnostic laboratories. We determine the likely underlying genetic cause for 43.2% of participants with similar yields regardless of prior phenotyping. This study demonstrates that a diagnostic workflow combining basic ocular phenotyping and a clinically available targeted NGS panel, can provide a high diagnostic yield for patients with infantile nystagmus, enabling access to disease specific management at a young age and reducing the need for multiple costly, often invasive tests. By describing diagnostic yield for groups of patients with incomplete phenotyping data, it also permits the subsequent design of ‘real-world’ diagnostic workflows and illustrates the changing role of genetic testing in modern diagnostic workflows for heterogeneous ophthalmic disorders.

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Accepted/In Press date: 26 July 2019
e-pub ahead of print date: 13 September 2019
Published date: 13 September 2019

Identifiers

Local EPrints ID: 434211
URI: http://eprints.soton.ac.uk/id/eprint/434211
ISSN: 2045-2322
PURE UUID: f608b7ef-2e77-45d7-bfb4-133551e872e1
ORCID for Andrew Lotery: ORCID iD orcid.org/0000-0001-5541-4305
ORCID for Arjuna Ratnayaka: ORCID iD orcid.org/0000-0002-1027-6938
ORCID for Diana Baralle: ORCID iD orcid.org/0000-0003-3217-4833
ORCID for Helena Lee: ORCID iD orcid.org/0000-0002-2573-9536
ORCID for Jane Gibson: ORCID iD orcid.org/0000-0002-0973-8285
ORCID for Sarah Ennis: ORCID iD orcid.org/0000-0003-2648-0869
ORCID for Jay E. Self: ORCID iD orcid.org/0000-0002-1030-9963

Catalogue record

Date deposited: 16 Sep 2019 16:31
Last modified: 22 Nov 2021 07:41

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Contributors

Author: Luke O'Gorman
Author: Chelsea Norman
Author: Luke Michaels
Author: Tutte Newall
Author: Andrew H. Crosby
Author: Christopher Mattocks
Author: Angela Cree
Author: Andrew Lotery ORCID iD
Author: Emma L. Baple
Author: Diana Baralle ORCID iD
Author: Helena Lee ORCID iD
Author: Daniel Osborne
Author: Fatima Shawkat
Author: Jane Gibson ORCID iD
Author: Sarah Ennis ORCID iD
Author: Jay E. Self ORCID iD

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