The 12Th Meeting of the UK Eye Genetics Group

The 12th Meeting of The UK Eye Genetics Group

& the 20th Meeting of The International Society for Genetic Eye Diseases & Retinoblastoma

Leeds, UK September 14-16, 2017 A Very Special Meeting Indeed

The UK EGG is delighted to be co-hosting this joint international meeting with ISGEDR to share research and clinical developments in this rapidly evolving and highly dynamic field of genomics in ophthalmology. This meeting represents a unique opportunity to establish and develop working relationships and collaborations within the ophthalmic genetics community worldwide, and will present a varied and engaging programme of presentations from scientists, clinicians and researchers at the cutting edge of the field. Amongst other things, ophthalmology is emerging at the very forefront of gene therapy research worldwide, with a number of early phase trials opening this year in the UK, so this is a very exciting and unique time for those working in the field. We welcome you to Leeds and hope you enjoy your stay and the exciting scientific programme.

Georgina Hall, President UK-EGG & Birgit Lorenz, President ISGEDR

Scientific Program Committee

Graeme Black, UKEGG Amanda Churchill, UKEGG Brenda Gallie, ISGEDR Chris Inglehearn, UKEGG Bart Leroy, ISGEDR Birgit Lorenz, ISGEDR Martin McKibbin, UKEGG Carmel Toomes, UKEGG Elias Traboulsi, ISGEDR

The UK Eye Genetics Group

The UK Eye Genetics Group (UK EGG) was formed in 2002 for ophthalmic clinicians, geneticists and genetic counsellors with a specialist interest and expertise in ophthalmic genetics in the UK. The group now has over 100 members, hosting an annual conference and AGM each year, and provides a unique networking environment for the largest group of genetics/ophthalmology experts in the UK.

The UK EGG committee was formed in 2012 to lead the UK EGG group as a professional organisation representing clinicians, scientists and researchers in the field. Further information about UK EGG and details of how to become a member is available on our website (http://ukegg.com).

Our current committee: Georgina Hall (Consultant Genetic Counsellor) (Chair), Amanda Churchill (Consultant Ophthalmologist) (treasurer), Stuart Ingram (Research Trials Co-ordinator) (secretary), Graeme Black (Professor in Genetics and Ophthalmology), Penny Clouston (Clinical Scientist), Barbara Norton (Patient Representative), Andrew Webster (Professor in Ophthlamic Genetics), Marcela Votruba (Professor of Ophthalmology), Catherine Willis (Genetic Counsellor), Nicola Ragge (Professor in Ophthalmology). Co-opted website co-ordinator, Susie Downes (Professor in Ophthalmology).

The International Society for Genetic Eye Diseases ISGEDR

Mission Statement

To bring together individuals interested in the field of genetic diseases of the eye and in retinoblastoma *** To provide a forum for researchers in the field of genetic diseases of the eye to share information *** To promote international collaborations in the study of genetic diseases of the eye and in Retinoblastoma *** To disseminate scientific knowledge through international conferences and through its official publication, Ophthalmic Genetics

ISGEDR Executive Committee Birgit Lorenz, Giessen, Germany, President David Mackey, Perth, Australia, Immediate Past President Elias I. Traboulsi, Cleveland, USA, Executive Vice President Brenda Gallie, Toronto, Canada, Member-at-Large – Retinoblastoma Bart Leroy, Ghent, Belgium, Member-at-Large – Genetics Alex Levin, Philadelphia, USA, Member-at-Large – Genetics Francis Munier, Lausanne, Switzerland, Member-at-Laarge – Retinoblastoma Richard Weleber, Portland, USA, Member-at-Large – Genetics

Welcome from the Local Organizing Committee Welcome to Leeds for the combined ISGEDR and EGG meeting, from members of the UK organising committee, and we do hope you will enjoy what promises to be a stimulating and exciting meeting. With sessions on genetic testing, phenotyping, interesting cases, interpretation of genetic tests, mitochondrial disease, therapies, free paper sessions on both ocular genetics and retinoblastoma and two poster sessions featuring work on a wide range of ophthalmic conditions, the committees of ISGEDR and EGG are proud to present to you an excellent and truly international scientific and clinical programme. The Rose Bowl, just off the Millennium square in central Leeds, provides a first class conference venue, with tea, coffee and croissants to start each day, a full lunch provided and further refreshments at regular intervals. Each day has a mix of targeted symposia, free paper sessions and posters (separate sessions on days one and two). In addition we have a social programme to which you are all warmly invited, that shows Leeds at its best while giving everyone plenty of opportunities to get to know each other better. This begins with a drinks reception in the Leeds city museum two minutes walk away on Thursday evening, followed by a Gala dinner with Ceilidh at the Royal Armouries on Friday night and closing with an evening in the historic city of York on the final day. We look forward to meeting you and welcoming you to Leeds, and we thank you all for participating in this meeting and making it a success.

Dr Amanda Churchill Consultant Ophthalmologist with specialist interest in Paediatric and Genetic Ophthalmology, United Hospitals Bristol NHS Foundation Trust, Honorary Clinical Lecturer, University of Bristol

Professor Chris Inglehearn Section Head, Section of Ophthalmology and Neuroscience, School of Medicine, University of Leeds

Mr Martin McKibbin Consultant Ophthalmologist, Leeds Teaching Hospitals NHS Trust Honorary Clinical Associate Professor, University of Leeds

Dr Carmel Toomes Associate Professor, Section of Ophthalmology and Neuroscience, School of Medicine, University of Leeds

The UK Eye Genetics Group and the International Society for Genetic Eye Disease & Retinoblastoma thank the following sponsors who have generously supported the 2017 Joint UK EGG and ISGEDR Meeting in Leeds, UK

Novartis Prevention Genetics Spark Therapeutics

Foundation Fighting Blindness Optos Santhera

Bronze Sponsors

Allergan Eyecare Bayer Blueprint Genetics Congenica Nightstar

Special Thanks

Sandy Wong Administrative Assistant ISGEDR Cleveland, USA

Sarah Janesz Meeting Website Administrator Cleveland, USA

Congratulations to the Travel Awardees

Adam Ali Medical Student University College London UK

Evangelia Panagiotou Resident in Ophthalmology University Department of Ophthalmology AHEPA Hospital Thessaloniki, Greece

Lev Prasov Resident in Ophthalmology University of Michigan USA

Raquel Sofia Silva Post-Doctoral Fellow University College London UK

Keynote and Named Lectures

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2017 Inaugural UK EGG Keynote Lecture: Andrew Read, Manchester, UK “Overview of the Human Genome” Thursday – 12:00 Noon

Keynote and Named Lecturers

Professor Andrew Read, PhD, FRCPath, FMedSci Emeritus Professor of Human Genetics University of Manchester Manchester, UK Andrew trained at Cambridge as an organic chemist, but after postdoctoral studies in Heidelberg and Warwick (UK) he gradually transformed himself into a geneticist. He is Professor of Human Genetics (now Emeritus) at the University of Manchester, UK. He was founder chairman of the

British Society of Human Genetics (now the British Society for Genetic Medicine). For the ESHG he was chair of the Scientific Programme Committee from 1999 to 2003, since when he has been Treasurer. He is co-author of the well-known textbooks Human Molecular Genetics (Strachan & Read; Garland, 5th edition in preparation 2017) and New Clinical Genetics (Read & Donnai, Scion Publishing, 3rd edition 2015).

.2017 Franceschetti Lecture: David Mackey, Perth, Australia “Eye Genetics at the Fork in the Road” Friday - 11:30 am

Keynote and Named Lecturers

PROFESSOR DAVID A MACKEY MBBS, MD, FRANZCO, FRACS, FARVO, FAHMS Managing Director, Lions Eye Institute, Perth Western Australia Professor of Ophthalmology Director, Centre for Ophthalmology & Visual Science The University of Western Australia Perth, Australia

Professor David Mackey has achieved international recognition as a genetic ophthalmologist who has spent 25 years studying the genetics of eye disease with over 340 publications. Although studying many genetic and environmental factors involved in eye disease, his major works centre on the optic nerve: glaucoma, optic neuropathies and the genetics of optic nerve biometry. A University of Tasmania medical graduate, David completed his ophthalmology training at the Royal Victorian Eye and Ear Hospital in Melbourne. After an MD thesis on Leber Hereditary Optic Neuropathy at the University of Melbourne he completed fellowships at the Johns Hopkins Center for Hereditary Eye Disease in Baltimore US and Moorfields Eye Hospital in London UK. He was awarded an Alcon Research Institute Award in 2010 and holds Silver Fellowship of ARVO. He has given the Lance, Council, Gillies and Gregg Lectures in Australia and the Marshall M Parks Lecture at the AAO meeting in 2015. In 2015 he was elected to the Australian Academy of Health and Medical Sciences. He is past-President of the International Society for Genetic Eye Disease and Retinoblastoma (and was convenor for the 1996 meeting in Hobart); Regional Secretary (Australian & New Zealand) and Chair of the Membership committee of the Asia-Pacific Academy of Ophthalmology; Executive Committee member of the Glaucoma Research Society; and Chair, Scientific Advisory Committee of the Ophthalmic Research Institute of Australia. He is a member of the American Academy of Ophthalmology’s Basic and Clinical Science Course sub–committee since 2011 and re-wrote the chapters on genetics. He currently chairs the monthly teleconferences of the International Glaucoma Genetics Consortium.

2017 François Lecture: Andreas Gal, Hamburg, Germany “From Congenital Stationary Night Blindness to Inherited Retinal Dystrophy: A Journey of 30 Years Discovering the Secrets of the Emerging Human Genome” Saturday – 9:45 am

Keynote and Named Lecturers

Andreas Gal, MD, FACMG Professor, Department of Human Genetics University of Hamburg Hamburg, Germany

Professor Andreas Gal graduated summa cum laude from Szeged University Medical School in Hungary in 1972. After ten years of research in Hungary at the Institute of Genetics, Hungarian Academy of Sciences, he moved to Germany and became the Head of the Laboratory of Molecular Human Genetics and DNA Diagnostics at the University of Bonn, going on to head the Laboratory of Molecular Human Genetics and DNA Diagnostics in Lubeck for 5 years. In 1994 he became Professor and Head of the Department of Human Genetics at the University Medical Center Hamburg Eppendorf in Hamburg. He held that position until 2013. He has received a number of

awards including Research award "Fighting blindness" of the German and Swiss Retinitis Pigmentosa Associations in 1989, the Alcon Research Institute Recognition Award for outstanding contributions in the field of vision research in 2006, the Recognition Award of Retina International for outstanding contributions in the field of vision research in 2012, and the Honorary Gold Medaille of the German Society of Human Genetics for outstanding accomplishments in the field of human genetics in 2013. Professor Gal has over 400 publications in peer-reviewed journals, including 19 in Nature Genetics, 15 in the American Journal of Human Genetics, and 18 in Human Molecular Genetics. He has been involved in the identification of 23 human disease genes. Dr. Gal has served as Associate Editor of Ophthalmic Genetics since the mid-1990s.

2017 Ellsworth Lecture: Annette C. Moll, The Netherlands “All for one: Retinoblastoma, Pineoblastoma and Second Primary Malignancies” Saturday – 11:45 am

Keynote and Named Lecturers

Annette C. Moll, MD, PhD, FEBOphth Professor of Ophthalmology Residency Program Director Department of Ophthalmology and Dutch Retinoblastoma Center VU University Medical Center Amsterdam, The Netherlands

Annette Moll received her MD (cum laude) from Leiden University, Leiden, The Netherlands in 1991. Since then she has been involved in retinoblastoma care and research. She is co-founder of the Dutch Retinoblastoma Center and takes care of the Dutch Retinoblastoma Register that includes patients from 1882. In 2015 the VU University Medical Rb Center obtained recognition as an expertise center for rare disease by the Dutch Ministry of Health. From 2016 the Center is part of the Retinoblastoma European Reference Network.

Dr. Moll defended her PhD thesis “"Epidemiological aspects of retinoblastoma in the Netherlands" in 1996. Since 1997 she is a staff-member at the Department of Ophthalmology at VU University Medical Center. In 1998 she obtained the registration of Epidemiologist. In 2013 she became Professor of Ophthalmology (in particular in retinoblastoma) and Residency Program Director in Ophthalmology.

Dr. Moll is head of the Retinoblastoma Research group and her interests focus on Epidemiology, especially Second Primary Malignancies, Late effects, Quality of Life, MR imaging in retinoblastoma, and Molecular Genetics. She was/is (co-)promotor of several PhD students. She is author of numerous book chapters on retinoblastoma and second primary malignancies and a frequent speaker at national and international meetings.

Dr. Moll is member of the European Retinoblastoma Group, Amsterdam and is responsible for the Work Package diagnosis, Late Effects and Quality of life.

Thursday, September 14, 2017 Joint UK EGG and ISGEDR Meeting (6.5 CPD points) UK EGG Day

8.00 REGISTRATION, TEA AND COFFEE POSTER SET-UP for DAY 1 (Posters 1-19)

8.30 WELCOME & OFFICIAL OPENING OF JOINT UK-EGG & ISGEDR MEETING - Georgina Hall, Birgit Lorenz and Chris Inglehearn

8.45 GENETIC TESTING (DIAGNOSTICS AND LABORATORY TESTING, ACCESS

TO GENETIC TESTING IN EUROPE V USA). Leads - Penny Clouston and Elias Thursday Spetember 14 I. Traboulsi

8.45 Introduction – Elias I. Traboulsi, Cole Eye Institute, Cleveland Clinic

8.47 Advances in Ophthalmic Genetic Testing: Review of last 10 Years – Simon Ramsden, Manchester Genomic Medicine Centre

8.57 Diagnostic Genetic Testing - UK Experience – Penny Clouston, Oxford Medical Genetics Laboratories

9.05 Diagnostic Genetic testing - German Experience – Birgit Lorenz and Markus Preising, Justus- Liebig-University Giessen

9.13 Diagnostic Genetic testing – USA Experience – Meghan DeBenedictis, Cleveland Clinic, Cole Eye Institute

9.21 Panel Discussion – A World View of Diagnostic Testing for Genetic Eye Disease

9.45 OPHTHALMIC GENETICS FREE PAPERS – (6* 10 minutes including questions) Moderator - Carmel Toomes/Tony Moore

9.45 Mutations in CTNNB1 (ß-Catenin) cause Familial Exudative Vitreoretinopathy (FEVR) - Evangelia Panagiotou, MD, MSc, 1St University Department of Ophthalmology, Aristotle University of Thessaloniki Co-Authors: James A. Poulter, PhD, University of Leeds, United Kingdom Carla Sanjurjo Soriano, PhD, University of Leeds, United Kingdom Hiroyuki Kondo, Fukuoka University, Japan Atsushi Hiyoshi, University of Occupational and Environmental Health, Japan Mark E. Tafoya, MD, Pacific Retina Care, United States Hon-Yin Brian Chung, The University of Hong Kong, China Rob W.J. Collin, PhD, Radboud University Medical Centre, the Netherlands Manir Ali, PhD, University of Leeds, United Kingdom Chris F. Inglehearn, PhD, University of Leeds, United Kingdom 12

Carmel Toomes, PhD, University of Leeds, United Kingdom

Introduction: FEVR is an inherited blinding disorder mostly caused by mutations in genes involved in the norrin/ß-catenin signaling pathway. Half of all FEVR cases do not harbour mutations in the known FEVR genes. The aim was to identify new genes underlying FEVR. Methods: Whole exome sequencing (WES) was performed on the Illumina HiSeq3000 using the Agilent SureSelect capture reagent. The CTNNB1 coding sequence was screened by Sanger sequencing. The pathogenicity of CTNNB1 mutations was assessed by TOPflash assay. Results: Three families carried heterozygous mutations in CTNNB1, the gene encoding ß-catenin. Two of them were familial, while one was de novo. Cell-based TOPflash assays showed that both familial mutations alter ß-catenin signaling. Conclusions: This is the first report of a familial disease caused by CTNNB1 mutations and the first confirmation that CTNNB1 mutations can cause non-syndromic FEVR, further establishing the role that ß-catenin signaling plays in retinal vascularisation.

9.55 Genetics of iridociliary cysts – Lee Prasov, University of Michigan Co-Authors:

Sarah Garnai, BS, Harvard Medical School, Boston, MA, United States Thursday Spetember 14 Carmen Gherasim, PhD, University of Utah, Salt Lake City, UT, United States Ruma Banerjee, PhD, University of Michigan, Ann Arbor, MI, United States Sayoko E. Moroi, MD, PhD, University of Michigan, Ann Arbor, MI, United States Hemant Pawar, PhD, Natera, San Carlos, CA, United States A. Bilge Ozel, PhD, University of Michigan, Ann Arbor, MI, United States Jun Z. Li, PhD, University of Michigan, Ann Arbor, MI, United States Louis R. Pasquale, MD, Harvard Medical School, Boston, MA, United States Robert Ritch, MD, New York Eye and Ear Infirmary, New York, NY, United States Julia E. Richards, PhD, University of Michigan, Ann Arbor, MI, United States Introduction: Iridociliary cysts can cause glaucoma by an appositional angle closure mechanism. As the mechanism for sporadic and autosomal dominant cases are unknown, our purpose is to investigate the genetics of iridociliary cysts in a 6-generation pedigree. Methods: Linkage analysis was performed on a large autosomal dominant pedigree with iridociliary cysts. Candidate gene variants were identified by exome sequencing of pooled affected and unaffected samples. Functional analysis was performed on the variants. Results: A linkage peak on chr5p13 (LOD score = 3.01) with a candidate MTRR gene (c.A1468G,

p.T490A) mutation was identified. This mutation was also found in 1/26 unrelated cases. Biochemical and protein analysis showed this was a loss-of-function variant. Conclusions: We describe a new locus associated with iridociliary cysts. The MTRR p.T490A mutation decreases protein stability and alters electron transport properties. The role of MTRR in the pathogenesis of iridociliary cysts remains to be fully elucidate.

10:05 North Carolina Macular Dystrophy is caused by duplication of non-coding region downstream of IRX1 at the MCDR3 locus - Raquel Silva, UCL Institute of Ophthalmology Co-Authors: Valentina Cipriani, PhD, UCL Institute of Ophthalmology, London, UK Gavin Arno, PhD, UCL Institute of Ophthalmology, London, UK Nikolas Pontikos, PhD, UCL Institute of Ophthalmology, London, UK Ambreen Kalhoro, MD, Moorfields Eye Hospital, London, UK Michel Michaelides, MD, Moorfields Eye Hospital, London, UK Baiba Lace, PhD, Riga Stradins University, Riga, Latvia Veronica Van Heyningen, PhD, UCL Institute of Ophthalmology, London, UK Andrew Webster, MD, Moorfields Eye Hospital, London, UK Anthony Moore, MD, UCSF School of Medicine, San Francisco, CA, USA

Introduction: Autosomal dominant North Carolina Macular Dystrophy is believed to represent a failure of macular development. The aim of this study was to identify any causative variants in unsolved families and further the understanding of the disease mechanism. Methods: Fifteen NCMD families were subjected to combination of sequencing studies including array-based comparative genomic hybridization and Whole Genome Sequencing. Publically available datasets were also queried. Results: Two novel overlapping duplications at the MCDR3 locus were identified in a gene desert downstream of IRX1. MCDR3 is refined to 39 kb that contains DHSs active at a restricted time window during retinal development. Five families remain unsolved. Conclusions: These findings provide novel diagnostic tools and further insight into the genetic pathways involved in macular development. Noncoding regulatory regions may harbour the answer to NCMD pathogenesis.

10.15 A novel missense mutation in LARGE causes recessively-inherited non-syndromic retinitis pigmentosa - Manir Ali, University of Leeds Co-Authors: Mohammed El-Asrag, PhD, Section of Ophthalmology and Neuroscience, Leeds Institute of

Biomedical and Clinical Sciences, University of Leeds Thursday S Martin McKibbin, FRCOphth, The Eye Department, St. Jamess University Hospital Kamron Khan, PhD FRCOphth, The Eye Department, St. Jamess University Hospital, Leeds James Poulter, PhD, Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds Graeme Black, DPhil, FRCOphth, Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Manchester Carmel Toomes, PhD, Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds e Chris Inglehearn, PhD, Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical p and Clinical Sciences, University of Leeds tember 14 Introduction: Retinitis pigmentosa (RP) is a group of genetically heterogeneous inherited eye disorders that are characterised by night blindness and loss of peripheral vision due to a defect in rod photoreceptors and eventually leads to blindness. To date, mutations in 82 genes have been shown to cause the condition. We have previously reported screening the RetNet genes using a customised targeted reagent and next generation sequencing (Watson et al, 2014 PLoS One 9, e104281). The aim of the present study was to identify the genetic cause of RP in a local consanguineous pedigree of

South Asian origin with multiple affected members in whom the causative mutation could not initially be identified. Methods: Whole exome next generation sequencing (WES) combined with single nucleotide polymorphism (SNP) genotyping was used on genomic DNA of affected family members. Candidate variants were analysed by direct Sanger sequencing and their pathogenicity assessed using bioinformatic software. Immunofluorescence of mouse retinal sections with confocal microscopy was used for protein localisation. Results: A novel homozygous missense variant (c.2089G>T, p.V697L) in the glycosyltransferase gene, LARGE, was the only candidate that segregated with the disease phenotype in this pedigree. This mutation was absent from the ExAC database and predicted to be pathogenic. The LARGE protein was present in the photoreceptor inner segment, outer nuclear and outer plexiform layers of the retina. Conclusions: Recessive mutations in LARGE have previously been associated with syndromic disease characterised by congenital muscular dystrophy, eye abnormalities and neuronal migration defects. To date, 17 mutations have been identified ranging from null alleles to missense variants. Here we present evidence to support for the first time a novel homozygous missense mutation in LARGE, towards the carboxy-terminus of the protein that represents the least severe end of the mutation spectrum, causes non-syndromic RP.

