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The Oculome panel test: next-generation sequencing to diagnose a diverse range of genetic developmental eye disorders

Patel, A; Hayward, JD; Tailor, V; Nyanhete, R; Ahlfors, H; Gabriel, C; Jannini, TB; ... Sowden, JC; + view all (2019) The Oculome panel test: next-generation sequencing to diagnose a diverse range of genetic developmental eye disorders. Ophthalmology , 126 (6) pp. 888-907. 10.1016/j.ophtha.2018.12.050. Green open access

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Abstract

PURPOSE: To develop a comprehensive next-generation sequencing panel assay which screens genes known to cause developmental eye disorders and inherited eye disease (Oculome test) and to evaluate its diagnostic yield in a paediatric cohort with malformations of the globe, anterior segment anomalies and/or childhood glaucoma. DESIGN: Evaluation of diagnostic test. PARTICIPANTS: 277 children age 0-16 years diagnosed with nonsyndromic or syndromic developmental eye defects without a genetic diagnosis. METHODS: We developed a new Oculome panel using a custom-designed Agilent SureSelect QXT target capture method to capture and perform parallel high through put sequencing analysis of 429 genes associated with eye disorders. We confirmed suspected pathogenic variants by bidirectional Sanger sequencing. MAIN OUTCOME MEASURES: We collated clinical details and the oculome molecular genetic results. RESULTS: The Oculome design covers 429 known eye disease genes; these are subdivided into 5 overlapping virtual sub-panels for anterior segment developmental anomalies and glaucoma (ASDA; 59 genes), microphthalmia-anophthalmia-coloboma (MAC; 86 genes), congenital cataracts and lens-associated conditions (CAT; 70 genes), retinal dystrophies (RET; 235 genes), and albinism (15 genes), and as well as additional genes implicated in optic atrophy and complex strabismus (10 genes). Panel development and testing included analysing n = 277 clinical samples and 3 positive control samples using Illumina sequencing platforms; >30 X read-depth was achieved for 99.5% of the targeted 1.77 Mb region. Bioinformatics analysis performed using a pipeline based on Freebayes and ExomeDepth to identify coding sequence and copy number variants respectively, resulted in a definitive diagnosis in 68 / 277 cases with variability in diagnostic yield between phenotypic sub-groups; MAC: 8.2% (8 of 98 cases solved), ASDA: 24.8% (28 of 113 cases solved), other / syndromic 37.5% (3 of 8 cases solved); RET: 42.8% (21 of 49 cases solved); CAT: 88.9% (8 of 9 cases solved). CONCLUSION: The Oculome test diagnoses a comprehensive range of genetic conditions affecting the development of the eye, potentially replacing protracted and costly multidisciplinary assessments and allowing for faster targeted management. The Oculome enabled the molecular diagnosis of a significant number of cases in our sample cohort of varied ocular birth defects.

Type: Article
Title: The Oculome panel test: next-generation sequencing to diagnose a diverse range of genetic developmental eye disorders
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ophtha.2018.12.050
Publisher version: https://doi.org/10.1016/j.ophtha.2018.12.050
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Anterior segment dysgenesis, childhood, coloboma, congenital cataracts, congenital glaucoma, developmental, genetics, microphthalmia, paediatric ophthalmology, retinal dystrophies
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Div of Psychology and Lang Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Div of Psychology and Lang Sciences > Experimental Psychology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10066559
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