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Next-Generation Sequencing to Diagnose a Diverse Range of Genetic Developmental Eye Disorders

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Next-Generation Sequencing to Diagnose a Diverse Range of Genetic Developmental Eye Disorders Accepted Manuscript The Oculome panel test: next-generation sequencing to diagnose a diverse range of genetic developmental eye disorders Aara Patel, Jane D. Hayward, Vijay Tailor, Rodney Nyanhete, Helena Ahlfors, Camila Gabriel, Tommaso B. Jannini, Yassir Abbou-Rayyah, Robert Henderson, Ken K. Nischal, Lily Islam, Maria Bitner-Glindzicz, Jane Hurst, Leonardo E. Valdivia, Mario Zanolli, Mariya Moosajee, John Brookes, Maria Papadopoulos, Peng T. Khaw, Thomas Cullup, Lucy Jenkins, Annegret Dahlmann-Noor, Jane C. Sowden PII: S0161-6420(18)31858-X DOI: https://doi.org/10.1016/j.ophtha.2018.12.050 Reference: OPHTHA 10632 To appear in: Ophthalmology Received Date: 3 August 2018 Revised Date: 18 December 2018 Accepted Date: 21 December 2018 Please cite this article as: Patel A, Hayward JD, Tailor V, Nyanhete R, Ahlfors H, Gabriel C, Jannini TB, Abbou-Rayyah Y, Henderson R, Nischal KK, Islam L, Bitner-Glindzicz M, Hurst J, Valdivia LE, Zanolli M, Moosajee M, Brookes J, Papadopoulos M, Khaw PT, Cullup T, Jenkins L, Dahlmann-Noor A, Sowden JC, The Oculome panel test: next-generation sequencing to diagnose a diverse range of genetic developmental eye disorders, Ophthalmology (2019), doi: https://doi.org/10.1016/j.ophtha.2018.12.050. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT 1 Title 2 The Oculome panel test: next-generation sequencing to diagnose a diverse range of 3 genetic developmental eye disorders 4 Running Title 5 Genetic testing of developmental eye disorders 6 Authors 7 Aara Patel 1 , Jane D Hayward 1 , Vijay Tailor 2, Rodney Nyanhete 3, Helena Ahlfors 3, 8 Camila Gabriel 1, Tommaso B Jannini 1, Yassir Abbou-Rayyah 4, Robert Henderson 4, 9 Ken K. Nischal 4,5 , Lily Islam 1,6, Maria Bitner-Glindzicz 1, Jane Hurst 1, Leonardo E. 10 Valdivia 7, Mario Zanolli 8, Mariya Moosajee 2, 4 , John Brookes 4, 9, Maria 11 Papadopoulos 9, Peng T Khaw 2,9, Thomas Cullup 3, Lucy Jenkins 1, 3, Annegret 12 Dahlmann-Noor 2, Jane C Sowden 1* 13 1. UCL Great Ormond Street Institute of Child Health, and NIHR Biomedical 14 Research Centre at Great Ormond Street Hospital for Children NHS Foundation 15 Trust and University College London, London,MANUSCRIPT UK 16 2. NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation 17 Trust, and UCL Institute of Ophthalmology London, UK 18 3. North East Thames Regional Genetics Laboratory, Great Ormond Street Hospital 19 for Children NHS Trust, London, UK 20 4. Department of Ophthalmology, Great Ormond Street Hospital for Children NHS 21 Trust, London, UK 22 5. UPMC Eye Center, Children's Hospital of Pittsburgh of UPMC, University of 23 Pittsburgh SchoolACCEPTED of Medicine, Pittsburgh, PA, USA. 24 6. Birmingham Women’s Hospital, Birmingham, UK 25 7. Centre for Integrative Biology, Facultad de Ciencias, Universidad Mayor, 26 Santiago, Chile 27 8. Facultad de Medicina Clínica Alemana de Santiago – Universidad del Desarrollo, 28 Santiago, Chile 1 ACCEPTED MANUSCRIPT 1 9. Glaucoma Service, Moorfields Eye Hospital NHS Foundation Trust, London, UK 2 3 These authors contributed equally to this work 4 5 *Correspondence : Professor Jane C. Sowden, PhD: [email protected], Birth 6 Defects Research Centre, Stem Cells and Regenerative Medicine Section, UCL 7 Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 8 1EH UK, Tel: +44 (0) 20 7905 2121, Fax: +44 (0) 20 7831 4366 9 10 Conflict of Interest : None 11 12 13 Key words: microphthalmia, coloboma, anterior segment dysgenesis, congenital 14 glaucoma, congenital cataracts, retinal dystrophiesMANUSCRIPT, genetics, developmental, 15 childhood, paediatric ophthalmology 16 ACCEPTED 2 ACCEPTED MANUSCRIPT 1 Abstract (346 words) 2 Purpose : To develop a comprehensive next-generation sequencing panel assay 3 which screens genes known to cause developmental eye disorders and inherited eye 4 disease (Oculome test) and to evaluate its diagnostic yield in a paediatric cohort with 5 malformations of the globe, anterior segment anomalies and/or childhood glaucoma. 6 Design : Evaluation of diagnostic test. 7 Participants : 277 children age 0-16 years diagnosed with nonsyndromic or 8 syndromic developmental eye defects without a genetic diagnosis. 9 Methods : We developed a new Oculome panel using a custom-designed Agilent 10 SureSelect QXT target capture method to capture and perform parallel high through 11 put sequencing analysis of 429 genes associated with eye disorders. We confirmed 12 suspected pathogenic variants by bidirectional Sanger sequencing. 