10.25 Investigation of a missense mutation in ribosome assembly-factor GRWD1 underlying a novel ribosomopathy featuring paediatric cataract - Rachel Taylor, Division of Evolution and Genomic Sciences, Faculty of Medicine biology and Health, The University of Manchester Co-Authors: Chris Kershaw, PhD, The University of Manchester Jill Clayton-Smith, FRCPath, Manchester Centre for Genomic Medicine & The University of Manchester Martin Pool, PhD, The University of Manchester Graeme Black, DPhil, FRCOpth, Manchester Centre for Genomic Medicine & The University of Manchester Introduction: To investigate the molecular consequence of a homozygous missense variant (c.1335C>G; p.(S445R)) in the ribosome assembly factor GRWD1, underlying a complex disease phenotype featuring congenital cataract, short stature, microcephaly and facial dysmorphism, reminiscent of a ribosomopathy. Methods: Complementation assays were conducted using a ‘shuffle’ technique in yeast transfected

with a plasmid containing the equivalent mutation (p.(S436R)) in the yeast homolog, RRB1. Protein T expression levels were indicated by Western blot. Polysome profiling was used to investigate the hursday S effect on ribosome assembly in patient cells. Results: The GRWD1 p.(S445R) and yeast equivalent RRB1 p.(S436R) mutations appear to result in reduced protein expression. RRB1 p.(S436R) results in lethal growth phenotype in yeast. Polysome profiling of patient cells revealed that the GRWD1 p.(S445R) mutation results in a reduction of the mature 60S large ribosomal subunit. Conclusions: Our findings show that the GRWD1 c.1335C>G; p.(S445R) homozygous mutation is likely causative of a novel ribosomopathy featuring congenital cataract. This mutation most probably e causes the protein to become unstable resulting in reduced protein turn over due to abnormal p ribosome assembly. tember 14

10.35 Identification of mutations in enucleated Coats eyes by genome wide analysis - Denisa Dzulova, Section of Ophthalmology and Neuroscience, Leeds Institute of Molecular Medicine, University of Leeds Co-Authors: Carla Sanjurjo Soriano, PhD, University of Leeds

James A. Poulter, PhD, University of Leeds Ian M. Carr, PhD, University of Leeds Waleed Abed Alnabi, MD, Wills Eye Hospital, Philadelphia, Pennsylvania, USA Nutsuchar Wangtiraumnuay, MD, Wills Eye Hospital, Philadelphia, Pennsylvania, USA Ralph Eagle, MD, Wills Eye Hospital, Philadelphia, Pennsylvania, USA Carol L. Shields, MD, Wills Eye Hospital and Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, USA Alex V. Levin, MD, Wills Eye Hospital and Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, USA Carmel, Toomes, PhD, University of Leeds

Introduction: Coats disease is an idiopathic, non-hereditary condition characterised by retinal telangiectasia, exudation and, in severe cases, total retinal detachment. It usually manifests as a unilateral disease and the majority affected are young males. Somatic mutations in NDP, the gene encoding norrin, have been previously identified in a small number of Coats disease patients. In this study, whole-exome sequencing (WES) was used to analyse the DNA of 7 enucleated Coats eyes to uncover new genes associated with this disorder. Methods: DNA was extracted from formalin-fixed, paraffin-embedded eyes and subjected to WES.

A cell based-luciferase reporter assay for β-catenin transcription (TOPflash) was used to determine the pathogenicity of the LRP5 variant. Results: A novel heterozygous missense mutation in LRP5 was found in one eye, c.2951A>G;; p.(Tyr984Cys). The pathogenicity prediction scores suggest that this variant is damaging. LRP5 encodes a co-receptor for the norrin-β-catenin pathway. TOPflash luciferase reporter assay for β- catenin transcription showed that this LRP5 missense variant results in significantly reduced levels of transcription compared to wild-type LRP5 (p= ≤ 0.05). Conclusions: This is the first reported case of an LRP5 mutation in Coats disease. This strengthens the evidence that Coats is caused by defects in the norrin-ß-catenin pathway and may be a somatic form of FEVR. Other putative variants were identified in more detailed analysis of whole exome sequencing data but these still need to be verified.

10.45 COFFEE, TRADE EXHIBITION, POSTER VIEWING

11.15 100,000 GENOME PROJECT, COUNSELLING/ETHICAL ISSUES, PATIENT EXPERIENCE. Lead - Georgina Hall

11.15 Patient experience: Patient and Family experience of living with inherited eye condition: hursday S hopes around genomics

11.30 Genetic Counselling challenges in genomics - Georgina Hall

11.45 Genomic testing: 100,000 Genome project and the future of genomic services in the UK - Jill Clayton Smith

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tember 14 12.00 THE INAUGURAL UK EGG KEYNOTE LECTURE: “Overview of the Human Genome” - Professor Andrew Read Introduction – Carmel Toomes Award – Georgina Hall

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12.40 LUNCH WITH POSTER (POSTERS 1-19) AND TRADE STAND VIEWING

13.40 INTERESTING OCULAR GENETICS CASES - ASK THE PANEL FOR ADVICE (6* 6 minutes, with 3 mins discussion) Panel - Amanda Churchill, Graeme Black, Andrew Webster, Elias Traboulsi, Alex Levin

13.40 OG Case 1 - Arif Khan, Abu Dhabi

13.50 OG Case 2 - Arif Khan, Abu Dhabi

14.00 OG Case 3 - Ashwin Reddy, London

14.10 OG Case 4 - Isabelle Audo, Paris

14.20 OG Case 5 - Raj Mukherjee, Leeds

14.30 OG Case 6 - Arif Khan, Abu Dhabi

14.40 Summing up

14.45 RETINOBLASTOMA FREE PAPERS – (6* 10 minutes incl questions) Moderators = Ian Simmons and Brenda Gallie

14.45 RB Case 1 - Christina Stathopoulos, Lausanne (6 minutes, with 3 mins discussion)

14.55 RB Case 2 - Ashwin Reddy, London (6 minutes, with 3 mins discussion)

15.05 Hidden familial retinoblastoma - Brenda Gallie

15.15 Report of genetic analysis, initial staging of disease and therapy outcome from the first prospective national registry for paediatric eye cancer in Germany and Austria - Madlen Reschke, Universtity Hospital Essen T Co-Authors: hursday S Matthias Borowski, Institute of Biostatistics and Clinical Research, University of Muenster, Germany Johannes Schulte, Prof., Charité-University Hospital Berlin, Germany, Department of pediatric oncology Petra Sovinz - Ritter, PD, Universtity Hospital Graz, Austria; Department of pediatric oncology Wolfgang Sauerwein, Prof., University Hospital Essen, Germany, Department of radiotherapy Sophia Göricke, PD, University Hospital Essen, Germany, Department of radiology Angelika Eggert, Prof., Charité-University Hospital Berlin, Germany, Department of pediatric e oncology p tember 14 Norbert Bornfeld, Prof., University Hospital Essen, Germany, Department of ophthalmology Dietmar Lohmann, Prof., University Hospital Essen, Germany, Department of human genetics Petra Temming, PD, University Hospital Essen, Germany: Department of pediatric oncology

Introduction: Retinoblastoma is the most frequent malignant, intraocular tumor in childhood. Course of disease and treatment depend on genetic background of the patients. Clinical trials and multicenter prospective data are rare.

Methods: RB-registry is a prospective multicenter observational clinical study for newly diagnosed pediatric eye cancer in Germany & Austria. Since 3.11.2014, we collect data on genetics, stage of disease at first diagnosis, choice of therapy and outcome. Results: We included 153 patients (146 RB;7 other eye tumors). Constitutional RB1 mutation was seen in 38%. Leading ICRB group:E; IRSS stage:1. Eye OS was 48.2% and correlated with ICRB. Eyes with bilateral disease were less likely to be enucleated (29%;56%). Conclusions: RB registry is a well-established clinical registry appropriate to gather data that, in the long-term, will help to improve therapy protocols and thus conserve vision, reduce late term side effects and increase quality of life.

15.25 RB1 genotype drives the mutational landscape and evolution of retinoblastoma - Adriana Salcedo - Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada Department of Medical Biophysics, University of Toronto, Toronto, Canada Co-Authors: Hilary Racher, Department of Medical Biophysics, University of Toronto, Toronto, Canada, Diane Rushlow, Department of Medical Biophysics, University of Toronto, Toronto, Canada

Donco Matveski, Department of Medical Biophysics, University of Toronto, Toronto, Canada Brenda L. Gallie, Department of Medical Biophysics, University of Toronto, Toronto, Canada, Impact Genetics, Bowmanville, Canada, and Hospital for Sick Children, Toronto, Canada Paul C. Boutros, Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada, Department of Medical Biophysics, University of Toronto, Toronto, Canada and Department of Pharmacology & Toxicology, University of Toronto, Toronto, Canada

Purpose: Despite being the first tumour to provide clear insight into the genetic basis of cancer, the genomic underpinnings of retinoblastoma are not fully elucidated, particularly when tumours harbor functional RB1 alleles. Methods: Whole genome sequencing (8 RB1+/+MYNC amplified and 11 RB1+/- (-/-) , including 2 metastatic) and copy number profiles (8 RB1+/+, 12 RB1+/-, and 79 RB1-/-) on retinoblastoma tumors Results: Genomic location of clustered rearrangements, somatic point mutation frequency and mutational signatures correlated with initiating genotype and suggested divergent evolution. Subclonality indicated copy number aberrations occurred later in tumour evolution than point mutations. Conclusions/ Significance: Initiating genotypes evolve differently, but ultimately converge. Evidence

of subclonal structure within retinoblastoma cautions against the use of targeted chemotherapy for T primary treatment. hursday S

15.35 Long-term survival and second malignancies in patients with retinoblastoma: a report from the German referral centre from 1940-2008 - Petra Temming, Department of Pediatric Hematology and Oncology, University Hospital Essen, Germany Co-Authors: Marina Arendt, Institute for Medical Informatics, Biometry and Epidemiology, University Hospital e Essen, Germany p Claudia LeGuin, Department of Ophthalmology, University Hospital Essen, Germany tember 14 Eva Biewald, Department of Ophthalmology, University Hospital Essen, Germany Madlen Reschke, Department of Pediatric Hematology and Oncology, University Hospital Essen, Germany Norbert Bornfeld, Department of Ophthalmology, University Hospital Essen, Germany Wolfgang Sauerwein, Department of Radiotherapy, University Hospital Essen, Germany Angelika Eggert, Department of Pediatric Hematology and Oncology, Charite Berlin, Germany

Karl-Heinz Jöckel, Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, Germany Dietmar R. Lohmann, Institute of Human Genetics, University Hospital Essen, Germany

Introduction: Retinoblastoma is the most common eye tumor in childhood. The 5-year overall survival for children with retinoblastoma is excellent. However, 50 % of patients have heritable retinoblastoma and are at risk to develop second primary malignancies. Methods: At the German referral center, 1194 national patients were treated for retinoblastoma between 1940 and 2008. Overall survival and incidence of second malignancies and the influences of RB1 mutation, IRSS and TNM staging, and treatment were analyzed. Results: Survivors of heritable retinoblastoma have a higher mortality later in life. The cumulative incidence ratio (per 1000 person years) of second cancers was 8.6 (95 % CI 7.0; 10.4). Treatment and RB1 mutation influenced the incidence of second cancers.

Conclusions: Long-term side effects of eye-preserving treatment need to be balanced carefully and alternative eye-preserving treatments are urgently required. For all survivors of heritable retinoblastoma, life-long regular oncological follow-up is crucial.

15.45 TEA AND COFFEE WITH TRADE STAND VIEWING

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15:45 UK EGG BUSINESS MEETING

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16.15 POSTER VIEWING – POSTERS 1 TO 19 All presenting authors to stand by posters

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16.45 MITOCHONDRIAL DISEASE SYMPOSIUM

Leads - Marcela Votruba and Patrick Yu-Wai-Man T hursday S 16.45 What is the risk of vision loss in LHON families? - David Mackey

17.00 Leber hereditary optic neuropathy – light at the end of the tunnel? - Patrick Yu-Wai-Man

17.15 Dominant optic atrophy: from bench to bedside - Marcela Votruba

17.30 OCT- angiography in inherited optic neuropathies - Neringa Jurkute e p tember 14 17.45 CLOSE AND REMOVAL OF POSTERS

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17:45 RECEPTION AT LEEDS CITY MUSEUM (2-minute walk from

conference center) (DRINKS AND CANAPÉS)

Friday, September 15, 2017 ISGEDR meeting (6.5 CPD points)

8.00 TEA AND COFFEE POSTER SET-UP for DAY 2 (Posters 20-38)

8.45 PHENOTYPING, PENETRANCE AND EXPRESSION SYMPOSIUM Leads - Martin McKibbin / Birgit Lorenz

8. 45 Phenotypic heterogeneity in CRB1 related retinal disease - Tony Moore – University of California, San Francisco, USA

9.00 Refsum disease - Radha Ramachandran

9.15 Update on the genetics of developmental eye disorders - Nicola Ragge – Friday S Developmental eye disorders, including anophthalmia, microphthalmia, and coloboma (AMC) are responsible for around 25% childhood visual impairment. Monogenic causes can be identified in at least 50% of moderate-severe bilateral cases, depending on level of severity, presence of syndromic features and method of analysis. The most common genes responsible for severe eye anomalies are SOX2, then OTX2, followed by GJA8, CHD7, FOXE3, TFAP2A, BCOR, ALDH1A3, BMP4, and

VSX2. Other causes include STRA6, SHH, PTCH1, COL4A1, HCCS, RARB, PAX6, BMP7, e TENM3 (ODZ3), MLL2, OLFM2, LRP2, GDF3, GDF6, ATOH7, RAX, C12orf57, SMCHD1, p PAX2 and YAP1. This talk will provide an update of AMC conditions, distinctive features associated tember 15 with particular conditions, with insights into phenotype-genotype correlations.

9.30 The common ABCA4 variant p.Asn1868Ile is associated with variable age-of-onset of Stargardt disease and shows low penetrance - Frans P.M. Cremers, PhD, Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical

Center, Nijmegen, The Netherlands Co-Authors: Esmee H. Runhart, MD, Department of Ophthalmology and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands Riccardo Sangermano, MSc, Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands Stéphanie S. Cornelis, MSc, Department of Human Genetics, and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands Joke B.G.M. Verheij, MD, Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Jan-Willem Pott, MD, PhD, Department of Ophthalmology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Alberta A.H.J. Thiadens, MD, PhD, Department of Ophthalmology and Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands Caroline C.W. Klaver, MD, PhD, Department of Ophthalmology and Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands L. Ingeborgh van den Born, MD, PhD, The Rotterdam Eye Hospital and the Rotterdam Ophthalmic Institute, Rotterdam, The Netherlands

Carel B. Hoyng, MD, PhD, Department of Ophthalmology and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands

Introduction: Biallelic ABCA4 variants were found in ~75% of Stargardt disease (STGD1) cases by us and others. Recently, Zernant et al. (J. Med. Gen., 54:404-412, 2017) proposed that the frequent coding variant p.(Asn1868Ile)(allele frequency: 0.06) explained ~50% of mono-allelic STGD1 cases and ~80% of late onset STGD1 cases. The goal of our study was to detect the causal variants in 65 mono-allelic STGD1 cases from the Netherlands. Methods: We revisited ABCA4 sequencing data and upon identifying p.(Asn1868Ile) in the probands, we performed segregation analysis in family members. Based on a previous study in which we collected all reported ABCA4 variants (Cornelis et al. Hum. Mut., 38:400-408, 2017; www.LOVD.nl/ABCA4), we estimated the cumulative allele frequency of severe ABCA4 variants in control individuals. Results: We found the p.(Asn1868Ile) variant in cis with known coding variants in 11/65 probands, most notably c.2588G>C and c.5461-10T>C. In 24/65 (37%) probands we identified the ‘non- complex’ p.(Asn1868Ile) variant in trans with severe ABCA4 variants. In a large proportion of these cases, the onset of disease was late (>45 yrs) due to foveal sparing. Moreover, STGD1 siblings carrying p.(Asn1868Ile) showed variable ages of onset. Based on the cumulative allele frequency of

severe ABCA4 variants in control individuals, we calculated a very low penetrance for F p.(Asn1868Ile). riday S Conclusions: A significant fraction of genetically unexplained STGD1 cases carries p.(Asn1868Ile) as a second causal variant. We determined a very low penetrance for this variant which can be due to cis or trans acting modifiers.

9.45 OPHTHALMIC GENETICS FREE PAPERS - (7* 10 minutes including questions) p

Moderators - Nicola Ragge / Michael Gorin tember 15

9.45 Foveal hypoplasia screen reveals novel genetic contributions - Robert Hufnagel, MD, National Eye Institute, National Institutes of Health Co-Authors: Aman George, PhD, National Eye Institute, National Institutes of Health Brian Brooks, MD PhD, National Eye Institute, National Institutes of Health

Introduction: Hereditary anomalies of the fovea are often associated with genetic mutation in critical determinants of ocular development and melanosome homeostasis. However, the genetic contribution is poorly understood, and many cases remain without an etiology. Methods: Over 11 years, 159 probands with foveal malformations were identified. Clinical descriptions, imaging, and genetic diagnoses were assessed. For selected cases, next-generation sequencing and functional studies were performed to establish diagnosis. Results: Genetic diagnosis was determined in 90% of cases, with predominance of reported and novel alleles in PAX6 and pigmentation genes. Of 11 patients with MITF-associated Waardenburg syndrome, all had foveal hypoplasia independent of TYR genotypes. Conclusions: Foveal hypoplasia is primarily genetic in origin and associated with albinism and aniridia in our experience. MITF mutations are independently associated with foveal hypoplasia, contrary to previous reports implicating MITF;TYR digenic inheritance.

9.55 Congenital primary aphakia: a case series - Ken K. Nischal, MD, UPMC Eye Center at Children's Hospital of Pittsburgh of UPMC Co-Authors: Hannah L. Scanga, MS, LCGC - UPMC Eye Center at Children's Hospital of Pittsburgh of UPMC Anagha Medsinge, MD - UPMC Eye Center William Moore, MD, FRCOphth - Great Ormond Street Hospital for Children 21

Asim Ali, MD, FRCSC - The Hospital for Sick Children Alex Levin, MD, MHSc, FRCSC - Wills Eye Hospital Erin D. Stahl, MD - University of Missouri-Kansas City

Introduction: Primary aphakia is a rare anomaly characterized by congenital absence of lens and severe anterior segment and globe deformities. Etiologies include infection, chromosome anomalies, and FOXE3 mutations. Here we describe 11 cases of primary aphakia. Methods: Retrospective case review of patients with diagnosis of anterior segment developmental anomalies. Eleven patients with primary aphakia were identified. All had complete ophthalmic evaluations and imaging. FOXE3 analysis was performed in 8 cases. Results: Eleven patients were included and various defects of the entire globe, anterior segment, and posterior segment were noted. At onset, all but one had glaucoma. Surgical intervention was attempted in 4 cases. FOXE3 mutations were identified in 6 cases Conclusions: To date, this is the largest series of primary aphakia and expands understanding of the condition and its outcomes. The condition is usually bilateral with poor visual potential, presenting a challenge for the ophthalmologist to provide useful vision

10.05 Ocular-eyelid coloboma and facial clefts: a genetic study to identify universal clefting genes -

Rose Richardson, PhD, University College London F Co-Authors: riday S Melissa Lees, MRCP, Great Ormond Street Hospital for Children, London, UK Yassir Abou-Rayyah, FRCOphth, Great Ormond Street Hospital for Children and Moorfields Eye Hospital, London, UK Mariya Moosajee, PhD FRCOphth, UCL Institute of Ophthalmology, Great Ormond Street Hospital for Children and Moorfields Eye Hospital, London, UK e p Introduction: We aim to dissect the genetic aetiology of a rare cohort of patients presenting with tember 15 combined unilateral eyelid coloboma, associated MAC and an extensive transverse orofacial cleft including cleft lip/palate, thereby uncovering universal clefting genes. Methods: Whole-exome sequencing of parent-offspring trios led to the identification of potential causative variants. Expression analyses were performed in human and zebrafish tissues. CRISPR- Cas9 was used to knock down zebrafish gene orthologues. Results: De novo missense mutations in genes PTPRR and NCLN were identified in affected

individuals; both are involved in pathways that govern facial development and have been implicated in myopia and cyclopia, respectively. Zebrafish mutants displayed key cramofacial and ocular defects. Conclusions: This study demonstrates functional analyses to delineate the pathophysiological mechanisms involved in embryonic fissure defects, whilst contributing to our understanding of rare ophthalmic clefting disorders.

10.15 Ophthalmic Manifestations of Heimler Syndrome due to PEX6 Mutations - Nutsuchar Wangtiraumnuay, MD, Queen Sirikit Natianal Institute of Child Health Co-Authors: Waleed Abed Alnabi, MD, Wills Eye Hospital Mai Tsukikawa, MD, Sidney Kimmel Medical College at Thomas Jefferson University Jenina Capasso, LCGC, Wills Eye Hospital Reuven Sharony, MD, Meir Medical Center affiliated with the Sackler Faculty of Medicine, Tel Aviv University Chris F Inglehearn, PhD, St. James's University Hospital, University of Leeds Alex V Levin, MD, MHSc, Wills Eye Hospital

Introduction: Pigmentary retinal dystrophy and macular dystrophy have been previously reported in Heimler syndrome due to mutations in PEX1. Here we reported the ocular manifestations in

Heimler syndrome due to mutations in PEX6. Methods: Medical records were reviewed to identify patient demographics, ophthalmic and systemic findings, and results of diagnostic testing including whole genome sequencing. Results: Both patients had heterozygous PEX6 mutations. They exhibited pigmentary retinopathy, hyperfluorescent deposits, depletion of photoreceptors with intraretinal cystoid spaces. Full field electroretinograms showed abnormal photopic with abnormal mfERG. Conclusions: Heimler syndrome due to biallelic PEX6 mutations demonstrates a macular dystrophy with characteristic fundus autofluorescence and may be complicated by intraretinal cystoid spaces.

10.25 Chromosomal Microarray in Congenital and Developmental Cataract - Michelle Lingao, MD, Department of Ophthalmology and Visual Science, University of The Philippines College of Medicine - Philippine General Hospital Co-Authors: Nutsuchar Wangtiraumnuay, MD, Department of Ophthalmology; Queen Sirikit National Institute of Child Health, Bangkok, Thailand Kristof Van Schelvergem, MD, Pediatric Ophthalmology and Ocular Genetics; Wills Eye Hospital, Philadelphia, Pennsylvania, USA Jenina Capasso, MS, Pediatric Ophthalmology and Ocular Genetics; Wills Eye Hospital, Philadelphia,

Pennsylvania, USA F

Wadakarn Wuthisiri, MD, Department of Ophthalmology; Ramathibodi hospital, Bangkok, riday S Thailandy YuHung Lai, MD, Department of Ophthalmology; Kaohsiung Medical University Hospital, Kaohsiung, Taiwan Erika Johnson, PhD, Cytogenetics; Thomus Jefferson Universtiy, Philadelphia, Pennsylvania, USA Mario Zanolli, MD, Facultad de Medicina; ICBM, Universidad De Chile, Santiago, Chile e Vikas Khetan, MD, Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, Chennai, p Tamil Nadu, India tember 15 Renu Bajaj, PhD, Thomas Jefferson University, Philadelphia, Pennsylvania, USA Alex Levin, MD, Pediatric Ophthalmology and Ocular Genetics; Wills Eye Hospital, Philadelphia, Pennsylvania, USA

Introduction: Most non syndromic congenital and developmental cataracts have no identifiable cause. We investigated the utility of chromosomal microarray in identifying the etiology of isolated

childhood cataracts. Methods: Single-nucleotide polymorphism (SNP) microarray was done on patients with isolated childhood catarct. Copy number variants (CNV) were compared with previous reports and analyzed for candidate genes. Results: 18/37 (48.65%) patients had abnormal microarray: 10(27.03%) with CNV, 5(13.51%) with regions of homozygosity, 3 with CNV and homozygosity. In 5 (13.51%) we found a potentially causative cataract gene. Conclusions: A high rate of abnormal SNPmicroarray findings was seen in isolated cataract patients relevant to counselling, identifying genes related to other abnormalities, and the discovery of new cataract genes

10.35 Autosomal recessive cutis laxa type 2 (ARCL2) associated with familial exudative vitreoretinopathy (FEVR) – Kozuma Oku Co-Authors: Yuusuke Matukane, MD, Kyushu Rosai Hospital Yoshito Ishizaki, MD Department of Pediatrics Graduate School of Medical Sciences Kyusyu University Nobuhiko Okamoto, MD, Osaka Women's and Children's Hospital Hiroyuki Kondo, MD, University of Occupational and Environmental Health

Introduction: ARCL2 is caused by mutations in the ATP6V0A2 gene. To date, no retinal abnormalities have been reported in patients with mutations in the ATP6V0A2 gene. We report a case with ARCL2 who also had characteristics of FEVR. Methods: A 6-year-old girl had wrinkly skin, facial dysmorphia, developmental delay, and brain abnormalities. She was found to have an ins-del mutation in the ATP6V0A2 gene (p.I536fs*). Search was made for mutations in the genes known to cause FEVR. Results: She had typical vascular abnormalities and avascularizations compatible with FEVR. At 14- years old, she had a retinal detachment bilaterally that required surgery. No mutations of the FEVR- causing genes, FZD4, LRP5, NDP, and TSPAN12 were detected. Conclusions: It is yet to be determined whether mutation in ATP6V0A2 resulted in retinal complications. A possible genetic heterogeneity may exist in FEVR-like retinal dystrophies.

10.45 Big Data and Ophthalmic Genetics - Michael Gorin, UC-Los Angeles, Stein Eye Insititute

Introduction: There is considerable interest in medicine to use big data from electronic health records and genetic data. A number of opportunities and challenges confront the use of this approach to address key issues in ophthalmic genetics. Friday Spetember 15 Methods: A literature review of recent efforts in medicine and ophthalmology to employ institutional Friday S and consortia biobanks and EMR data in conjunction with genome wide, next generation sequencing and/or genotyping to elucidate genetic components of disease. Results: A number of projects have used selective data from large data sets to test for associations with genetic variants/markers and highlight the challenges of defining phenotypes and using this information for genetic disease. Conclusions: Genetic association studies with big data can provide preliminary results or partially e confirm family-based or case-control association studies. Mendelian Randomization offers a new p approach to exploring the causality of disease using genetics. tember 15

11.00 TEA AND COFFEE WITH POSTER (POSTERS 20-38)AND TRADE STAND VIEWING ***

11.30 FRANCESCHETTI LECTURE – Professor David Mackey “Eye Genetics at the Fork in the Road” Introduction – Elias I. Traboulsi Award – Birgit Lorenz

Heritability in ophthalmology has been known since the time of Hippocrates. However, it was Helmholz’ 1851 invention of the ophthalmoscope that led to over a century of phenotyping that gave us the syndromes and eponymous names we know today. The only “treatment” we could give patients was an accurate diagnosis and assumed risk of having affected children. The 1990s saw the discovery of most major genes for inherited retinal dystrophies in a little over a decade. This opened the potential for 1) predictive genetic testing and pre-implant genetic diagnosis as well as 2) gene based therapies. In addition, we have seen 3) a revolution in adaptive technologies taking rehabilitation beyond guide dogs, canes and Braille.

With all these potential “treatments” for genetic eye disease, how do we decide which ones to invest our research funds and later to expend health care funds to best improve the lives 24

of our patients? When approved treatments aren’t yet available, how do we guide patients to clinical trials and away from “quack” remedies such as stem cell tourism?

***

12.00 RETINOBLASTOMA: FROM DETECTION AND COMMUNICATION TO RETINOBLASTOMA FOR LIFE. Lead - Ashwin Reddy

12.00 Lag time in Retinoblastoma - Ashwin Reddy

12.20 Retinoblastoma Survivorship and second malignancies - Helen Jenkinson

12.40 DePICTRB : evidence for child, family, caregivers and the future - Brenda Gallie

13.00 LUNCH WITH POSTER AND TRADE STAND VIEWING

14.00 PARALLEL FREE PAPERS SESSIONS (90 minutes each) F riday S OPHTHALMIC GENETICS FREE PAPERS – (9 * 10 minutes incl. questions) Moderators - Chris Inglehearn / Alex Levin (Lecture Theatre A)

14.00 “My Retina Tracker” patient registry - Kari Branham on behalf of Foundation Fighting p

Blindness tember 15

14.10 ERN-EYE : the European Reference Network dedicated to European patients with Rare Eye Diseases - Hélène Dollfus, MD, PhD, Hôpitaux Universitaires De Strasbourg Co-Authors: Dorothée Leroux, PharmD PD, Hôpitaux Universitaires de Strasbourg, France All ERN-EYE Coordinating Committee Members

Introduction: Rare Eye Diseases display major heterogeneity & represent the leading cause of visual impairment/loss in children/young adults.Barriers remain for early diagnosis/patient management/research.EUexperts chose to join forces in a EuropeanReference Network Methods: ERN-EYE currently consists of 29 healthcare providers from 13 Member States, with important interactions with patients and patient groups. We will present the general organisation of the ERN as well as mapping of all collaborators across the EU. Results: ERN-EYE will address retinal diseases, paediatric ophthalmic diseases incl. syndromic ones, neuroophthalmological disorders, anterior segment diseases and cover genetic diagnosis, clinical research, clinical trials & registries, training & guidelines Conclusions: We anticipate that ERN-EYE network will improve upon existing resources dedicated to patients with Rare Eye Diseases (RED) across the EU and create new facilities to better diagnose, understand and treat patients and families with RED.

14.20 Genetic eye abnormalities detected in the Deciphering the Mechanisms of Developmental Disorders (DMDD) programme - Stefan Geyer, MD, Medical University of Vienna Co-Authors: The DMDD Consortium, dmdd.org.uk

Introduction: DMDD is a detailed primary screen of embryonic lethal knockout mouse lines. It aims to shed light on the genetic mechanisms that underlie normal organ and tissue development, and to identify mutations that may lead to congenital abnormalities. Methods: Multiple mutant embryos from each line are imaged in 3D at near-histological resolution using High Resolution Episcopic Microscopy. They are then subjected to comprehensive morphological phenotyping. Results: Of the first 70 lines (562 embryos), 42 have at least one eye phenotype. These include abnormal muscle shape, the absence of single, several, or all muscles, abnormal form and position of the optic cup and absence or dislocation of the lens. Conclusions: We will describe the statistics of these malformations, the gene knockouts from which they arise, and the potential of DMDD data (which is freely available at https://dmdd.org.uk) to shed light on the genetic basis of developmental eye disorders.

14.30 Mutational Hotspot RPGR (isoform C) ORF15 Analysis Improves Diagnostic Yield for Inherited Retinal Disorders - Madhulatha Pantrangi, PhD, Prevention Genetics, LLC Co-Authors: Sharon Wolfe-Schwartz, MS, LGC, Scheie Eye Institute Jocelyn Schroeder, BS, Prevention Genetics, LLC

Nicole Hanutke, MT (ASCP), Prevention Genetics, LLC Friday

Introduction: Approximately 70% of the RPGR variants causative for inherited retinal disorders reside in the purine rich ORF15 (exon 15) region. The ORF15 analysis is included in multiple NGS panels at PreventionGenetics, to help increase the diagnostic yield.

Methods: NGS analysis was performed using a custom designed oligo capture set for targeted genes S including RPGR. Specialized Sanger sequencing was performed for the ORF15 region (~c.2370 to e c.3381) that cannot be analyzed via NGS or regular Sanger sequencing. p Results: To date, over 330 patients were tested for RPGR via either targeted ORF15 (~37% of tests) tember 15 or as part of panels. Great majority of the causative variants (63%) were small frameshift deletions/duplications leading to premature protein termination. Conclusions: Due to the genetic heterogeneity and phenotypic overlap, identifying the genetic cause for retinal disorders is often challenging. Our experience demonstrates the importance of specialized testing of the mutational hotspot ORF15.

14.40 Pre-screened inherited retinal disease patients: The UK Inherited Retinal Disease Consortium - Gavin Arno, PhD, UCL Institute of Ophthalmology Co-Authors: Alessia Fiorentino, PhD, UCL Institute of Ophthalmology, London, UK Nikolas Pontikos, PhD, UCL Institute of Ophthalmology, London, UK UK Inherited Retinal Disease Consortium Michael E Cheetham, PhD, UCL Institute of Ophthalmology, London, UK Andrew R Webster, MD(res), FRCOphth, UCL Institute of Ophthalmology, London, UK; Moorfields Eye Hospital, London, UK Michel Michaelides, MD (Res), FRCOphth, UCL Institute of Ophthalmology, London, UK; Moorfields Eye Hospital, London, UK Alison J Hardcastle, PhD, UCL Institute of Ophthalmology, London, UK

Introduction: Current gene panel testing for inherited retinal disease (IRD) is successful in 50-60% of cases suggesting that pathogenic mutations exist outside of the coding regions of known genes and novel disease genes remain to be discovered. Methods: Following negative genetic testing, whole exome sequencing (WES) was performed through the UK Inherited Retinal Disease Consortium (UKIRDC) on 92 probands with a broad spectrum of IRD attending Moorfields Eye Hospital inherited eye disease clinics.

Results: WES identified mutations in 18/92 cases, including 3 novel genes (GNB3, REEP6, CWC27), 4 syndromic disease genes (IQCB1, PRPS1, PNPLA6, PMM2), 2 recently characterized genes (POC1B, MFSD8) and 2 poorly covered exons of known genes (RP1L1, BEST1). Conclusions: Unbiased WES facilitates novel gene discoveries and augments gene panel testing to improve the diagnostic success rate, illustrated here by findings in unknown or unsuspected genes and poorly covered regions of known genes.

14.50 Leber Congenital Amaurosis in Chuukese Population: A Founder Mutation in the CRB1 Gene - Jenina Capasso, LCGC, Wills Eye Hospital Co-Authors: John Chiang, PhD, FACMG, Molecular Vision Lab Tom Glaser, MD, PhD, UC Davis Donna McNear, MA, Independent Education Consultant Sarina Kopinsky, MS, Einstein Medical Center, Philadelphia Anamaria Yomai, MD, FSM Adele Schneider, MD, Einstein Medical Center, Philadelphia Alex V. Levin, MD, MHSc, FRCSC, Wills Eye Hospital

Introduction: To identify the causative mutation in children born with Leber congenital amaurosis F

(LCA) in Chuuk, Micronesia. riday S Methods: A multidisciplinary team carried out a 7 day clinic in Micronesia. Blood was collected for DNA analysis on every consenting individual. A panel of 280 retinal dystrophy genes were sequenced. Results: Five individuals from two different families were diagnosed with LCA by clinical examination. DNA analysis revealed a novel frameshift variant in CRB1 (c.3134delT) which e segregated in the families. p Conclusions: This is likely a founder mutation in CRB1 causing LCA in the Chuukese population. tember 15 The scarcity of this variant in the general population supports the possibility it is unique to this South Pacific population.

15.00 Assessment of the incorporation of CNV surveillance into gene panel next-generation sequencing testing for inherited retinal diseases -Jamie Ellingford, MD, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester

Academic Health Sciences Centre, St Mary's Hospital, Manchester, UK Co-Authors: Catriona Tate, Congenica Ltd, Wellcome Genome Campus, Hinxton, Cambridge, UK Bradley Horn, and Christopher Campbell, and Sanjeev Bhaskar, and Panagiotis I Sergouniotis, and Rachel L Taylor, and Graeme CM Black, and Simon C. Ramsden, and Stephanie Barton, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre Keren J. Carss, Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge, UK F Lucy Raymond, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK Gavin Arno, and Michel Michaelides, and Andrew R Webster, UCL Institute of Ophthalmology, Moorfields Eye Hospital, London, UK

Introduction: Diagnostic use of gene panel next-generation sequencing (NGS) techniques is commonplace for individuals with inherited retinal dystrophies (IRDs), a highly genetically heterogeneous group of disorders. However, these techniques have often failed to capture the complete spectrum of genomic variation causing IRD, including copy number variants (CNVs). This study assessed the applicability of introducing CNV surveillance into first-tier diagnostic gene panel

NGS services for IRD. Methods: Three read-depth algorithms were applied to gene panel NGS datasets for 550 referred individuals, and informatics strategies utilized for quality assurance and CNV filtering. CNV events were confirmed and reported to referring clinicians through an accredited diagnostic laboratory. Results: We confirmed the presence of 33 deletions and 11 duplications, determining these findings to contribute to the confirmed or provisional molecular diagnosis of IRD for 25 individuals. We show that at least 7% of individuals referred for diagnostic testing for IRD have a CNV within genes relevant to their clinical diagnosis, and determined a positive predictive value of 79% for the employed CNV filtering techniques. Conclusions: Incorporation of CNV analysis increases diagnostic yield of gene panel NGS diagnostic tests for IRD, increases clarity in diagnostic reporting and expands the spectrum of known disease- causing mutations.

15.10 Analytic Validation of Oligonucleotide-Selective Sequencing Panels for Clinical Diagnostics of Inherited Eye Disorders - Tero-Pekka Alastalo, MD, Blueprint Genetics Co-Authors: Samuel Myllykangas, PhD, Blueprint Genetics Pertteli Salmenperä, PhD, Blueprint Genetics

Mikko Muona, PhD, Blueprint Genetics F

Massimiliano Gentile, PhD, Blueprint Genetics riday S Juha Koskenvuo, PhD, Blueprint Genetics

Introduction: Genetics diagnostics of ophthalmology patients has been affected by poorly validated genetic tests, lack of transparency, and testing solutions that are not optimized for maximal diagnostic yield. Our goal was to develop a high quality next generation sequencing (NGS) platform e based on oligonucleotide-selective sequencing, transparently and comprehensively validate its quality p and performance, and report here our experiences with hundreds of patients suffering from retina tember 15 disorders. Methods: We developed and validated a set of NGS tests (303 genes, 806175 bps), with traceable sample sets, for detecting single-nucleotide variants (SNVs), insertions and deletions (INDELs) and deletions and duplications (DELDUPs). Our assay targeted the coding exons the splice regions, and 49 selected deep intronic variants. We also utilized this platform to diagnose hundreds of patients during 2016-17.

Results: We demonstrate, on average, 0.993 sensitivity, 0.999 specificity, 0.992 positive predictive value for detecting SNVs and 0.960, 0.884 and 0.667 sensitivity for detecting INDELs of 1-10, 11-20, and 21-30 bases. Repeatability and reproducibility of the assays were 0.994 and 0.998, respectively. 99.5% of the target regions were covered with over 15x sequencing depth. We showed that the assays had 0.748 sensitivity to detect single-exon DELDUPs and 1.000 sensitivity to detect copy number aberrations covering two or more exons. Using ACMG guidelines for variant classification a diagnosis was established in 47% of retina patients, a likely diagnosis in 23%, and 30% were considered negative. Conclusions: Our results demonstrate the analytic validity of the developed tests and show that the technology is well-suited for clinical diagnostics of inherited eye disorders. It also demonstrated a cost-effective diagnostic tool to simultaneously diagnose various types of mutations from SNVs to copy number variations.

15.20 KCNJ13-related severe early onset retinal degeneration associated with a mitochondrial aging pathophysiology - Maria Toms, MSc, Department of Ocular Biology and Therapeutics, UCL Institute of Ophthalmology, London, United Kingdom. Co-Authors: Dhani Tracey-White MSc, UCL Institute of Ophthalmology Rose Richardson PhD, UCL Institute of Ophthalmology

Thomas Burgoyne PhD, UCL Institute of Ophthalmology Mariya Moosajee MBBS BSc PhD FRCOphth, Moorfields Eye Hospital NHS Foundation Trust, Great Ormond Street Hospital for Children, UCL Institute of Ophthalmology

Introduction: Mutations in KCNJ13, which encodes an inwardly-rectifying K+ channel (Kir7.1) expressed in the apical membrane of RPE, cause Leber Congenital Amaurosis (LCA). Here, we characterise the kcnj13-/- zebrafish, to investigate the retinal pathophysiology. Methods: Retinal structure was examined using histology, electron microscopy and SD-OCT. Levels of cell death, Müller cell activity, ATP and heat shock protein 60 (hsp60) were investigated. qRT- PCR of mitochondrial genes; polg2, fis1, opa1, pgk1, ldha, sod1/2 Results: Mitochondrial proliferation was observed in the RPE from 6 months. qRT-PCR showed increases in mitochondrial-related genes. Retinal degeneration was noted at 12 months. Müller cell activation, reduced ATP, increased hsp60 were detected at both ages. Conclusions: The mitochondrial changes observed resemble those seen in models of age-related macular degeneration and other disorders. This study highlights mitochondrial activity as a potential therapeutic target.

RETINOBLASTOMA FREE PAPERS – (9 * 10 minutes incl. questions)

Moderators - John Ainsworth / Manoj Parulekar/ Mandeep Sagoo Friday (Room 229)

14.00 Collaborative Study on the Risk of Extraocular Extension in Retinoblastoma Eyes Receiving Intravitreous Chemotherapy - Jasmine Francis, MD, Memorial Sloan Kettering Cancer Center Co-Authors: S David Abramson, MD, Memorial Sloan Kettering Cancer Center e p

Xunda Ji, MD, Xin Hua Hospital tember 15 Carol Shields, MD, Wills Eye Hospital Luiz Teixeira, MD, Pediatric Oncology Institute Federal University of Sa~o Paulo Amy Schefler, MD, Children's Memorial Hermann Hospital Nathalie Cassoux, MD, Institut Curie Doris Hadjistilianou, MD, University of Siena Jesse Berry, MD, Children's Hospital Los Angeles Shahar Frenkel, MD, Hadassah Medical Center

Francis Munier, MD, Jules-Gonin Eye Hospital

Introduction: To evaluate the risk of extraocular extension in eyes with retinoblastoma that have been injected with intravitreous chemotherapy. Methods: Ten international retinoblastoma centers performed 3565 intravitreous injections (3213 melphalan, 335 topotecan & 17 methotrexate) in 705 eyes of 656 patients and evaluated risk of extraocular extension, injection and precautionary techniques. Results: There were no events of extraocular tumor related to prior intravitreous injections (calculated proportion of 0 extraocular events per eye). All ten centers included in this study used at least 2 presumed precautionary injection methods. Conclusions: In this collaborative study of ten high-volume retinoblastoma centers, using at least two presumed precautionary safety methods, the risk of extraocular extension of tumor is extraordinarily low.