13 Main outcome measures : We collated clinical details and the oculome molecular 14 genetic results. 15 Results : The Oculome design covers 429 known eye disease genes; these are 16 subdivided into 5 overlapping virtual sub-panels for anterior segment developmental 17 anomalies and glaucoma (ASDA; 59 genes), microphthalmia-anophthalmia- 18 coloboma (MAC; 86 genes), congenital cataractsMANUSCRIPT and lens-associated conditions 19 (CAT; 70 genes), retinal dystrophies (RET; 235 genes), and albinism (15 genes), 20 and as well as additional genes implicated in optic atrophy and complex strabismus 21 (10 genes). Panel development and testing included analysing n = 277 clinical 22 samples and 3 positive control samples using Illumina sequencing platforms; >30 X 23 read-depth was achieved for 99.5% of the targeted 1.77 Mb region. Bioinformatics 24 analysis performed using a pipeline based on Freebayes and ExomeDepth to 25 identify coding sequence and copy number variants respectively, resulted in a 26 definitive diagnosis in 68 / 277 cases with variability in diagnostic yield between 27 phenotypic sub-groups; MAC: 8.2% (8 of 98 cases solved), ASDA: 24.8% (28 of 113 28 cases solved),ACCEPTED other / syndromic 37.5% (3 of 8 cases solved); RET: 42.8% (21 of 49 29 cases solved); CAT: 88.9% (8 of 9 cases solved). Conclusion : The Oculome test 30 diagnoses a comprehensive range of genetic conditions affecting the development of 31 the eye, potentially replacing protracted and costly multidisciplinary assessments 32 and allowing for faster targeted management. The Oculome enabled the molecular 3 ACCEPTED MANUSCRIPT 1 diagnosis of a significant number of cases in our sample cohort of varied ocular birth 2 defects. 3 4 Introduction 5 An estimated 1.4 million children are blind. 1 The incidence of childhood blindness 6 ranges from 0.3-0.4 per 1000 in developed countries to 1.2 per 1000 in 7 undeveloped countries. 2 In all countries, childhood blindness occurs as a result of 8 congenital and developmental abnormalities. In the UK developmental eye 9 defects resulting in severe visual impairment or blindness affect 4 in 10,000 10 children each year. Microphthalmia, anophthalmia and coloboma (MAC) affect an 11 estimated 1.19 per 10,000 children by the age of 16 years, 3 congenital glaucoma 12 affects 1 in 20,000 children 4; approximately 3 in 10,000 children under 15 years 13 old are affected by congenital cataracts 5; retinal dystrophies affect 2.2 in 10,000 14 children by the age of 16, with retinitis pigmentosa being the most common retinal 15 dystrophy 6, 7 ; albinism has a global prevalence of 1 in 20,000. 8 Although these 16 developmental disorders are individually rare, they collectively account for a 17 significant proportion of global blindness. TheMANUSCRIPT proportion due to genetic causes is 18 unresolved. 19 20 Molecular diagnoses are largely unavailable for children with developmental eye 21 disorders due to the genetic heterogeneity of these conditions, the limited availability 22 of multi-gene panel tests and the low level of diagnosis achieved by sequential 23 screening of individual candidate genes. Next generation sequencing (NGS) is a 24 more cost-effective method to provide a genetic diagnosis in a wide range of 25 congenital and developmental conditions. 9-13 Whilst genetic panel tests are available 26 for some eye conditions, notably retinal dystrophies and congenital cataract, 13-16 27 comprehensiveACCEPTED panel assays are not available for a wide range of conditions 28 affecting the development of the anterior segment and whole globe, such as 29 congenital or juvenile glaucoma, anterior segment dysgenesis, MAC, optic atrophy 30 and nystagmus. A molecular diagnosis of the genetic changes underlying MAC and 31 anterior segment developmental anomalies (ASDA) is particularly challenging, as 32 these conditions have highly heterogeneous presentations and diverse genetic 4 ACCEPTED MANUSCRIPT 1 causes. Many developmental eye disorders form part of a syndrome involving 2 additional metabolic, developmental, physical or sensory abnormalities. These can 3 be difficult to define and may be missed if children are examined solely by an 4 ophthalmologist. Panels that allow for simultaneous testing of a large number of 5 genes are particularly attractive for phenotypically diverse and sometimes 6 overlapping conditions. 7 We aimed to develop a single comprehensive test, which would provide a molecular 8 diagnosis of a wide range of conditions of developmental eye defects. We grouped 9 genes into virtual subpanels to evaluate a narrower gene range where necessary.
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