14.10 Metastasis of retinoblastoma in relation to eye staging by International Intraocular Retinoblastoma Classification and American Joint Committee on Cancer Staging - Brenda Gallie and Terö Kivela for the Ophthalmic Oncology Task Force

Purpose: Children with retinoblastoma (Rb) have approximately 5% chance of metastases, predictable by pathology of removed eyes. Initial staging of cancer at diagnosis may predict risk of metastasis. Methods: Patients diagnosed from Jan 2001 – Dec 2011 in 18 centres (13 countries) were staged (International Intraocular Retinoblastoma Classification, IIRC, Murphree; American Joint Committee on Cancer Staging, TNM7). Time to metastasis was analyzed by Kaplan-Meier. Results: Of 1,533 patients, 66% (median age 24 months) were unilateral (URb); 34% (9 months) bilateral (BRb). At diagnosis IIRC (Group A–E) and AJCC (T1, T2a/b, T3) proportions were similar for URb and worse eye of BRb patients. Metastases were present at diagnosis in 18 (1%) and at last follow-up in 89 (6%). Kaplan-Meier estimate of metastases at 1–3 years was 0–0% (Group A–cT1), 1–2% (Group B–D and cT2), and 7–11% (Group E–cT3). Conclusion: Children with IIRC Group E or TNM cT3 Rb have 10% risk of metastasis within 3 years, compared to 1% for less involved eyes. Enucleation of Group E–cT3 eyes may facilitate detection of high-risk features and potential adjuvant therapy to avoid metastases.

14.20 Understanding and overcoming barriers to living with an artificial eye - Deanna Gibbs, MD, Barts Health NHS Trust Co-Authors:

Laura Reynolds, BSc, Judith Kingston Retinoblastoma Unit, Barts Health NHS Trust Friday S Tara Shea, MSSc, Judith Kingston Retinoblastoma Unit, Barts Health NHS Trust

Introduction: This study explores the experiences of children and families following enucleation for retinoblastoma in order to develop clinical guidelines and promote innovation in resource development to support adaptation to living with an artificial eye. Methods: A qualitative participatory action design was used to explore the difficulties experienced e and the strategies perceived as being effective post-enucleation. Interviews were conducted with 11 p parents and 7 children, analysed via content coding. tember 15 Results: Six themes were identified: Entry into the world of retinoblastoma; The importance of specialist support; A family learning to cope; Navigating school; Parent adaptation; and child adaptation. Conclusions: The study findings provide a deeper understanding of the impact that diagnosis and treatment procedures have on children and families. The findings will support future engagement with families in the design of clinical practice recommendations.

14.30 Benchmarking retinoblastoma service delivery: The Australasian experience - Sandra Staffieri, Centre for Eye Research Australia Co-Authors: John McKenzie, FRANZCO, Royal Children's Hospital, Melbourne James Elder, FRANZCO, Royal Children's Hospital, Melbourne, Australia Ashwin Mallipatna, MBBS, MS, DNB, Women's and Children's Hospital, Adelaide, Australia Michael Jones, FRANZCO, Sydney Children's Hospital Network, Sydney, Australia Glen Gole, FRANZCO, Lady Cilento Children's Hospital, Brisbane, Australia Geoffrey Lam, FRANZCO, Princess Margaret Hospital for Children, Perth, Australia Yvonne Ng, FRANZCO, Auckland District Health Board, Auckland, New Zealand

Introduction: Delivery of a comprehensive retinoblastoma (Rb) treatment service, to a geographically dispersed, low-density population such as Australasia remains challenging. Collaboration and co- operation is key to achieving optimal outcomes. Methods: Collaboration with Australasian ophthalmologists identified the resources available at each centre for the provision of retinoblastoma treatment. Clinical data for new patients treated between 2014-2016 inclusive were collected and analysed. Results: Six Rb treatment centres were identified in Australasia, all offering focal therapy, systemic

therapy and plaque brachytherapy. One centre is approved for intra-arterial chemotherapy. 70 new cases of Rb were identified from 2014-2016 Conclusions: A co-operative approach facilitates the provision of the full suite of current treatments for Rb for children in the region. The collaborative collection of longitudinal clinical data provides unique opportunities to explore long-term outcomes for Rb

14.40 RB1 mutation in China - Junyang Zhao, MD, Beijing Children's Hospital Co-Authors: Marc Zhao Hilary Racher Brenda Gallie

Introduction: RB1 mutation testing is important for the many retinoblastoma families in China Methods: RB1 tests (Geneseeq: Next Generation Sequencing, Sanger sequencing and quantitative PCR for validation and low coverage areas) and interpretation (Impact Genetics: data and report generation) were delivered to families by retinoblastoma specialist. Results: For 342 families, RB1 mutations were identified: 4/21 with no available proband and 89/321 probands (17 mosaic, 8 with family history); 36/266 unilateral (15 mosaic); 53/55 bilateral (2 mosaic). Conclusions: This international collaboration achieved state-of-the-art RB1 mutation identification in 96% bilateral and 14% unilateral probands. Overall 6% are mosaic, with 42% of unilateral non- Friday S familial RB1 mutation carriers being mosaic.

14.50 Novel molecular investigation utilising somatic studies and cell-free DNA technologies can underpin significant change in retinoblastoma management - Trevor Cole:- Clinical Genetics Unit, Birmingham Women and Children’s NHS Foundation Trust, Birmingham e

Co-Authors: p

Stephanie Allen and Amy Gerrish, Regional Genetics Unit, Birmingham Women and Children’s tember 15 NHS Foundation Trust, Birmingham Women's Hospital, Mindelsohn Way, Birmingham, B15 2TG Manoj Parulekar and John Ainsworth, Birmingham Children’s Hospital Eye department, Birmingham Women and Children’s NHS Foundation Trust, Steelhouse Lane, Birmingham, B4 6NH Christopher Campbell and Simon Ramsden, Central Manchester University Hospitals - NHS Foundation Trust, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL Helen Jenkinson and Bruce Morland, Birmingham Children’s Hospital Eye department, Birmingham Women and Children’s NHS Foundation Trust, Steelhouse Lane, Birmingham, B4 6NH Ina Nicklaus-Wollenteit and Isabel Colmenero, Histopathology, Birmingham Women and Children’s NHS Foundation Trust, Birmingham Children’s Hospital, Steelhouse Lane, Birmingham, B4 6NH Sue Carless, :- Clinical Genetics Unit, Birmingham Women and Children’s NHS Foundation Trust, Birmingham Michael Parks, Nonacus Ltd, The BioHub Birmingham®, 97 Vincent Dr, Birmingham, B15 2SQ

Purpose: To improve detection of the 60% of retinoblastoma cases arising through post-zygotic mutations resulting in mosaicism, from the 40% due to germline mutations, and to assess the distribution of this mosaicism so that a more accurate assessment can be made for the risk of retinoblastoma in family members and the contra-lateral eye. Methods: Molecular testing, as proof of principle studies, was undertaken from 2 novel sources, namely the cut nerve end and intra-ocular fluid, the later analysing cell free DNA. Results: DNA analysis was achieved from the cut optic nerve and sheath end, with results in agreement from traditional germline and tumour analysis. In one bilateral retinoblastoma with no identifiable germline mutation the risk to the contra-lateral eye was predicted by cut nerve analysis. A separate study proved both molecular “hits” in the Rb gene could be identified from intra-ocular free DNA.

Conclusions: These novel tests could transform the molecular genetic analysis and clinical management of Retinoblastoma by identifying contra-lateral Retinoblastoma risk following enucleation and the molecular aetiology in non-enucleated unilateral Retinoblastoma.

15.00 Integration of Genetic Testing for Unilateral Retinoblastoma in Clinical Practice - A Single Institutes Experience in Japan - Hiroyoshi Hattori, MD, Department of Pediatrics, National Hospital Organization, Nagoya Medical Center Co-Authors: Maki Morikawa, Master, Genetic Counselling Unit, National Hospital Organization Nagoya Medical Center, Nagoya, Japan Toshinobu Kubota, Doctor, Departments of Ophthalmology, National Hospital Organization Nagoya Medical Center, Nagoya, Japan Nobuhiro Akita, Doctor, Departments of Pediatrics, National Hospital Organization Nagoya Medical Center, Nagoya, Japan Masahiro Sekimizu, Doctor, Departments of Pediatrics, National Hospital Organization Nagoya Medical Center, Nagoya, Japan Mizuho Ichikawa, Doctor, Departments of Pediatrics, National Hospital Organization Nagoya Medical Center, Nagoya, Japan

Naoko Maeda, Doctor, Departments of Pediatrics, National Hospital Organization Nagoya Medical F

Center, Nagoya, Japan riday S Mineko Ushiama, Bachelor, Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan Teruhiko Yoshida, Doctor, Department of Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan Kokichi Sugano, Doctor, Oncogene Research Unit/Cancer Prevention Unit, Tochigi Cancer Center e Research Institute, Utsunomiya, Japan p Keizo Horibe, Doctor, Departments of Pediatrics, National Hospital Organization Nagoya Medical tember 15 Center, Nagoya, Japan

Introduction: The genetic testing for the unilateral retinoblastoma enables us to provide the individualized follow up based on the germline RB1 gene status. In Japan, the test was not constantly used in the practice since the lack of health insurance coverage. Methods: We have introduced the RB1 genetic testing in the clinical practice since 2016. All newly

diagnosed RB patients were informed about the genetic testing. 14 unilateral patients desired and received the genetic test after the genetic counselling. Results: Two RB1 mutations out of 6 were identified. We discontinued regular brain MRI for the mutation negative patients whereas the follow-up was continued for the positive case. One of the parents felt psychological stress to accept the unexpected result. Conclusions: The genetic test of RB1 has to be beneficial for all the patients. The parents basically expect the negative result. Therefore, considering the psychological status of the affected families are essential when the mutation positive result is returned.

15.10 Cosmetic results of enucleation for the treatment of retinoblastoma - Daphne Mourits, MD, VU University Medical Center Co-Authors: Dyonne Hartong, MD PhD, VU University Medical Center Machteld Bosscha, MD, VU University Medical Center H. Stevie Tan, MD, PhD, VU University Medical Center Annette Moll, MD, PhD, VU University Medical Center

Introduction: Purpose: To evaluate the cosmetic effects and patient satisfaction after enucleation and/ or external beam radiation therapy (EBRT) for the treatment of retinoblastoma

Methods: Measurements of the eyelids, orbits and prostheses were performed and standardised photos were taken. Patients satisfaction was inquired with questionnaires. Results: Of 195 patients (4.6-88.4 yrs) 84% was satisfied with facial/ ocular appearance. We registered ptosis (28.3%), lower lid sagging (24.4%), volume loss (66.9%). Prosthesis motility was better in patients with orbital implant, regardless of the size. Conclusions: In our study population where enucleation was performed at young age, bigger sized orbital implants were associated with a considerable higher incidence of ptosis. Bigger sized implant were not beneficial with respect to orbital volume or motility.

15.20 BAP1 germline mutations in Finnish uveal melanoma patients - Joni Turunen, MD, Ophthalmology, University of Helsinki and Helsinki University Hospital, Finland Co-Authors: Joni A. Turunen, MD, PhD. FEBO, Ophthalmology, University of Helsinki and Helsinki University Hospital, Finland Pauliina Repo, MSc, Folkhälsan Institute of Genetics, Helsinki, Finland Reetta-Stiina Järvinen, BSc, Folkhälsan Institute of Genetics, Helsinki, Finland Johannes Jäntti, BM, Folkhälsan Institute of Genetics, Helsinki, Finland Rosi Wilska, MD, Ophthalmology, University of Helsinki and Helsinki University Hospital, Finland Martin Täll, MD, Ophthalmology, University of Helsinki and Helsinki University Hospital, Finland Virpi Raivio, MD PhD, Ophthalmology, University of Helsinki and Helsinki University Hospital, F Finland riday S Anna-Elina Lehesjoki, MD PhD, Folkhälsan Institute of Genetics, Helsinki, Finland Tero T. Kivelä, MD PhD FEBO, Ophthalmology, University of Helsinki and Helsinki University Hospital, Finland

Introduction: Germline pathogenic variants of the BRCA-1 associated protein-1 (BAP1) gene p

predispose to uveal melanoma and several other cancers. Testing for germline BAP1 mutations tember 15 should be performed if typical BAP1 cancer predisposition syndrome tumors have been diagnosed in the family. We report the frequency of germline pathogenic variants of BAP1 in consecutive Finnish uveal melanoma patients. Methods: In Finland, uveal melanomas are treated centrally in the Ocular Oncology Service, Helsinki University Hospital. We collected clinical data and genomic DNA from 309 of 455 consecutive patients diagnosed from January 2010 to December 2016. The 17 exons and exon-intron junctions of BAP1 were sequenced. Results: We found two pathogenic germline variants, a T-insertion in exon 14 in four patients and donor splice site mutation in a highly conserved region immediately after exon 2 in two patients. The families of these patients also had typical BAP1-related cancers (cutaneous melanoma, mesothelioma, and renal cell carcinoma). The mutations were not found in 10,490 Finnish controls from the Sequencing Initiative Suomi (SISu) database. Further, we identified two nonsynonymous variants of unknown significance in exon 13. The overall frequency of BAP1 pathogenic variants was 1.9% (6/309; 95% confidence interval, 0.7-4.2). Conclusions: The frequency of BAP1 germline pathogenic variants in consecutive Finnish patients with uveal melanoma who come from a high-risk region for the development of this cancer is comparable with reports from other populations.

15.30 TEA AND COFFEE WITH TRADE STAND VIEWING

16.00 POSTER VIEWING – POSTERS 20 TO 38 All presenting authors to stand by posters

16.30 INTERPRETATION OF GENETIC TEST RESULTS FROM LAB TO PATIENT (MDT STYLE). Lead - Graeme Black; with contributions from Georgina Hall, Panagiotis Sergouniotis and Simon Ramsden.

*** 17.30 ISGEDR BUSINESS MEETING

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18.00 CLOSE AND REMOVAL OF POSTERS

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19.00- DINNER: ROYAL ARMOURIES MUSEUM, LEEDS Transport will pick up and drop off guests at city centre locations (to be

confirmed later). The Royal Armouries is a 10-minute drive or 30 minute walk F from the Conference Center. Address: Armouries Drive, Leeds LS10 1LT riday S

e p tember 15

Saturday, September 16, 2017 ISGEDR meeting (5 CPD points)

8.00 TEA AND COFFEE

8.45 OPHTHALMIC GENETICS FREE PAPERS – (6* 10 minutes incl. questions) Moderators = Frans Cremers/Amanda Churchill

8.45 Retinal dystrophy can be the primary presenting symptom in patients with JAG1 mutations usually associated with systemic disease - Kari Branham, MS, CGC, University of Michigan Kellogg Eye Center Co-Authors: Kaylie Jones, MS, Retina Foundation of the Southwest Dianna Wheaton, PhD, Retina Foundation of the Southwest Dana Schlegel, MS, MPH, University of Michigan Kellogg Eye Center Sara Bowne, PhD, Human Genetics Center, School of Public Health, The University of Texas Saturday S Health Science Center Lori Sullivan, PhD, Human Genetics Center, School of Public Health, The University of Texas Health Science Center Naheed Khan, PhD, University of Michigan Kellogg Eye Center David Birch, PhD, Retina Foundation of the Southwest Abigail Fahim, MD, PhD, University of Michigan Kellogg Eye Center

Steve Daiger, PhD, Human Genetics Center, School of Public Health, The University of Texas e

Health Science Center p

John Heckenlively, MD, University of Michigan Kellogg Eye Center tember 16

Introduction: Alagille syndrome (AGS) is associated with hepatic, renal, cardiovascular, skeletal, and ophthalmic findings, caused by mutations in the JAG1 and NOTCH2 genes. We describe the retinal phenotype in our patients affected with JAG1 mutations. Methods: A chart review was conducted on the four patients seen in our retinal dystrophy clinics with JAG1 mutations identified. Information was collected on medical history, ERG responses, photography, and visual fields (VF).

Results: In 3 patients, retinal disease was the presenting symptom, and the 4th patient had an existing diagnosis of AGS. All patients had abnormal ERGs and reduced VA and/or VF, including one legally blind patient. No patients had known liver disease. Conclusions: Patients with AGS often have good vision, but these 4 patients have vision loss due to retinal degeneration. Mutations in JAG1 should be considered in patients presenting with retinal degeneration, even those not known to have AGS syndromic findings.

8.55 Mutation Spectrum in 9 Patients with Sector RP - Elias I Traboulsi, MD, MEd, Cole Eye Institute, Cleveland Clinic Co-Authors: Diana Basali, MD, Cleveland Clinic Meghan M. DeBenedictis, MGC, Cleveland Clinic Akiko Maeda, MD, PhD, Case School of Medicine

Introduction: Sector RP refers to a mild form of RP in which retinal pigmentary changes are predominantly inferior and symptoms are mild and of late onset. Patients generally have mutations in rhodopsin. We present 9 patients with sector RP and review their clinic

Methods: Chart review of 9 consecutive patients with sector RP collected over the course of 5 years in a specialized retinal dystrophy clinic. Clinical and imaging studies were reviewed. Molecular testing was performed at CLIA laboratories. Results: 9 patients (3M:6F) with an average age of 49 years (30 75) are included. 8 patients had mutations in RHO (p.Pro23His (2), p.Leu226Pro, p.Ser270Arg (2), p.Asn15Ser (2), and p.Gly109Arg) and one in RPGR (c.3092_3093delAG). All patients had classic fi Conclusions: Sector RP is predominantly caused by mutations in the rhodopsin gene. The spectrum of such mutations includes some recurrent ones and some unique sequence variants..

9.05 Natural History of Individuals With Retinal Degeneration Due to Biallelic Mutations in the RPE65 Gene - Birgit Lorenz, MD, Justus-Liebig-University Giessen Co-Authors: Daniel C. Chung, DO, Spark Therapeutics, Philadelphia, PA, USA Michael Larsen, MD, Department of Ophthalmology, Rigshospitalet, Glostrup, Denmark Mark E. Pennesi, MD, PhD, Casey Eye Institute, Oregon Health and Science University, Portland, OR, USA Bart P. Leroy, MD, PhD, Ghent University Hospital and Ghent University, Ghent, Belgium

Christian P. Hamel, MD, PhD, Maladies Sensorielles Génétiques, CHRU, Montpellier, France; S

INSERM U1051, Institute for Neurosciences of Montpellier, Montpellier, France; Université aturday S Montpellier, Montpellier, France Eric Pierce, MD, PhD, Massachusetts Eye and Ear Infirmary, Boston, MA, USA Juliana Sallum, MD, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil Kathleen Reape, MD, Spark Therapeutics, Philadelphia, PA, USA Katherine A. High, MD, Spark Therapeutics, Philadelphia, PA, USA RPE65 Natural History Study Team e p Introduction: Retrospective chart review of 70 individuals with inherited retinal disease (IRD) due to tember 16 confirmed biallelic mutations in the RPE65 gene to elucidate the disease natural history, using longitudinal ocular history review and clinical testing results. Methods: Chart data on visual acuity (VA), visual field (VF), optical coherence tomography (OCT), demographics, ocular history and examination, and genetic and clinical diagnoses were collected and analyzed from 7 worldwide tertiary referral centers. Results: Significant (P0.0001) age effects on VA and Goldmann VF were observed. On OCT, no

significant age effect on foveal or outer nuclear layer thickness was observed. Orientation and/or mobility issues were reported by 74%, and 80% used low vision aids. Conclusions: The significant relationships between age and declines in VA and VF support the proposition that therapeutic intervention for IRD due to RPE65 mutations prior to extensive retinal degeneration may alter the progressive nature of this disease.

9.15 Phenotype characterisation of 9 subjects with pathogenic variants in the CERKL gene - Tham Nguyen, MD, Oxford University Hospitals NHS Foundation Trust Co-Authors: Vicki Tai, Medical student, Oxford University Hospitals NHS Foundation Trust Mital Shah, MD and research fellow, Oxford University Hospitals NHS Foundation Trust and Nuffield Laboratory of Ophthalmology, University of Oxford S. Halford, MSc, research staff, Nuffield Laboratory of Ophthalmology, University of Oxford M. Shanks, MSc, research staff, Nuffield Laboratory of Ophthalmology, University of Oxford P. Clouston, MSc, research staff, Nuffield Laboratory of Ophthalmology, University of Oxford Susan Downes, professor and surgeon ophthalmology consultant, Oxford University Hospitals NHS Foundation Trust and Nuffield Laboratory of Ophthalmology, University of Oxford

Introduction: To describe the range of phenotypes associated in 9 subjects with mutations in the CERKL gene identified by testing on the Oxford NGS gene RP panel. Methods: Nine patients with CERKL mutations were characterised by ophthalmic history, clinical examination, fundus autofluorescence , optical coherence tomography , visual fields and electrophysiology. Results: Of the 9 patients, 4 were homozygous for CERKL mutations and 5 were compound heterozygotes. Age of onset of symptoms ranged from 20 to 48 years of age. Results of electrophysiology, retinal imaging and genotype correlation are presented. Conclusions: CERKL mutations in the population described here show heterogeneous phenotypes.

9.25 COMMAD: a novel syndrome caused by biallelic mutation of the MITF gene syndrome - Brian Brooks, MD, PhD, National Eye Institute Co-Authors: Aman George, PhD, NEI Dina J. Zand, MD, Children's National Medical Center Robert B Hufnagel, MD, PhD, NEI Ruchi Sharma, PhD, NEI

Yuri V Sergeev, PhD, NEI Saturday S Janet M Legare, MD, University of Wisconsin Gregory M Rice, MD, University of Wisconsin Jessica A S Schwoerer, MD, University of Wisconsin David M Gamm, MD, PhD, University of Wisconsin Kapil Bharti, PhD, NEI

Introduction: To describe the clinical and molecular features of a novel syndrome, COMMAD coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism and deafness) caused by biallelic e mutations in the basic helix-loop-helix zipper gene, MITF. p Methods: Deep clinical phenotyping, DNA sequencing, in vitro molecular characterization tember 16 Results: Both probands exhibit the COMMAD phenotype, reminiscent of the mi/mi mouse model. DNA binding, nuclear localization, & transactivation were variably affected by different mutations. Conclusions: COMMAD represents a novel constellation of signs and symptoms, leading to profound sensory system impairment. Neither set of parents recognized their underlying dx, making recognition of Waardenburg syndrome, type 2a, particularly important.

9.35 What is an ocular geneticist and how do we make more? - Alex Levin, MD, Wills Eye Hospital

Introduction: Ocular genetics is an emerging ophthalmology subspecialty. The number of ocular geneticists worldwide is estimated to be 70-80. Yet, ocular genetic disease is one of the leading causes of blindness worldwide. Methods: This is an open presentation to stimulate discussion. Questions to be considered include strategies to standardize training curricula, and increase numbers of ocular geneticists and ocular genetics counsellors worldwide. Results: N/A Conclusions: Patients desire prompt expert assessment regarding their rare conditions. Defining/increasing training programs addresses need and improves care.

9.45 FRANÇOIS LECTURE - Professor Andreas Gal “From Congenital Stationary Night Blindness to Inherited Retinal Dystrophy: A Journey of 30 Years Discovering the Secrets of the Emerging Human Genome” Introduction – Bart Leroy Award – Birgit Lorenz

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10.15 TEA, COFFEE WITH TRADE STAND VIEWING

10.45 OPHTHALMIC GENETICS FREE PAPERS – (6* 10 minutes incl. questions) Moderators = Brian Brooks/Elias Traboulsi

10.45 Molecular pathology of Warburg, Micro and Martsolf syndromes - Mark Handley, MD, Sa University of Leeds

Warburg Micro syndrome and Martsolf syndromes are severe autosomal recessive conditions turday S associated with eye, nervous system and endocrine abnormalities. Eye abnormalities are often the first signs of disease. Bilateral congenital cataracts are commonly accompanied by microphthalmia and microcornea (<10mm diameter). Affected individuals also usually display small atonic pupils that are unresponsive to light or mydriatic agents, progressive optic atrophy and severe cortical visual impairment. This talk will review recent studies establishing the genetic and molecular bases of Micro

and Martsolf syndromes. e p tember 16 10.55 Identification of pseudoexons due to deep-intronic ABCA4 variants in Stargardt disease - Riccardo Sangermano, MSc, Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands Co-Authors: Alejandro Garanto, PhD, Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands

Miriam Bauwens, MSc, Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium Mubeen Khan, MSc, Department of Human Genetics, and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands Nathalie M. Bax, MD, Department of Ophthalmology and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands Caroline C.W. Klaver, MD, PhD, Department of Ophthalmology and Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands L. Ingeborgh van den Born, MD, PhD, The Rotterdam Eye Hospital and the Rotterdam Ophthalmic Institute, Rotterdam, The Netherlands Ana Fakin, MD, PhD, UCL Institute of Ophthalmology, Moorfields Eye Hospital, London, UK Andrew R. Webster, MD, PhD, UCL Institute of Ophthalmology, Moorfields Eye Hospital, London, UK Carel B. Hoyng, MD, PhD, Department of Ophthalmology and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands Elfride De Baere, MD, PhD, Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium

Silvia Albert, PhD, Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands Rob W.J. Collin, PhD, Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands Frans P.M. Cremers, PhD, Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands

Introduction: In ~25% of patients affected by autosomal recessive Stargardt disease (STGD1), none or one variant was identified in the protein coding elements and splice sites of ABCA4. It is our aim to identify the missing causal variants and assess their effect on ABCA4 mRNAs. Methods: Haloplex-based whole ABCA4 gene sequencing was performed in 78 unsolved STGD1 cases (67 monoallelic, 11 with no ABCA4 variants). In silico predictions of splice abnormalities were made and the effect of candidate disease variants was tested in vitro by transfecting midigene constructs into HEK293T cells. Fibroblasts of selected STGD1 cases were reprogrammed into induced pluripotent stem cells and differentiated into photoreceptor precursor cells (PPCs). The effect of deep-intronic variants on RNA splicing was assessed by reverse RT-PCR of PPC mRNA. Results: Analysis of sequence data identified the frequent p.(Asn1868Ile) variant in 24 probands and

283 rare intronic variants in 78 probands. In silico predictions revealed putative splice abnormalities Saturday S for 48 variants and in vitro splice assays revealed 7 different splicing abnormalities in 22 of 40 monoallelic STGD1 cases not carrying p.(Asn1868Ile). The variants activated either cryptic splice acceptor or donor sites which resulted in pseudoexon insertions. RT-PCR of patient-derived PPC mRNA corroborated the in vitro findings. Conclusions: Whole ABCA4 gene sequencing and in vitro and in vivo assessments of the effect of rare deep-intronic variants enabled us to identify several novel STGD1-associated variants and revealed the cause of disease in the majority of the cases. e 11.05 Deep phenotyping identified novel anatomical and functional characteristics in Stargardt p disease - Kamron Khan, MD, PhD, Leeds Teaching Hospitals NHS Trust and Moorfields NHS tember 16 Trust, UK Co-Authors: Melissa Kasilian, PhD, Moorfields NHS Trust, UK Amy Pai, MD, PhD, Moorfields NHS Trust, UK Omar Mahroo, MD, PhD, Moorfields NHS Trust, UK Angelos Kalitzeos, PhD, Moorfields NHS Trust, UK

Anthony Robson, PhD, Moorfields NHS Trust, UK Anthony Moore, MD, University of California, San Francisco, USA Takeshi Iwata, MD, PhD, National Institute of Sensory Organs, Tokyo, Japan Kaoru Fujinami, MD, PhD, National Institute of Sensory Organs, Tokyo, Japan Michel Michaelides, MD, Moorfields NHS Trust, UK

Introduction: Stargardt disease (STGD1), or ABCA4 retinopathy, is associated with a range of clinical phenotypes. In this work we describe a number of previously unreported features of disease, and provide insight into mechanisms of disease. Methods: Retrospective review of electronic patient records at Moorfields Eye Hospital (2000-2017) aiming to identify patients with STGD1. Results: 618 patients were identified. 5 eyes (4 patients) had choroidal neovascularisation (CNVM). 8 patients with childhood-onset disease were identified prior to the development of foveal atrophy. 10 patients had electronegative electroretinography. Conclusions: Childhood-onset disease initially spares the foveola. CNVM is a rare complication of STGD1. Rarely electronegative ERGs may occur in STGD.

11.15 The majority of persons with ABCA4 disease-associated genotypes do not present with visual disability - Ana Fakin, MD, PhD, Eye Hospital, University Medical Centre Ljubljana; UCL Institute of Ophthalmology; Moorfields Eye Hospital, London, UK Co-Authors: Stanley Lambertus, MD, PhD, Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, Netherlands Valentina Cipriani, PhD, UCL Institute of Ophthalmology, Moorfields Eye Hospital, UCL Genetics Institute (UGI), London, UK Gavin Arno, PhD, UCL Institute of Ophthalmology, Moorfields Eye Hospital, London, UK Nathalie Bax, MD, PhD, Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, Netherlands John Chiang, PhD, Molecular Vision Laboratory, Hillsboro, OR, USA Anthony T. Moore, MD, PhD, Department of Ophthalmology, UCSF School of Medicine, San Francisco, CA, USA Keren Carss, PhD, Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

Michel Michalides, MD, PhD, UCL Institute of Ophthalmology, Moorfields Eye Hospital, London, Saturday S UK Carel Hoyng, MD, PhD, Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, Netherlands Andrew R. Webster, MD, PhD, UCL Institute of Ophthalmology, Moorfields Eye Hospital, London, UK

Introduction: The population variant data suggests higher frequency of disease-associated variants in ABCA4 than expected considering the rarity of disease. To surmount the lack of data on the true e prevalence of visual loss due to ABCA4 mutation, we assumed full penetrance of those with p nullizygous genotypes and determined which other genotypes (if any) were under-represented in tember 16 patients. Methods: Hypothetical distributions of genotypes generated from GnomAD and NIHR-Bioresource allele frequency data were compared with those observed in patient cohorts (397 probands from UK; 166 from Netherlands). Phenotypes were analyzed using fundus autofluorescence imaging (FAF). Results: There was significantly skewed distribution of nullizygous (N/N), hemizygous (N/M) and bialleic missense (M/M) genotypes in patients with at least 11-fold paucity of missense genotypes.

Two specific genotype subclasses occurred in homozygous but never in the compound heterozygous state. These patients had different patterns of retinal pathology on FAF. Conclusions: Results suggest low penetrance of ABCA4 genotypes. Cis and trans modifying factors are likely and a reevaluation of the haplotypes is warranted. Hardy Weinberg Disequilibrium of specific allele subclasses suggests there is reciprocal compensation of different dysfunctions of ABCA4 protein in some cases.

11.25 DNA Methylation Studies in Age-related Macular Degeneration: Sex and Senescence - Louise Porter, University of Liverpool, Department of Eye and Vision Sciences Co-Authors XiongYang Fang, University of Liverpool, Centre for Genomic Research Anneke den Hollander, Radboud UMC, Department of Ophthalmology, the Netherlands Paul Bishop, University of Manchester, School of Biomedicine. Lakis Liloglu, University of Liverpool, Institute of Translational Medicine Eiko de Jong, Radboud UMC, Department of Ophthalmology, the Netherlands Simon Clark, University of Manchester, School of Biomedicine.

Introduction

Epigenetic mechanisms of gene regulation, including DNA methylation, are of considerable interest in age-related macular degeneration (AMD). DNA methylation is sex-specific. Sexually dimorphic gene expression patterns often tissue-specific. We hypothesize that genomic DNA in retinal cells is subjected to epigenetic changes. We investigate a role for differential DNA methylation in dry AMD, and a role for sample gender stratification in AMD EWAS data analysis. Materials and Methods Epigenome-wide case/control study (EWAS) was performed using the Illumina Human Methylation450 BeadChip Array on a total of 48 samples RPE/choroid extracted DNA from phenotyped donor eyes with dry AMD (n=24) and control eyes (n=24). Following bisulphite conversion, DNA methylation levels were measured using the Illumina Human Methylation450 BeadChip Array. Quality control was conducted in GenomeStudio software (Illumina). Results were obtained using the log2 ratio beween unmethylated and methylated probes (M-values) and the beta-statistics [methylated/(unmethylated + methylated)]. Raw data was analysed using Bioconductor lumi package. Preprocessing was performed using SWANN normalization. All probes with detection p-values ³ 0.01 were removed. Benjamini-Hochberg false-discovery rate (FDR) method was applied to control for multiple testing and P-values corrected for multiple testing using FDR. Statistically significant differences in DNA methylation level between groups were

identified by ANOVA with post-hoc test. S Two separate identical analyses were performed, the first using AMD versus controls; a second aturday S analysis using sex matching: M AMD versus M controls, F AMD versus F controls.

Biological replication studies were performed using both the Illumina Human Methylation450 BeadChip Array, and biological/technical replication using pyrosequencing on a PyroMark Q96 on a total of 20 independent RPE/choroid samples, and further technical replication on 48 samples (24 AMD, 24 controls). Results e Cases and control samples did not differ significantly in mean age or sex distribution. p tember 16 Analysis of the discovery cohort (total n=48) using Illumina 450k array without sex matching did not reveal any differentially methylated loci with genome-wide significance or a FDR of 5%. Use of basic sex-stratification on the identical dataset revealed 20 differentially methylated individual CpG loci with p<10-8 and false discovery rate < 5%, with a total of 44 CpG loci identified with FDR <10%. Novel genes playing roles in P53 hypoxia-triggered apoptosis, autophagy and lipid metabolism were identified. cg18158385 was noted to by hypermethylated in AMD samples versus controls (log2FC 2.39) with p-value of 4.96 x10-9, a significant signal above the methylation difference of M versus F at

this locus (log2FC -0.48, p-value of 0.16). Replication studies using the Illumina Human Methylation450 BeadChip Array on 20 samples confirmed 2 CpG loci with FDR <10%. These were cg18158385 within the CpG island of CNN3; and cg04270405 within the CpG island of ING1. Pyrosequencing studies confirmed and replicated the above findings in an independent sample set (10 AMD, 10 controls). Pyrosequencing replication studies on a further 18 loci are ongoing. Conclusions This is the largest genome-wide DNA methylation dataset of AMD derived from ocular-tissue, and the first analysis to formally investigate background differences in sex-related DNA methylation using gender matching of RPE/choroid DNA samples. This study is the first to identify loci of differential DNA methylation with genome-wide significance, identifying novel candidate loci for dry AMD functional research, CNN3 and ING1.

11.35 The rs4910623 variant is not associated with response to anti-VEGF treatment in age-related macular degeneration - Amanda Churchill, MD, University of Bristol Co-Authors: James Carter, PhD, Medical Research Council, Swindon Gareth McKay, PhD, University of Belfast, Belfast

Sobha Sivaprasad, MD, Moorfields Eye Hospital, London Sascha Fauser, MD, University Hospital of Cologne, Cologne Nic Timpson, PhD, University of Bristol, Bristol

Introduction: Personalised treatment for exudative age related macular degeneration may improve response rates and is driven by the high prevalence of disease in the aging population, the cumulative cost of treatment and the introduction of novel therapies. A recent study by Riaz et al. found that poor response to intravitreal lucentis treatment at 6 months (defined as loss of 5 or more ETDRS letters) was associated with the single nucleotide variant rs4910623. The G/A allele frequency was 0.49/0.51 in responders (n=234) compared to 0.72/0.28 in poor responders (n=62). The rs4910623 variant lies in the promoter region of the OR52B4 gene, a member of the G-coupled protein receptor family, the function of which is currently unknown in the eye. Methods: In this study we sought to replicate this finding but chose to look at extremes of response to further purify the phenotype: genotype association. We identified 465 individuals with age related macular degeneration who had undergone similar intravitreal lucentis treatment as that outlined in the study by Riaz et al. and had either a very good or very poor response to treatment. We defined good responders as a gain of 15 or more ETDRS letters and a poor response as a loss of 10 or more

ETDRS letters at 6 months. S

Results: The G/A allele frequency was 0.56/0.44 in good responders (n=230) and 0.50/0.50 in poor aturday S responders (n=235). Conclusions: With larger numbers of poor responders we have not been able to replicate the original findings.

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e 11.45 ELLSWORTH LECTURE - Professor Annette Moll p “All for one: Retinoblastoma, Pineoblastoma and Second Primary tember 16 Malignancies” Introduction – Brenda Gallie Award – Birgit Lorenz ***

12.15 LUNCH AND TRADE STAND VIEWING

13.00 OPHTHALMIC GENETICS FREE PAPERS – (5* 10 minutes incl. questions) Moderators - Birgit Lorenz/Arif Khan

13.00 An unusual retinal phenotype solved only by whole exome sequencing – Case Presentation - Bart Leroy

13.10 Clinical characterisation of the retinal dystrophy caused by dominant mutation in RGR- Rola Ba-Abbad, MBBS, FRCS, UCL Institute of Ophthalmology, Hospital for Sick Children & University of Toronto Co-Authors: Gavin Arno, PhD, UCL Institute of Ophthalmology & Moorfields Eye Hospital, London, UK Xinjing Wang, PhD, University of Oklahoma Health Sciences Center, USA Monique Leys, MD, WVU Eye Institute, West Virginia University, Morgantown WV, USA Keren J. Carss, PhD, Department of Haematology, University of Cambridge, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, UK

Christina Chakarova, PhD, UCL Institute of Ophthalmology, London, UK Graham E. Holder, PhD, Moorfields Eye Hospital, UCL Institute of Ophthalmology (UK), National University of Singapore (Singapore) Marybeth Hummel, MD, Department of Pediatrics, West Virginia University, Morgantown WV, USA F. Lucy Raymond, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK Andrew R. Webster, MD, FRCS, FRCOphth, UCL Institute of Ophthalmology & Moorfields Eye Hospital, London, UK

Introduction: This study describes the clinical features and progression of a rare retinal dystrophy, caused by the heterozygous mutation c.824dupG in RGR, in two families from the USA and the UK. Methods: An observational case-series; data included visual acuity (VA), Goldmann visual fields (GVF), fundus features on multimodal imaging, electroretinography (ERG), next generation and whole genome sequencing (NGS &WGS), and haplotype analysis. Results: Patients had subnormal VA & GVF; showed reticular pigmentation, chorioretinal atrophy on fundoscopy; and subnormal ERG in symptomatic patients. The c.824dupG allele was segregated,

with shared haplotype. Saturday S Conclusions: This report details the early and advanced features of dominant RGR retinopathy and suggests that the c.824dupG allele has a toxic effect on RGR. Recognition of the phenotype will guide targeted gene sequencing in future cases.

13.20 Acrodermatitis enteropatica and retinal ganglion cell dysfunction - is there a causal relationship? - Neringa Jurkute, University College London, Institute of Ophthalmology, London, UK; Moorfields Eye Hospital NHS Foundation Trust, London, UK Co-Authors: e Graham Holder, University College London, Institute of Ophthalmology, London, UK; Moorfields p Eye Hospital NHS Foundation Trust, London, UK tember 16 Andrew Webster, University College London, Institute of Ophthalmology, London, UK; Moorfields Eye Hospital NHS Foundation Trust, London, UK Patrick Yu Wai Man, University College London, Institute of Ophthalmology, London, UK; Moorfields Eye Hospital NHS Foundation Trust, London, UK

Introduction: Acrodermatitis enteropathica is a rare zinc deficiency disorder caused by homozygous

or compound heterozygous mutation in the SLC39A4 gene on chromosome 8q24. A few cases of optic atrophy have been reported in association with this genetic disorder. Methods: We report on two sisters diagnosed with acrodermatitis enteropathica in the first year of life who later developed bilateral optic atrophy. Results: Different grade optic nerve head atrophic changes were seen and confirmed by OCT structural analysis in both sisters. Electrodiagnostic tests suggested retinal ganglion cell dysfunction without optic nerve conduction delay. Conclusions: The earlier diagnosis of acrodermatitis enteropathica and the prompt initiation of zinc supplementation for the younger sister could account for her better visual prognosis.

13.30 Christina Fasser - TBD

13.40 CLINICAL TRIALS, EMERGING NEW TREATMENTS AND THE ROLE OF PHARMA. Leads - Bart Leroy and Alun Barnard

13.40 Gene Therapy for RPGR-Related XLRP - Anna Paola Salvetti

13.55 Gene Therapy for RPE65-Related IRD: Results of a Phase 3 Trial - Bart P Leroy 43

14.10 Gene Therapy for Choroideremia - Alun Barnard

14.25 Can the mouth ulcer drug, amlexanox, be used to treat choroideremia? - Mohamed Adam Ali, MBBS, BSc, UCL Co-Authors: Dhani Tracey-White, BSc, UCL Institute of Ophthalmology Matthew Smart, PhD, UCL Institute of Ophthalmology Andrew Webster, FRCOphth, UCL Institute of Ophthalmology, Moorfields Eye Hospital Mariya Moosajee, PhD FRCOphth, UCL Institute of Ophthalmology, Moorfields Eye Hospital

Introduction: Amlexanox is a drug used for treating oral ulcers with dual action of nonsense- mediated decay (NMD) inhibition and translational readthrough. Choroideremia, an X-linked recessive chorioretinal dystrophy, has 30% of cases caused by nonsense mutations. Methods: In the chm-/- zebrafish and CHM patient fibroblasts, the following were undertaken: dose-response experiments, survival studies, histology, cell death assays, qRT-PCR, western blot and functional prenylation assays.

Results: chm-/- zebrafish showed: increased survival of 9.4 days versus 4.8 in untreated (p0.01); 1.8- S fold more mRNA indicating NMD inhibition; 50.6% more REP1 with 66% functionality. Treated aturday S fibroblasts had 1.1-fold more mRNA and 18.8% functionality. Conclusions: Amlexanox was successful at treating choroideremia in two disease models. Repurposing or discovering drugs with combination action of NMD inhibition and translational readthrough may be a more effective approach to treating genetic retinal disease.

14.35 Argus II Retinal Prosthesis System Post-Approval US Cohort 1 Year Outcomes - Alex Yuan, MD, Cole Eye Institute, Cleveland Clinic e Co-Authors: p Aleksandra Rachitskaya, MD, Cleveland Clinic Cole Eye Institute tember 16 Meghan Debenedictis, MGC, Cole Eye, Cleveland Clinic Jessy Dorn, Second Sight Medical Products Hossein Ameri, MD, PhD, USC Roski Eye Institute David Birch, PhD, Retina Foundation of the Southwest Raymond Iezzi, MD, Mayo Health System Allen Ho, MD, Mid Atlantic Retina

Thiran Jayasundera, MD, University of Michigan Kellogg Eye Center Gregg Kokame, MD, Retina Consultants of Hawaii Jennifer Lim, MD, University of Illinois, Eye and Ear Infirmary

Introduction: The Argus II Retinal Prosthesis System is the only approved treatment in the United States for patients with advanced retinitis pigmentosa and bare light perception vision. This prospective post-marketing surveillance study is the first report to evaluate the real world clinical outcomes of Argus II patients in the US. Methods: We analyzed the patient demographic, intraoperative and postoperative serious adverse events (SEAs), and visual function performance including square localization, direction of motion, and grating visual acuity. Results: Twenty-six patients (8 females and 18 males) in the Argus II post-approval study with at least one year of follow up as of October 31, 2016 were included for analysis. Average age at the time of surgery was 64 years old (range: 44-88). There were zero implant failures and zero explants. Five serious adverse events were device- or procedure-related as of October 31, 2016. There was a statistically significant improvement in Square Localization mean error was statistically significantly less with the System ON than when patients used only their residual vision (system OFF) in 45% (3 months), 47% (6 months), and 56% (12 months) of patients. Similarly, Direction of Motion was

better with the System ON than with system OFF in 43% (3 months), 39% (6 months), and 29% (12 months) of patients. In the implanted eye, 14%-23% of patients had logMAR vision better than 2.9 with the device ON versus 0% with the device OFF at 3, 6, and 12 months. Conclusions: In a post-approval setting, the Argus II appears to be safe and results in improved visual function in patients with advanced retinitis pigmentosa.

14.45 The Role of Pharma - Aniz Girach

15.00 MEETING CONCLUDES

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OPTIONAL VISIT AND GUIDED TOUR IN THE MEDIEVAL CITY OF YORK

Saturday S e p tember 16

Posters

Poster Author Author First Title Number Last Name Name

THURSDAY

1 Manir Ali Next generation sequencing identifies a novel CPAMD8 mutation in a family with recessively-inherited anterior segment dysgenesis 2 Gavin Arno Whole genome sequencing in inherited retinal dystrophy; harvesting the high- hanging fruit

3 Rola Ba-Abbad Multimodal imaging in patients with LCHADD suggests a primary RPE degeneration

4 Irina Balikova Microcoria due to a duplication at a chromosome 13q32 and maternal mosaicism

5 Cagri Besirli Ocular Complications of Stickler Syndrome Associated with Known and Novel COL2A1 Mutations

6 Diogo Bitoque In vitro tools to model Retinitis Pigmentosa

7 Choi Mun Chan A family with Maternally Inherited Diabetes and Deafness (MIDD) from Singapore

8 Yanmei Chen Widespread reticular drusen as a presenting feature of Late Onset Retinal Degeneration (LORD)

9 Tillie Chiu Effectiveness of genetic testing for ocular conditions; a two-year review.

10 Maria Cross EyeDraw Pedigree: a novel open source clinical genetics application

11 Erica di Martino Unravelling the genetic basis of keratoconus

12 Mohammed Elasrag The Second Reported Missense Mutation of EFEMP1 Causing Autosomal Recessive Leber Congenital Amaurosis

13 Nervine ElMeshad Modeling human mutations in pre-mRNA processing factors in retinal cell lines

14 Ana Fakin USH2A patient presenting with cone-rod dystrophy and double hyperautofluorescent rings

15 Carol Gardiner The role of a multidisciplinary Ophthalmology-Genetics Clinic in improving clinical and molecular diagnosis of single gene eye disorders in the West of Scotland 16 Christina Gerth-Kahlert Phenotype-genotype analysis in a family with MCOR

17 Anne-Marie Hinds A Case of exudative vitreoretinopathy and chorioretinal coloboma associated with microcephaly in a female with contiguous Xp11.3-11.4 deletion 18 Emma Lord Whole genome sequencing reveals missing structural mutations in SLC38A8 in patients with nystagmus, foveal hypoplasia and optic nerve decussation defects. 19 Gabrielle Wheway A novel hypothesis for the role of pre- mRNA processing factors in retinitis pigmentosa

FRIDAY

20 Sarah Hull Whole genome sequencing in the molecular diagnosis of familial exudative vitreoretinopathy and microcephaly

21 Hiroyuki Kondo Mutations of Wnt signalling genes in patients with FEVR-associated rhegmatogenous retinal detachments

22 Kentaro Kurata Long-Term Clinical Course in a Patient with Complete Congenital Stationary Night Blindness

23 Alex Levin Optical Coherence Tomography in Knobloch Syndrome

24 David Maskill A novel ATOH7 mutation causes recessively-inherited primary fetal vasculature in an Egyptian family

25 Martin McKibbin Retinal vascular calibre and tortuosity in inherited retinal disease

26 Andreas Mitsios Phenotyping of choroideremia carriers, including use of a portable electroretinogram recording device.

27 Ken K. Nischal Intact Iris, Pyramidal Cataracts, and Nystagmus: A Novel Phenotype Associated with PAX6 Missense Variants

28 Charlotte Onsiong Investigating the frequency of myocilin mutations in local patients with a diagnosis of primary open angle glaucoma

29 James Poulter Use of clinical exome sequencing to diagnose inherited retinal dystrophy cases in Yorkshire

30 Hannah Scanga Vertical Nystagmus in Siblings with Autosomal Recessive Congenital Stationary Night Blindness: A Rare Presentation with Novel Mutations 31 Hannah Scanga Iris Flocculi and Congenital Mydriasis: When to Test for ACTA2 Mutations?

32 Panagiotis Sergouniotis Multigene panel testing in 85 consecutive children with inherited retinal disease.

33 Mital Shah Phenotype based panel testing in Inherited Retinal Dystrophies

34 Morag Shanks The incidence and spectrum of copy number variants (CNVs) in a diagnostic inherited retinal degeneration cohort

35 Claire Smith Sequence analysis of 108 genes associated with non-syndromic inherited retinal dystrophies in 302 individuals using molecular inversion probes. 36 Joanne Topping Identification of novel mutations in COL4A1 in patients presenting with familial retinal arteriolar tortuosity (fRAT)

37 Tatyana Vasilyeva A recurrent character and a high frequency of 11p13 deletion affecting PAX6 downstream regulatory regions in aniridia patients from Russia 38 Nutsuchar Wangtiraumnuay Bioinformatic Analysis of ABCA4 in Ocular Genetic Disease

Poster Abstracts Poster 1

Next Generation Sequencing Identifies a Novel CPAMD8 Mutation In a Family With Recessively-Inherited Anterior Segment Dysgenesis - Manir Ali, MD, University of Leeds Co-Authors: Kamron Khan, PhD, FRCOphth, The Eye Department, St. James University Hospital, Leeds James Poulter, PhD, Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds Martin McKibbin, FRCOphth, The Eye Department, St. James University Hospital, Leeds

Introduction: Anterior segment dysgenesis (ASD) describes a heterogeneous group of developmental disorders that affect the structures at the front of the eye including the cornea, iris, ciliary body, lens and trabecular meshwork. We have ascertained a consanguineous. Methods: Whole exome next generation sequencing was performed on genomic DNA of affected cases. Sanger sequencing was used for segregation analysis. Results: A novel homozygous nonsense mutation in CPAMD8 (C3 and PZP like, alpha-2- macroglobulin domain containing 8) (NM_015692; c.3868CT, p.Q1290*) was identified that segregated with disease in the family as expected for a recessively-inherited condition. Conclusions: Recessive CPAMD8 mutations were recently described as causing ASD in a single article which reported five mutations in three families. Here we present the second report of biallelic mutations in CPAMD8 causing an eye disease.

Poster 2

Whole Genome Sequencing In Inherited Retinal Dystrophy; Harvesting The High- HangingFruit - Gavin Arno, PhD, UCL Institute of Ophthalmology Co-Authors: Keren J. Carss, PhD, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK Sarah Hull, FRCOphth, PhD, UCL Institute of Ophthalmology, London, UK; Moorfields Eye Hospital, London, UK Mingchu Xu, BS, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA Rui Chen, PhD, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA Michel Michaelides, MD (Res), FRCOphth, UCL Institute of Ophthalmology, London, UK; Moorfields Eye Hospital, London, UK Anthony T. Moore, MA, FRCOphth, UCL Institute of Ophthalmology, London, UK; Moorfields Eye Hospital, London, UK; Ophthalmology, University of California, San Francisco, USA F. Lucy Raymond, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK Andrew R. Webster, MD, FRCS, FRCOphth, UCL Institute of Ophthalmology & Moorfields Eye Hospital, London, UK

Introduction: Inherited retinal dystrophy (IRD) is a leading cause of blindness encompassing a vastly heterogeneous spectrum of disease at the phenotype, biological pathway, gene and allele levels, making it an ideal disease model for unbiased genomic studies. Methods: We performed whole exome or whole genome sequencing (WES, WGS) on 722 probands with IRD. Rare variant filtering was performed, prioritising variants that affect 224 genes previously associated with IRD in the first instance. Results: Pathogenic IRD gene variants were identified in 404/722 (56%) patients. In 19 novel genes, 16/247 unsolved patients with possible autosomal recessive disease harbored 2 loss of function variants, a subset of which are undergoing functional studies. Conclusions: Many IRD patients are unsolved following IRD gene screening suggesting novel causes of disease exist outside the exons of known genes. WGS permits unbiased interrogation of the complete variome enabling discovery of such novel causes of disease.

Poster 3

Multimodal Imaging In Patients With Lchadd Suggests A Primary Rpe Degeneration - Rola Ba-Abbad, MBBS, FRCS, UCL Institute of Ophthalmology, Hospital for Sick Children & University of Toronto Co-Authors: Ajoy Vincent, MBBS, MS, FICO, Hospital For Sick Children & University of Toronto Katelyn MacNeill, MSc, Hospital For Sick Children Heather MacDonald, MSc, CGC, CCGC, Hospital For Sick Children Elise Heon, MD, FRCSC, Hospital For Sick Children & University of Toronto

Introduction: Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a rare inherited systemic disorder, associated with progressive chorioretinal atrophy. This study describes the features of this retinopathy in two 16-year-old unrelated patients. Methods: Patients, with metabolically confirmed LCHADD, were identified and underwent full ocular examination including visual acuity (VA), visual fields (VF), electroretinography (ERG), optical coherence tomography (OCT), and fundus autofluorescence (FAF). Results: Asymmetrical retinopathy: macular atrophy and reduced FAF were noted. VA: 20/2520/125; VFs: normal or reduced central sensitivity; ERG: mild generalized retinal dysfunction; OCT: outer retinal tubulation and interlaminar bridges. Conclusions: LCHADD retinopathy shows OCT features reminiscent of primary RPE degeneration in choroideremia, gyrate atrophy, RGR retinopathy, and MIDD. There is experimental evidence of primary RPE involvement in LCHADD; possibly an accessible target for therapy.

Poster 4

Microcoria Due To A Duplication At A Chromosome 13Q32 And Maternal Mosaicism - Irina Balikova, MD, Ghent University, Free University of Brussels Co-Authors: Elise Pozza, MD, University Hospital Queen Fabiola, Brussels, Belgium Hanna Verdin, University of Ghent, Ghent, Belgium Bjorn Menten, PhD, University of Ghent, Ghent, Belgium Hilde Deconinck, MD, Cliniques Sud Luxembourg, Luxembourg Lavinia Postolache, MD, University Hospital Queen Fabiola, Brussels, Belgium

Kristof Van Schil, PhD, University of Ghent, Ghent, Belgium Elfride De Baere, MD, PhD, University of Ghent, Ghent, Belgium

Introduction: Microcoria is an eye anomaly characterized by a pupil narrower than 2mm, caused by underdevelopment of the muscle dilator of the pupil. It was shown recently to be caused by microdeletions of chr13q32.1 involving the GPR180 gene. Methods: A girl presented with a blue iris and small pupils nonreactive to cycloplegic drops. Her mother had milder phenotype, namely bleu iris with hypoplastic crypts and mild myopia. The proband was analyzed using array comparative genome hybridization. Results: A small duplication of chromosome 13q32.1 was identified. The duplication has a size of 289kb, encompassing 11 genes including GPR180. This genetic anomaly was inherited from the mother, carrier of the duplication in a mosaic form. Conclusions: We describe a duplication on chromosome 13q32.1 causing microcoria. Interestingly, the patient has the same phenotype as the carriers of the reciprocal deletion. We show also the presence of parental mosaicism, important for the genetic counselling.

Poster 5

Ocular Complications Of Stickler Syndrome Associated With Known And Novel Col2A1 Mutations - Cagri Besirli, University of Michigan Co-Authors: Thomas Wubben, MD/PhD, University of Michigan Brenda Bohnsack, MD/PhD, University of Michigan Kari Branham, MS, CGC, University of Michigan

Introduction: To investigate genetic findings, ocular manifestations, and surgical outcome, we conducted a retrospective, single-center, case series of patients with Stickler syndrome. Methods: Data collection included demographic information, family history, genetic mutations, visual acuity, refractive error, systemic and ocular manifestations, surgical interventions, and surgical outcomes. Results: We identified three novel mutations in the COL2A1 gene associated with Stickler syndrome. Our study highlights the risk of retinal detachment and glaucoma in patients with Stickler syndrome and the poor outcomes notwithstanding surgical intervention. Conclusions: This investigation emphasizes the importance of recognizing the ocular complications of Stickler syndrome and its therapeutic challenges. A multidisciplinary approach should be utilized for optimal management of these patients.

Poster 6

In Vitro Tools To Model Retinitis Pigmentosa - Diogo Bitoque, Msc, CEDOC/NMS, Cedoc/NMS New University of Lisbon Co-Authors: Daniela Santos, Msc, CEDOC/NMS Rute Araújo, Msc, CEDOC/NMS Gabriela Silva, PhD, CEDOC/NMS

Introduction: The disease mechanism in the rd10 mouse, a model for Retinitis Pigmentosa, is still

52 poorly understood. We have established new genetic tools for its study and to design new therapeutic approaches. Methods: We cloned the PDE6ß gene in a pEPito-hCMV plasmid and recreated the mutation present in rd10 mice using site-directed mutagenesis, confirmed by Sanger sequencing and immunoblotting. Results: Site directed mutagenesis reflecting rd10 genotype changes arginine to cysteine, leading to protein misfolding. This most likely affects the catalytic domain of PDE6ß, preventing its binding to cGMP. Conclusions: We have created tools to further study the disease mechanism and enhance the development of new interventional therapies for Retinitis Pigmentosa.

Poster 7

A Family With Maternally Inherited Diabetes And Deafness (MIDD) From Singapore - Choi Mun Chan, MD, Singapore National Eye Centre Co-Authors: Sures Rama Chandran, FRCP, Singapore General Hospital Daphne Gardner, FRCP, Singapore General Hospital

Introduction: Monogenic diabetes accounts for 1% of adult diabetes(DM). Confirming the diagnosis by genetic testing allows therapy modification and offers screening for family. Aim: To report the first family with maternally inherited diabetes and deafness (MIDD). Methods: A 52 year-old Chinese diabetic with features typical of MIDD underwent genetic testing. She had diabetic ketoacidosis; weighed 30.9kg; had deafness and DM since 28 years; and cardiomopathy. Her HbA1c averaged 7%. She had bilateral macular dystrophy. Results: MIDD genetic testing was performed using the TaqMan genotyping assay (Exeter, UK), confirming a substitution of A to G at position 3243 of the mitochondrial genome. Conclusions: Mitochondrial genome is entirely maternally inherited, so all maternal family members were offered genetic testing. This illustrates the importance of attributing diabetes aetiology accurately since it affects therapy and risk stratification.

Poster 8

Widespread Reticular Drusen As A Presenting Feature Of Late Onset Retinal Degeneration (LORD) - Yanmei Chen, MD, Sunderland Eye Infirmary Co-Authors: Ajay, Kotagiri, FRCOphth, Sunderland Eye Infirmary

Introduction: Late onset retinal degeneration (LORD) is an autosomal dominant condition characterised by long anteriorly inserted zonules and retinal pigment epithelium (RPE) atrophy. We describe three patients with severe reticular drusen as a presenting feature. Methods: Patients presented to Sunderland Eye Infirmary with nyctalopia and widespread reticular drusen. They underwent clinical assessment, multimodal imaging, electro-diagnostics and molecular testing for LORD. Results: All patients had strong family history of blindness in the fifth decade. Their RPE atrophic changes ranged from minimal and widespread. Electro-diagnostics showed rod cone dystrophy, and molecular testing revealed C1QTNF5 mutation, confirming LORD.

Conclusions: This series highlights widespread reticular drusen as a presenting phenotypic feature of LORD, before typical temporal RPE atrophy becomes apparent. Differential diagnoses include macular degeneration and dominant drusen, carrying varied prognosis.

Poster 9

Effectiveness Of Genetic Testing For Ocular Conditions; A Two-Year Review - Tillie Chiu, MSc, CHEO Genetics Co-Authors: Alexa Ehlebracht, CHEO Genetics Gail Graham, MD, MSc, CHEO Genetics

Introduction: The Children’s Hospital of Eastern Ontario Regional Genetics Program provides genetics services for a population of approximately 1.4 million. We cover a large geographical area including Eastern Ontario, Western Quebec, and Nunavut, and see 5000-6000 patients per year for a wide range of indications. Until May 2015, one clinical geneticist (GG) was seeing all Ocular Genetics referrals as part of her clinical caseload. Due to increasing demand, a subspecialty Ocular team was created and a genetic counsellor (TC) was recruited to see patients who were unlikely to need a physical exam or already had a clinical diagnosis from an eye specialist. The purpose of this study was to review Ocular Genetics patients to determine referral indications and diagnostic yield for this population. Methods: We undertook a chart review of Ocular Genetics patients seen from May 1, 2015 to April 30, 2017 and noted the reason for referral, whether the patient was affected or referred for a family history of an ocular condition, whether genetic testing was offered, and the results of the testing. Results: A total of 98 patients were seen by the Ocular Genetics team in the two-year review period (33 GC & 65 MD cases). Eighty-four affected patients and 14 individuals with a family history of an ocular condition were seen. Retinitis pigmentosa, cone-rod dystrophy, and oculocutaneous/ocular albinism were the most common indications of the >20 referral types we received. Of 84 affected individuals, 75 (89%) decided to pursue genetic testing and 43 (57%) received a positive (pathogenic) genetic testing result. Conclusions: Ocular Genetics referrals cover a wide range of conditions but over half of the patients were referred for our top three indications. The vast majority of affected individuals opted to have genetic testing and the diagnostic yield for these patients was 57%, within the 51-70% rate seen in other studies. Our experience speaks to the advantages of having one geneticist and one genetic counsellor serving the Ocular Genetics patients in order to develop expertise and to become familiar with increasingly diverse testing options. With increasing exposure to oculogenetic conditions, the GC has been able to expand the number of indications assigned to her.

Poster 10

Eyedraw Pedigree: A Novel Open Source Clinical Genetics Application Maria Cross, University College London Co-Authors: Robert, Henderson, MD FRCOphth, Great Ormond Street Hospital for Children George, Aylward, MD FRCS, Moorfields Eye Hospital Jugnoo, Rahi, PhD FRCOphth, UCL GOS Institute of Child Health

Introduction: With the rise of personalised medicine, pedigree drawing has become integral to patient care, but robust tools are lacking. We aimed to develop and test an open source pedigree drawing tool that is appropriate for use within patient consultations. Methods: A novel web-based application was developed utilising HTML5, JavaScript and open source software (OpenEyes Foundation). A retrospective medical record review was performed identifying pedigrees from notes, and used to test application performance. Results: 48 pedigrees (range 3-33 members, 2-5 generations) were tested. One with multiple consanguineous loops had a high degree of line crossing; 47 could be drawn easily including complex features (multiple mates, consanguinity, multiple descent lines). Conclusions: Further development is needed, but the EyeDraw Pedigree tool is suited to the majority of small but potentially complex pedigrees encountered during clinical ophthalmic consultation.

Poster 11

Unravelling The Genetic Basis Of Keratoconus - Erica Di Martino, MD, University of Leeds Co-Authors: Erica Di Martino, PhD, University of Leeds, UK Layal Abi Farraj, PhD, University of Leeds, UK Salina Siddiqui, Leeds Teaching Hospital NHS Trust, UK Aine Rice, East Kent Hospitals University NHS Trust, UK Gretta Abou Sleymane, American University of Science and Technology, Lebanon Carmel Toomes, PhD, University of Leeds, UK Chris Inglehearn, PhD, University of Leeds, UK Manir Ali, PhD, University of Leeds, UK

Introduction: Keratoconus (KC) is an early on-set and progressive degenerative corneal disease. Higher frequencies in endogamous populations, familiarity, concordance in monozygotic twins, and association with genetic syndromes suggest a strong genetic aetiology. Dominant, recessive, X-linked and atypical modes of inheritance have been suggested. The purpose of this investigation is to clarify the genetic basis of KC. Methods: DNA was collected from familial and sporadic KC cases of Pakistani, Indian, Lebanese, Iranian, South Arabic and Belgian origin. Whole exome sequencing (WES) was performed to identify rare genetic variants (MAF < 2%) segregating with KC. Dominant, recessive, and biallelic modes of inheritance were tested. Results: A large number of novel rare genetic variants were identified in KC patients. Variants in genes previously reported as associated with KC (FLG, IL1A, IL1RN, COL4A3, COL5A1, DOCK9, ZNF469, LOX, ZEB1, XRCC1, HGF, CDH11) were also found in some of the cases. Conclusions: Our data suggest that KC is a complex disease with a polygenic origin.

Poster 12

The Second Reported Missense Mutation Of EFEMP1 Causing Autosomal Recessive Leber Congenital Amaurosisb - Mohammed El-Asrag, PhD, Section of Ophthalmology & Neuroscience, Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, United Kingdom \ Department of Zoology, Faculty of Science, Benha University, Benha, Egypt

Co-Authors: Martin McKibbin, The Eye Department, St. Jamess University Hospital, Leeds, UK Moin D. Mohamed, Section of Ophthalmology & Neuroscience, Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, United Kingdom Carmel Toomes, Section of Ophthalmology & Neuroscience, Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, United Kingdom Chris F. Inglehearn, Section of Ophthalmology & Neuroscience, Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, United Kingdom Manir Ali, Section of Ophthalmology & Neuroscience, Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, United Kingdom

Introduction: Purpose. To identify the disease-causing mutation in a consanguineous Pakistani family of four siblings affected with autosomal recessive non-syndromic Leber congenital amaurosis (LCA)/early-onset retinitis pigmentosa (EORP). Methods: DNA from affected members of family MEP58 family were subject to SNP chip genotyping, homozygosity mapping and whole-exome sequencing. Sanger sequencing was used to confirm mutations which were also screened for in ethnically matched control DNAs. The programme TASSER was used to predict effect on for protein structure and function. Results: A combination of homozygosity mapping in two of the siblings and WES the remaining two identified a novel missense mutation in EFEMP1 (NM_001039349:exon8:c.A924C:p.Q308H). Segregation analysis confirmed that this variant is the cause of disease symptoms in this family. This mutation was absent in both 154 ethnically matched control DNAs and in 138,632 subjects on the gnomAD database. Parents showed a mild carrier phenotype. Conclusions: The novel mutation described in this study is the second mutation identified for EFEMP1, expanding the mutational spectrum of this gene. It is also the second reported case of recessive inheritance of EFEMP1-related retinopathy.

Poster 13

Modelling human RP mutations in pre-mRNA processing factors in retinal cell lines - Nervine Meshad, MBChB, MD, FRCS, Bristol Eye Hospital, University Hospitals Bristol NHS Foundation Trust Co-Authors: Asmaa Ghazwani, Centre for Research in Biosciences, University of the West of England, Bristol Joyan Simon-Fletcher, Centre for Research in Biosciences, University of the West of England, Bristol Joshua Vaughan, Centre for Research in Biosciences, University of the West of England, Bristol Man-Kim Cheung, PhD, Centre for Research in Biosciences, University of the West of England, Bristol Amanda Churchill BSc, MBChB, PhD, FRCOphth, Bristol Eye Hospital, University Hospitals Bristol NHS Foundation Trust Gabrielle Wheway PhD, PGCertHE, FHEA, Centre for Research in Biosciences, University of the West of England, Bristol

Introduction: To further understand the role of pre-mRNA processing factors mutated in human patients with autosomal dominant retinitis pigmentosa (adRP), specifically investigating the functions of these proteins outside of the nucleus, building on previous work linking these proteins

56 to primary cilia. Methods: CRISPR/Cas9 genome editing will be used to introduce human RP-associated mutations in PRPF6, PRPF8 and PRPF31 in retinal pigment epithelial and photoreceptor cell lines to study the cell biology of this disease. Dual nickase approach will be attempted to introduce knock-ins with lower off-target effects than WT Cas9 approach. Results: We have characterized the cell lines for this study, and cloned constructs encoding paired guide RNAs to target PRPF6 c.2185C>T, PRPF8 c.6353C>T, c.6901C>A/T, PRPF31 c.581C>A and c.646G>C in human RPE1 cells. Conclusions: Production of retinal cell lines with monoallelic mutations in PRPF6, 8 and 31 will provide useful, accurate cell models of human adRP, to allow further elucidation of the molecular mechanism of this disease. It is hoped that this will lead to identification of pathways of disease, which can be targeted for therapy.

Poster 14

USH2A Patient Presenting With Cone-Rod Dystrophy And Double Hyperautofluorescent Rings - Ana Fakin, MD, PhD, Eye Hospital, University Medical Centre Ljubljana; UCL Institute of Ophthalmology; Moorfields Eye Hospital, London, UK Co-Authors: Maja Utar, PhD, Eye Hospital, University Medical Centre Ljubljana Jelka Brecelj, PhD, Eye Hospital, University Medical Centre Ljubljana Crystel Bonnet, PhD, Institut de la Vision, UMRS 1120 INSERM/UPMC,Paris, France Christine Petit, MD, PhD, Institut de la Vision, UMRS 1120 INSERM/UPMC, Paris, France; Institut Pasteur, Collège de France, Paris, France; College de France, 75005 Paris, France Andrej Zupan, PhD Department of Molecular Genetics, Institute of Pathology, University of Ljubljana, Korytkova 2, Ljubljana Damjan Glavac, PhD, Department of Molecular Genetics, Institute of Pathology, University of Ljubljana, Korytkova 2, Ljubljana Martina Jarc-Vidmar, MD, PhD, Eye Hospital, University Medical Centre Ljubljana Saba Battelino, MD, PhD, Department of Otorhinolaryngology and Cervicofacial Surgery, University Medical Centre Ljubljana, Zaloka 2, University of Ljubljana, Ljubljana, Slovenia Marko Hawlina, MD, PhD, Eye Hospital, University Medical Centre Ljubljana

Introduction: USH2A mutations are known to cause isolated retinitis pigmentosa (RP) and Usher syndrome type 2 (USH2). We present a patient with mutations in USH2A exhibiting cone-rod dystrophy and double hyperautofluoresent rings, a novel phenotype. Methods: The patient (female, 61 y) was identified from a cohort of patients with double hyperautofluorescent rings on fundus autofluorescence (FAF), who underwent USH2A screen due to observation of this phenotype in two USH2A RP patients. Full-field electroretinography, visual fields, and optical coherence tomography (OCT) were performed. Results: Patient harbored p.Trp3955Ter and p.Gly56Arg in USH2A. Double hyperautofluorescent rings (partial in one eye) were seen on FAF. Preserved retinal structure and function was noted outside the rings. Greater loss of cone than rod function was noted on electroretinography. Conclusions: The cone-rod phenotype of this USH2A patient is atypical and expands the phenotypic spectrum of USH2A-retinopathy. Hence, USH2A mutations should be considered in cone-rod dystrophy patients exhibiting FAF patterns of hyperautofluorescent rings with preserved fovea.

Poster 15

The Role Of A Multidisciplinary Ophthalmology-Genetics Clinic In Improving Clinical And Molecular Diagnosis Of Single Gene Eye Disorders In The West Of Scotland - Carol Gardiner, MD, West of Scotland Clinical Genetics Service Co-Authors: Daniela Pilz, Consultant in Clinical Genetics, West of Scotland Genetics Service, Glasgow David Gilmour, Consultant Ophthalmologist, Gartnavel General Hospital, Glasgow Pedro Gonzalez, Consultant Paediatric Ophthalmologist, Royal Hospital for Children, Glasgow Anne McQuiston, Senior Electrophysiologist, Centre for Ophthalmic Research, Glasgow Sinead Walker, Principle Clinical Scientist, Centre for Ophthalmic Research, Glasgow Ruth Begbie, Medical Student, Glasgow University Sarah Wedderburn, ST4 Clinical Genetics, West of Scotland Genetics Service, Glasgow Ashleigh Mellors, Specialist Orthoptist, Gartnavel General Hospital, Glasgow Stuart Parks, Consultant Clinical Scientist, Centre for Ophthalmic Research, Glasgow

Introduction: To optimise the use of molecular genetic testing in single gene eye disorders, a monthly multi-disciplinary ophthalmology clinic was instituted in Glasgow for both adults and children in 2014 involving Ophthalmologists, Clinical Geneticists, Clinical Scientists and Optometrists. The joint clinics are an efficient and effective option for patients, as they see both Ophthalmologists and Clinical Geneticists in one clinic appointment. Specialists also learn from each other, optimising patient care and management. Patients are asked to agree to have their clinical and molecular results stored on a database, allowing them to be informed about relevant research studies. Methods: Two audits have been performed, using the same audit proforma, collecting data on reason for referral, the referrer, the tests performed and their results, diagnosis after clinical review, and type of molecular test and diagnostic pick up rate. Results: Two hundred and twenty four patients have been seen in total in the two audit periods (01/04/2014-31/12/2015 and 01/01/2016-31/12/2016)- 92 adult and 132 paediatric patients. After phenotyping, over 65% of the patients, who had retinal dystrophy had a pathogenic mutation using a retinal dystrophy panel had a molecular diagnosis, and over 70% of the patients with a clinical diagnosis of macular dystrophy. These results will be discussed in more detail. Conclusions: In the West of Scotland, the multi-disciplinary approach to the clinical and molecular diagnosis of single gene eye disorders has been shown to a good model with a high concordance of clinical and molecular phenotypes. Patients have valued the one-stop clinic as an effective model for communication and management.

Poster 16

Phenotype-Genotype Analysis In A Family With MCOR - Christina Gerth-Kahlert, MD, Department of Ophthalmology, University Hospital Zurich, Zurich, Switzerland Co-Authors: Marc Töteberg-Harms, MD, Department of Ophthalmology, University Hospital Zurich, Zurich, Switzerland Samuel Koller, PhD, Institute of Medical Molecular Genetics, University of Zürich, Schlieren, Switzerland Jordi Maggi, PhD, Institute of Medical Molecular Genetics, University of Zürich, Schlieren,

Switzerland Amit Tiwari, PhD, Institute of Medical Molecular Genetics, University of Zürich, Schlieren, Switzerland Birgit Budde, PhD,Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany Peter Nürnberg, PhD, Institute of Medical Molecular Genetics, University of Zürich, Schlieren, Switzerland Wolfgang Berger, PhD, Institute of Medical Molecular Genetics and Zurich Center for Integrative Human Physiology (ZIHP), University of Zürich, Schlieren, Switzerland; Neuroscience Center Zurich (ZNZ), University and ETH Zürich, Zürich, Switzerland

Introduction: Congenital microcoria (MCOR) is an anterior segment disorder with only few cases described in the literature. Here, we report the detailed anterior segment phenotype associated with MCOR in a family. Methods: Phenotype analysis: dilated eye examination, anterior segment SD-OCT. Genotype analysis: aCGH, WES, deletion breakpoint mapping by conventional and long range PCR and Sanger sequencing of the junction fragments. Results: Phenotype: congenital small, non-dilating pupil, VA 0.1 to 0.6, iris thinning with transillumination, no goniodysgenesis, no glaucoma, high myopia. Genotype: heterozygous deletion on 13q32.1 including TGDS and GPR180. Conclusions: The MCOR phenotype in this family is milder without goniodysgenesis or developmental glaucoma compared with the reported cases. Genotype analysis confirmed the newly identified deletion.

Poster 17

A Case Of Exudative Vitreoretinopathy And Chorioretinal Coloboma Associated With Microcephaly In A Female With Contiguous Xp11.3-11.4 Deletion - Anne-Marie Hinds, Royal London Hospital Co-Authors: Elisabeth Rosser, MBBS FRCP, Royal London Hospital M. Ashwin Reddy, MD FRCOphth, Royal London Hospital

Introduction: To report a case of microcephaly, bilateral colobomata and exudative vitreoretinopathy (EVR) in an infant due, not to KIF11 mutation, but to a contiguous gene deletion on chromosome Xp. Methods: Ophthalmic examination of a 4 day old South Asian girl with microcephaly found inferior chorioretinal colobomata, peripheral avascular retina and exudation. Exudation resolved following diode laser and the retina remained flat. Results: Genome wide array analysis using Affymetrix 750K indicated a copy number loss: Xp11.4p11.3(41,125,680-45,050,380)x1, a deletion of 3.9Mb. Deletion of this region includes the OMIM morbid genes CASK and NDP, among others. Conclusions: Norrie disease may affect girls due to Lyonisation. It is known to be associated with EVR and microcephaly but not coloboma, whilst CASK deletion is. This case shows genetic heterogeneity for the constellation of microcephaly, coloboma and EVR.

Poster 18

Whole Genome Sequencing Reveals Missing Structural Mutations In SLC38A8 In Patients With Nystagmus, Foveal Hypoplasia And Optic Nerve Decussation Defects - Emma Lord, Section of Ophthalmology and Neuroscience, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK Co-Authors: James A. Poulter, PhD, The University of Leeds Andrew R. Webster, MD, UCL Panagiotis I. Sergouniotis, MD, The University of Manchester Kamron Khan, MD, The University of Leeds UK Inherited Disease Consortium Manir Ali, PhD, The University of Leeds Chris Inglehearn, PhD, The University of Leeds Carmel Toomes, PhD, The University of Leeds

Introduction: Foveal hypoplasia with optic nerve decussation defects in the absence of albinism (FHONDA) is a rare recessive disorder which presents with congenital nystagmus. To date, only mutations in SLC38A8 have been reported to underlie this phenotype, however, many patients do not have detectable mutations. The aim of this study was to genetically analyse a cohort of FHONDA patients using next generation sequencing technologies to look for missing SLC38A8 mutations. Methods: Whole exome sequencing (WES) or whole genome sequencing (WGS) was performed on patient DNA. ExomeDepth, BreakDancer and Delly2 were used to look for copy number variation or structural rearrangements. Results: Patient I is a 22 year-old female with foveal hypoplasia, chiasmal misrouting and mild nystagmus with a large region of homozygosity spanning SLC38A8. WGS identified a homozygous structural inversion of exons 6, 7 and 8 of SLC38A8, g.84015974_84027074inv. Patient II is an 11 year-old consanguineous female with foveal hypoplasia, chiasmal misrouting and nystagmus. WES and subsequent ExomeDepth analysis revealed a homozygous duplication in exons 6 and 7 of SLC38A8, but the breakpoints were not defined. Conclusions: This is the first study to characterize large structural mutations in SLC38A8 and highlights the need to perform WGS before excluding mutations in this gene in patients with FHONDA syndrome.

Poster 19

A Novel Hypothesis For The Role Of Pre-Mrna Processing Factors In Retinitis Pigmentosa - Gabrielle Wheway, PhD, PGCertHE, FHEA, University of The West of England

Introduction: A hypothesis-neutral approach was taken to identify all genes in the entire genome with a function in the process of ciliogenesis (formation of the primary cilium, including the photoreceptor outer segment). Methods: A whole genome siRNA knockdown screen was carried out in a ciliated cell line to identify all genes involved in ciliogenesis, using high-throughput imaging to identify cells with a loss of cilia phenotype. Results: Many genes involved in splicing, including the pre-mRNA processing factors PRPF6, 8 &

31 which are mutated in retinitis pigmentosa (RP) patients, were found to localize to the base of retinal photoreceptor cells & cause loss of cilia upon knockdown. Conclusions: These findings suggest that pre-mRNA processing factors may have a role beyond splicing & that this role is important for formation and maintenance of photoreceptors, providing a novel hypothesis for the molecular aetiology of this form of RP.

Poster 20

Whole Genome Sequencing In The Molecular Diagnosis Of Familial Exudative Vitreoretinopathy And Microcephaly - Sarah Hull, FRCOphth, PhD,, UCL Institute of Ophthalmology & Moorfields Eye Hospital, London Co-Authors: Gavin Arno, UCL Institute of Ophthalmology & Moorfields Eye Hospital, London Pia Ostergaard, PhD, Human Genetics Research Centre, Biomedical Sciences, St George's University of London Andrew Webster, UCL Institute of Ophthalmology & Moorfields Eye Hospital, London Sahar Mansour, FRCP, South West Thames Regional Genetics Service, St George's Healthcare NHS Trust, London Anthony Moore, FRCOphth, UCL Institute of Ophthalmology & Moorfields Eye Hospital, London and Ophthalmology, University of California, San Francisco Michel Michaelides, MD(Res), UCL Institute of Ophthalmology & Moorfields Eye Hospital, London

Introduction: Familial exudative vitreoretinopathy (FEVR) associated with microcephaly is rarely reported. A group of ten families were presented at ISGEDR 2015 in whom four had a molecular diagnosis. Five families subsequently underwent whole-genome sequencing. Methods: Twelve patients from ten families with a diagnosis of FEVR and microcephaly underwent a full clinical assessment including retinal imaging. Molecular investigations included candidate gene Sanger sequencing, whole-exome and whole-genome sequencing. Results: Initial investigations identified variants in KIF11 (two families), TUBGCP6 and LRP5. Whole-genome sequencing identified two deletions in KIF11 and one variant in LRP5 not identified by Sanger sequencing. Three families remain unsolved. Conclusions: Whole genome analysis enabled molecular diagnosis in 3 families after prior negative Sanger sequencing of the causative gene, enabling patient specific care with targeted investigations and accurate family counseling.

Poster 21

Mutations Of Wnt Signaling Genes In Patients With FEVR-Associated Rhegmatogenous Retinal Detachments - Hiroyuki Kondo, MD, University of Occupational and Environmental Health, Japan Co-Authors: Kazuma Oku, MD, Department Ophthalmology University of Occupational and Environmental Health, Japan Toshiaki Asano, MD, Department Ophthalmology University of Occupational and Environmental Health, Japan

Eiichi Uchio, MD, Fukuoka Univserity Takaaki Hayashi, MD, Jikei University Shunji Kusaka, MD, Kindai University Sakai Hospital

Introduction: To search for mutations in the Wnt signaling genes in patients with familial exudative vitreoretinopathy-associated rhegmatongenous retinal detachment (FEVR-RRD) that is uncommon in Western populations but is prevalent in Asians. Methods: Sanger sequencing for Wnt signaling genes known to cause FEVR and/or exome sequence was performed on 25 patients with FEVR-RRD. The clinical characteristics were determined for the patients who had gene mutations. Results: Eleven patients (44%) had 10 different FEVR-causing heterozygous mutations in FZD4, TSPAN12, LRP5, NDP, or CTNNB1. Eyes with mutations showed typical stage 1 phenotype of incomplete vascularization in the peripheral retina associated with the RRD. Conclusions: FEVR-RRD can be caused by mutations in the Wnt signaling genes. There was not a specific mutation spectrum, which can explain the prevalence of RRD in the Asian populations. Other genetic modifiers possibly predispose Asians to RRD.

Poster 22

Long-Term Clinical Course In A Patient With Complete Congenital Stationary Night Blindness - Kentaro Kurata, Department of Ophthalmology, Hamamatsu University School of Medicine Co-Authors: Katsuhiro, Hosono, PhD, Department of Ophthalmology, Hamamatsu University School of Medicine Yoshihiro, Hotta, MD, Department of Ophthalmology, Hamamatsu University School of Medicine

Introduction: The purpose of this study is to assess the long-term clinical course in a 45-year-old man with complete congenital stationary night blindness (CSNB1) who has been followed up for 38 years. Methods: Best corrected visual acuity (BCVA), refractive error, appearance of the fundus as well as electroretinograms and various waveform components were monitored continuously. Results: BCVA had increased by correcting myopia with glasses. The fundus showed only myopic changes. No changes were seen in the amplitude or implicit time of either the a-wave, b-wave, or b/a-wave ratio. Conclusions: To our knowledge, this is the longest follow-up of a patient with CSNB1. No changes in the clinical course have been seen. These findings may assist with predicting prognosis in patients with CSNB1.

Poster 23

Optical Coherence Tomography In Knobloch Syndrome - Alex Levin, MD, Wills Eye Hospital Co-Authors: Mai Tsukikawa, MD, Pediatric Ophthalmology and Ocular Genetics, Wills Eye Hospital, Philadelphia, Pennsylvania, USA Waleed Abed Alnabi, MD, Pediatric Ophthalmology and Ocular Genetics, Wills Eye Hospital, Philadelphia, Pennsylvania, USA

Nustuchar Wangtiraumnuay, MD, Department of Ophthalmology; Queen Sirikit National Institute of Child Health, Bangkok, Thailand Sulaiman Alsulaiman, MD, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia Murtaza Adam, MD, Pediatric Ophthalmology and Ocular Genetics, Wills Eye Hospital, Philadelphia, Pennsylvania, USA Jenina Capasso, MS, Pediatric Ophthalmology and Ocular Genetics, Wills Eye Hospital, Philadelphia, Pennsylvania, USA Marc Spirn, MD, Pediatric Ophthalmology and Ocular Genetics, Wills Eye Hospital, Philadelphia, Pennsylvania, USA

Introduction: Knobloch syndrome is a genetic disorder classically defined by a triad of occipital defect, high myopia, and vitreo-retinal degeneration. This study aims to describe the optical coherence tomography (OCT) findings in this syndrome. Methods: This retrospective case series reports findings on nine eyes from six patients with a clinical diagnosis of Knobloch syndrome who received OCT testing as part of their clinical care. Three eyes were excluded due to retinal detachments. Results: Mean age 9.1 years (range, 3 months to 39 years). OCT findings include a macular thickness mean of 114.3 microns, thin retinas and poor lamination, RPE atrophy, RP depletion, and a choroidal thickness mean of 168.5 microns. Conclusions: Patients with Knobloch syndrome have characteristic OCT findings, which may aid in diagnosis, understanding of disease process, and have therapeutic implications.

Poster 24

A Novel ATOH7 Mutation Causes Recessively-Inherited Primary Fetal Vasculature In An Egyptian Family - David Maskill, University of Leeds Co-Authors: Ebtesam Abdalla, MD PhD, Department of Human Genetics, Medical Research Institute, Alexandria University, Egypt Karim Nabil, MBBS, Department of Ophthalmology, Faculty of Medicine, Alexandria University, Egypt Manir Ali, PhD, Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds

Introduction: Primary fetal vasculature (PFV), formerly known as persistent hyperplastic primary vitreous, is a vitreoretinopathy in which the hyaloid vasculature fails to regress during eye development. It can be caused by recessive mutations in ATOH7 or NDP. The aim of this work was to investigate the molecular basis of PFV in affected members from three consanguineous families of Egyptian ethnicity. Methods: Microsatellite genotyping was performed on genomic DNA to establish whether the condition was linked. Any linked families were analysed by direct Sanger sequencing of the protein- coding regions and splice recognition signals. Bioinformatics and in silico analysis was used to confirm the pathogenicity of mutations. Results: One of the three families was linked to chromosome 10. Sanger sequencing identified a novel missense mutation in ATOH7, NM_145178; c.254C>T, p.Ala85Val, that segregated with the disease in the family. This mutation which maps to the DNA-binding motif in the protein was

63 predicted as damaging using pathogenicity prediction software. The other two families were not consistent with linkage to ATOH7 or NDP and are therefore candidates for whole exome sequencing. Conclusions: To date, there have been five ATOH7 mutations identified as causing recessive disease in four published reports. Here we describe another report causing recessive disease and the first in patients of Egyptian ethnicity.

Poster 25

Retinal Vascular Calibre And Tortuosity In Inherited Retinal Disease - Martin Mckibbin, FRCOphth, MD, Leeds Teaching Hospitals Nhs Trust Co-Authors: Mike Stockton, Leeds Teaching Hospitals NHS Trust Raj Mukherjee, Leeds Teaching Hospitals NHS Trust Tom MacGillivray, University of Edinburgh Emanuele Trucco, University of Dundee

Introduction: Retinal arterial narrowing is a sign of retinitis pigmentosa (RP) but not of macular dystrophies (MD). Changes in venous calibre and tortuosity have not been investigated. Methods: Arterial and venous calibre and tortuosity were measured in zones B and C of fundus photographs of patients with RP, MD and controls using the VAMPIRE software (v3). Data from 1 eye of each patient was included in inter-group comparison. Results: Median central retinal artery and vein equivalents were significantly less in the 9 RP eyes (18.70 and 32.47 pixels) than in the 10 MD (28.44 and 39.61 pixels) or 20 control eyes (27.09 and 35.34 pixels). Median AVR was also reduced in the RP eyes. Conclusions: Semi-automated imaging of retinal vessels with VAMPIRE software identified differences in arterial and venous calibre in eyes with RP compared to MD and controls. Measurement of vascular calibre may provide a biomarker of photoreceptor activity.

Poster 26

Phenotyping Of Choroideremia Carriers, Including Use Of A Portable Electroretinogram Recording Device - Andreas Mitsios, Moorfields Eye Hospital, UCL Institute of Ophthalmology, London, UK Co-Authors: Alessandro Abbouda, MBBS, Moorfields Eye Hospital and UCL Institute of Ophthalmology, London, UK Omar Mahroo, PhD FRCOphth, Moorfields Eye Hospital and UCL Institute of Ophthalmology, London, UK Adam Dubis, PhD, Moorfields Eye Hospital and UCL Institute of Ophthalmology, London, UK Andrew Webster, MD FRCOphth, Moorfields Eye Hospital and UCL Institute of Ophthalmology, London Mariya Moosajee, PhD FRCOphth, Moorfields Eye Hospital and UCL Institute of Ophthalmology, London

Introduction: To explore aspects of the functional retinal phenotype in choroideremia (CHM) carriers, including use of a handheld, portable electroretinogram (ERG) device to provide rapid

64 assessment of panretinal cone system function. Methods: Participants underwent photopic ERG testing using the RETeval system (LKC Technologies) and psychophysical testing also with the Macular Integrity Assessment (MAIA) system (mesopic, cyan and red stimuli scotopic microperimetry). Results: Five carriers (mean age 52 years; range 30-69) were tested. Areas of scotoma on cyan scotopic microperimetry were seen in 4 subjects. One carrier showed subnormal ERG amplitudes and delayed peak times. Conclusions: Carriers displayed changes consistent with localised rod system dysfunction in cyan scotopic microperimetry, and, in one case, generalised cone system involvement. The portable ERG device was well-tolerated and invites evaluation in a larger study.

Poster 27

Intact Iris, Pyramidal Cataracts, And Nystagmus: A Novel Phenotype Associated With PAX6 Missense Variants - Ken K. Nischal, MD, UPMC Eye Center at Children's Hospital of Pittsburgh of UPMC Co-Authors: Hannah L. Scanga, MS, LCGC - UPMC Eye Center at Children's Hospital of PIttsburgh of UPMC Anagha Medsinge, MD - UPMC Eye Center Smaragda Kamakari, MSc, PhD - OMMA Opthalmological Institute of Athens Eva Gajdosova, MD, PhD - Great Ormond Street Hospital for Children Bharesh Chauhan, PhD - UPMC Eye Center

Introduction: PAX6 mutations are associated with aniridia and, in some, anterior polar cataracts. These cataracts may have a pyramidal morphology. We report three cases of anterior pyramidal cataracts, nystagmus, and irregular astigmatism with PAX6 variants. Methods: Retrospective case review of patients with bilateral anterior pyramidal cataracts was performed. Four female patients were identified and each had undergone complete ophthalmic evaluation and PAX6 analysis. Results: Three patients had bilateral anterior pyramidal cataracts, nystagmus, irregular corneal astigmatism, and intact iris with PAX6 missense variants. A fourth patient had the same findings without nystagmus and a normal PAX6 sequence. Conclusions: While cataracts and nystagmus have been linked to mutations in PAX6, the precise phenotype of nystagmus, anterior pyramidal cataracts, irregular corneal astigmatism, and intact iris has not been described. Such patients undergo PAX6 testing.

Poster 28

Investigating The Frequency Of Myocilin Mutations In Local Patients With A Diagnosis Of Primary Open Angle Glaucoma - Charlotte Onsiong, Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, UK Co-Authors: Salina Siddiqui, PhD FRCOphth, The Eye Department, St. Jamess University Hospital, Leeds Peter Galloway, FRCOphth, The Eye Department, St. Jamess University Hospital, Leeds Mitch Menage, FRCOphth, The Eye Department, St. Jamess University Hospital, Leeds Chris Inglehearn, PhD, Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds

Manir Ali, PhD, Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds

Introduction: Primary open angle glaucoma (POAG) is an adult-onset eye condition that is characterised by high intraocular pressure (IOP) and irreversible optic nerve damage that leads to reduced peripheral vision and eventually blindness if left untreated. It is one of the leading causes of blindness worldwide with a prevalence of 3.5% in the general population of individuals between 40- 80 years old. Though most cases are of unknown aetiology, myocilin (MYOC) mutations are a rare cause of POAG. The aim of this study was to investigate the frequency of MYOC mutations in local patients with a diagnosis of POAG that had been recruited from a West Yorkshire clinic. Methods: Genomic DNA was extracted from peripheral blood leucocytes. PCR and Sanger sequencing was used to analyse the coding regions and splice recognition signals of MYOC. Bioinformatic analysis was used to search for the frequency of mutations in the general population. Results: Of the 176 unrelated patient DNAs that were analysed, four patients (2.3%) had a MYOC mutation that could account for their disease. These 4 patients had the same MYOC mutation (NM_000261; c.1102C>T; p.Q368*) and all had undergone ocular surgery to lower their IOP suggesting that they had severe disease. The p.Q368* mutation was found at 0.1% in the ExAC database. Conclusions: The p.Q368* MYOC mutation accounts for around half of MYOC-glaucoma and has been observed in cases from European, African and South Asian populations. Here we present that only 2.3% of the POAG cohort had MYOC mutations, which is consistent with a previous study in the UK. The patients with MYOC mutations and their families can now receive genetic counselling and individuals carrying the mutation advised to undergo regular ophthalmic testing before disease symptoms arise to allow appropriate management of their condition.

Poster 29

Use of clinical exome sequencing to diagnose inherited retinal dystrophy cases in Yorkshire - James A Poulter, Section of Ophthalmology & Neuroscience, University of Leeds, Leeds, UK.

Co-Authors Kamron Khan1,2,3 Claire E L Smith1 UK Inherited Retinal Disease Consortium Donna Billingham4, Ian Berry4 Raj Mukherjee2 Chris F Inglehearn1 Ruth Charlton4 Martin McKibbin2. 1Section of Ophthalmology & Neuroscience, University of Leeds, Leeds, UK. 2Eye Clinic, St James’ University Hospital, Leeds, UK. 3Moorfields Eye Hospital, London, UK. 4Yorkshire Regional Genetics Service, St James’ University Hospital, Leeds, UK. * E-mail: [email protected]

Purpose: Inherited retinal dystrophies (IRDs) represent a clinically and genetically heterogeneous group of disorders. Identifying the underlying mutation may help with diagnosis, predicting disease

66 progression and guide future care. As additional genetic causes of IRDs are discovered, targeted gene screening becomes increasingly challenging. Here we report the results of clinical exome sequencing in a prospective, consecutive series of 100 patients with IRD. Methods: Venous blood was taken with consent from patients and DNA extracted. Genomic DNA was sequenced using the Focussed Exome, containing approximately 6000 known disease-causing genes. The data was analysed for rare potentially pathogenic variants in >250 genes known to cause non-syndromic and syndromic IRDs. Results: A definitive molecular diagnosis was possible in 55 cases in 35 different genes. USH2A and ABCA4 were the most commonly mutated genes followed by RPGR and PRPH2. For 8 cases, only one of two suspected disease-causing variants were identified, suggesting the second variant was missed with this approach. In 4 cases, only variants of unknown significance were identified, and a confident diagnosis was not made. No potentially pathogenic variants were identified in 33 cases. Conclusions: Clinical exome sequencing appears to be a useful first pass screen for IRDs, enabling a diagnosis in 63% of cases. In 10 cases the results of testing significantly altered clinical management. The use of this specific platform enabled a diagnosis to be made in 10 cases (9 genes) that would have not been detected using a comparable retinal dystrophy panel sequencing approach. Patients with only heterozygous mutations in recessive disease genes are currently undergoing whole genome sequencing. Patients for whom no definitive variants were identified are currently undergoing whole exome or whole genome sequencing by the UK Inherited Retinal Disease Consortium (UKIRDC).

Poster 30

Vertical Nystagmus In Siblings With Autosomal Recessive Congenital Stationary Night Blindness: A Rare Presentation With Novel Mutations - Hannah Scanga, MS, LCGC, UPMC Eye Center at Children's Hospital of Pittsburgh of UPMC Co-Authors: Anagha Medsinge, MD - UPMC Eye Center Valeria Fu, PhD - UPMC Eye Center Christin Sylvester, DO - UPMC Eye Center at Children's Hospital of Pittsburgh of UPMC Ken K. Nischal, MD, FRCOphth - UPMC Eye Center at Children's Hospital of Pittsburgh of UPMC

Introduction: CSNB is a retinal disorder characterized by nyctalopia, myopia, reduced vision, strabismus, and nystagmus. Vertical nystagmus is very rarely seen in CSNB. We report siblings presenting with vertical nystagmus and novel mutations in the TRPM1 gene. Methods: Retrospective observational case study of three siblings, one female and two males. The patients underwent complete ophthalmology evaluation, genetic counseling, and genetic testing. Electroretinogram studies were performed per the ISCEV protocol. Results: Three siblings, one female and two males, were evaluated for nystagmus. Clinical features were consistent with CSNB and ERG showed a negative profile with reduced b/a ratio in all. Genetic testing revealed three novel missense variants in TRMP1. Conclusions: This is the first report of CSNB with novel mutations in TRPM1 presenting with vertical nystagmus. Retinal pathology should be ruled out by electrodiagnostics in any child presenting with congenital nystagmus, irrespective of the type of nystagmus.

Poster 31

Iris Flocculi And Congenital Mydriasis: When To Test For ACTA2 Mutations? - Hannah Scanga, MS, LCGC, UPMC Eye Center at Children's Hospital of Pittsburgh of UPMC Co-Authors: Christin Sylvester, DO - UPMC Eye Center at Children's Hospital of Pittsburgh of UPMC Ellen Mitchell, MD - UPMC Eye Center at Children's Hospital of Pittsburgh of UPMC Ken K. Nischal, MD, FRCOphth - UPMC Eye Center at Children's Hospital of Pittsburgh of UPMC

Introduction: Mutations of ACTA2 are associated with several systemic conditions with various iris abnormalities including congenital mydriasis, flocculi, and persistent pupillary membrane. Herein we describe the clinical and genetic findings of 23 patients. Methods: Retrospective review of patients presenting with mydrasis, iris flocculi, andor persistent pupillary membrane. 23 patients underwent complete ophthalmic evaluation and genetic counseling. Cardiology evaluation and ACTA2 testing were offered to all. Results: Of 23 cases, 16 had iris flocculi, 6 had persistent pupillary membranes, and 3 had congenital mydraisis. Systemic findings were identified in 5 cases. ACTA2 analysis was performed in 14 cases and a mutation was identified in two systemic cases. Conclusions: This series suggests that patients presenting with congenital mydrasis or iris flocculi with systemic findings should offered ACTA2 testing, while genetic testing or cardiac evaluation may not be worthwhile in cases of isolated iris flocculi.

Poster 32

Multigene Panel Testing In 85 Consecutive Children With Inherited Retinal Disease - Panagiotis Sergouniotis, MD, Central Manchester University Hospitals & University of Manchester Co-Authors: Rachel Taylor, PhD, Central Manchester University Hospitals & University of Manchester Neil Parry, PhD, Central Manchester University Hospitals & University of Manchester Stephanie Barton, BSc, Central Manchester University Hospitals Georgina Hall, MSc, Central Manchester University Hospitals & University of Manchester Simon, Ramsden, PhD, Central Manchester University Hospitals Jill, Clayton-Smith, Central Manchester University Hospitals & University of Manchester Susmito, Biswas, FRCOphth, Central Manchester University Hospitals Chris, Lloyd, FRCOphth, Central Manchester University Hospitals Jane, Ashworth, PhD, Central Manchester University Hospitals & University of Manchester Graeme, Black, PhD, Central Manchester University Hospitals & University of Manchester

Introduction: Inherited retinal disease(IRD) is a major cause of reduced vision in children. Advances in DNA sequencing have revolutionised genetic testing, accelerating diagnosis. We aimed to assess the current clinical utility of genetic testing in pediatric IRD. Methods: 85 children with IRD were ascertained over a 30-month period. Participants underwent a detailed clinical assessment, which included electrophysiology in 72 cases. Panel-based genetic testing(105 or 177 IRD-associated genes) was subsequently performed. Results: 78.8% (n=67) of cases received a probable molecular diagnosis; 7.5% (n=5) of these had AD disease, 25.4% (n=17) had XL disease, and 67.2% (n= 45) had AR disease. In a further 5.9%

(n=5) of cases, a single heterozygous ABCA4 variant was identified. Conclusions: Panel-based testing pointed to a molecular diagnosis in 84.7% of children with IRD. We propose the introduction of genetic testing early in the diagnostic pathway in children with clinical and/or electrophysiological findings suggestive of IRD.

Poster 33

Phenotype Based Panel Testing In Inherited Retinal Dystrophies - Mital Shah, MD, Oxford University Hospitals NHS Foundation Trust and Nuffield Laboratory of Ophthalmology, University of Oxford Co-Authors: Morag Shanks, PhD, Oxford University Hospitals NHS Foundation Trust Emily Packham, Oxford University Hospitals NHS Foundation Trust Andrea H. Nemeth, MD, Oxford University Hospitals NHS Foundation Trust Penny Clouston, PhD, Oxford University Hospitals NHS Foundation Trust Susan M. Downes, MD, Oxford University Hospitals NHS Foundation Trust and Nuffield Laboratory of Ophthalmology, University of Oxford

Introduction: Diagnostic next generation sequencing (NGS) services for patients with inherited retinal dystrophies (IRD) traditionally use gene panel based approaches. We present the molecular findings of the Oxford NGS IRD phenotype-based gene panels. Methods: The results of 953 patients referred for phenotype-based NGS IRD genetic testing panels were reviewed to assess the diagnostic yield. Results: The diagnostic yield depends on the clinical phenotype; with very low yield for late onset macular disease and highest with distinct phenotypes: 75.9% for choroideremia, 74.2% for Usher, 43.9% for RP and RP like phenotypes and 30.1% for macular disease. Conclusions: Phenotype based NGS genetic testing panels provide a targeted testing approach, reduce bioinformatics demand and yet achieve the same diagnostic yield as traditional gene panel approaches.

Poster 34

The Incidence And Spectrum Of Copy Number Variants (CNVs) In A Diagnostic Inherited Retinal Degeneration Cohort - Morag Shanks, PhD, Oxford University Hospitals NHS Foundation Trust Co-Authors: Emily Packham, Oxford University Hospitals NHS Foundation Trust Jesse Hayesmoore, PhD, Oxford Medical Genetics Laboratories, Churchill Hospital, Oxford Susan Downes, MBChB, MD, FRCOphth, Oxford Eye Hospital, John Radcliffe Hospital, Headington, Oxford Penny Clouston, PhD, Oxford Medical Genetics Laboratories, Churchill Hospital, Oxford

Introduction: CNVs are not routinely detected using current next-generation sequencing analysis pipelines. We investigated the diagnostic yield and spectrum of these events occurring in an unselected retinal dystrophy cohort. Methods: Patients were screened on phenotype targeted gene panels (HaloPlex targeted enrichment) and sequenced using Illumina MiSeq. CNVs were identified using a custom dosage quotient tool.

Results: CNVs are present in ~2% of positive molecular diagnostic cases. The frequency of CNVs varies between genes and is more prevalent in USH2A and CHM compared to ABCA4, a gene with a similar diagnostic yield. Conclusions: CNVs are a rare but important cause of inherited retinal dystrophy. Their detection increases the diagnostic yield in common and rare genes and highlights variation in occurrence between the different gene-associated phenotypes.

Poster 35

Sequence Analysis Of 108 Genes Associated With Non-Syndromic Inherited Retinal Dystrophies In 302 Individuals Using Molecular Inversion Probes - Claire Smith, MD, University of Leeds Co-Authors: James Poulter, PhD, University of Leeds Martin McKibbin, MBBS, Leeds Teaching Hospitals NHS Trust Kamron Khan, MB BChir, Leeds Teaching Hospitals NHS Trust Raj Mukherjee, MBBS, Leeds Teaching Hospitals NHS Trust Muhammad Khan, PhD, Radboud University Nijmegen Carmel Toomes, PhD, University of Leeds Manir Ali, PhD, University of Leeds Frans Cremers, PhD, Radboud University Nijmegen Chris Inglehearn, PhD, University of Leeds

Introduction: Non-syndromic inherited retinal dystrophies (IRDs) are clinically and genetically heterogeneous. Neither screening by Sanger sequencing nor whole exome sequencing (WES) is cost effective for diagnostic purposes in large patient cohorts. Molecular inversion probes (MIPs) allow specific targetted capture of known IRD genes for sequencing and are a high throughput, low cost alternative. Methods: 302 individuals were recruited at Leeds as part of a larger collaborative study. Of these, over half were diagnosed with retinitis pigmentosa, around one third cone-rod dystrophy and the remainder Leber congenital amaurosis, cone rod dystrophy or retinal dystrophy. In collaboration with researchers at Radboud University, Nijmegen, 6,200 MIPs were designed to capture 1600 exons and their flanking intronic regions for 108 known IRD genes, as well as selected deep intronic variants and deletion breakpoints. 3,200 IRD samples were sequenced in total at Radboud, with 120 captured samples pooled per lane and sequenced using an Illumina NextSeq500.Paired end reads were aligned to the GRCh37 reference sequence and variants called and annotated using an in-house pipeline. Putatively pathogenic variants will be verified by Sanger sequencing by a clinical laboratory. Results: Mean coverage per probe was 500x. Data from 274 individuals have been analysed to date. Putatively causal variants were identified in 132 samples. An additional 85 samples carried multiple variants in IRD genes and require further study. 57 samples were deemed negative for variants in IRD genes and will be submitted for WES. Variants were most frequently identified in ABCA4, USH2A and PROM1. RPGR ORF 15 remains uncovered by the MIPs assay. Conclusions: The current cost of MIPs per sample, including library preparation and sequencing, is significantly less than WES whilst its diagnostic efficiency is comparable. Results indicate that

70 clinical diagnosis shouldn’t determine the IRD genes to be screened as use of large gene panels can maximise diagnostic yield.

Poster 36

Identification Of Novel Mutations In COL4A1 In Patients Presenting With Familial Retinal Arteriolar Tortuosity (fRAT) - Joanne Topping, University of Leeds Co-Authors: Evangelia Panagiotou, MD, MSc, University of Leeds Ambreen Kalhoro, MD, Department of Ophthalmology, St. James' University Hospital Raj Mukherjee, MD, Department of Ophthalmology, St. James' University Hospital Martin McKibbin, MD, Department of Ophthalmology, St. James' University Hospital Carmel Toomes, PhD, University of Leeds

Introduction: fRAT is a rare autosomal dominant disorder characterized by progressive tortuosity of the second- and third-order retinal arterioles. The aim of this study was to identify the molecular basis of fRAT in two unrelated patients. Methods: Ophthalmologic evaluation included fundus examination, fluorescein angiography and OCT imaging. Whole exome sequencing (WES) or direct Sanger sequencing was performed to identify the mutations. Results: Patient 1 is a white 37-year old male with fRAT and a history of spontaneous retinal hemorrhage, myocardial infarction and systemic hypertension. He was a member of a large family containing seven members affected with fRAT. WES revealed a novel heterozygous missense mutation in COL4A1, c.1582G>C, p.(G528R) which segregated with the phenotype in family members. Patient 2 is a 39-year old white male with isolated RAT. Sanger sequencing of exons 23-25 of COL4A1 revealed a novel heterozygous missense mutation c.1547G>A, p.(Gly516Asp). Both mutations are predicted to be pathogenic and are located in the same domain. The patients are being counseled with regard to the investigation of the systemic features of COL4A1 disease). Conclusions: This study identified two novel mutations in COL4A1 in patients with fRAT and highlights the systemic phenotypic variability seen in patients with COL4A1 mutations.

Poster 37

A Recurrent Character And A High Frequency Of 11P13 Deletion Affecting PAX6 Downstream Regulatory Regions In Aniridia Patients From Russia - Tatyana Vasilyeva, Research Centre for Medical Genetics Co-Authors: Anna A. Voskresenskaya, MD, Cheboksary branch of S. Fyodorov Eye Microsurgery Federal State Institution Vitaly V. Kadyshev, PhD, Research Center for Medical Genetics Nadezhda A. Pozdeyeva, DSC, Cheboksary branch of S. Fyodorov Eye Microsurgery Federal State Institution Olga V. Khlebnikova, DSC, Research Center for Medical Genetics Rena A. Zinchenko, DSC, Research Center for Medical Genetics, Pirogov Russian National Research Medical University Andrey V. Marakhonov, PhD, Research Center for Medical Genetics, Moscow Institute of Physics and Technology

Introduction: Aniridia (OMIM 106210) is autosomal dominant congenital panocular disorder caused by PAX6 gene damage by large deletions and small mutations. The study aimed to determine PAX6 mutation spectrum in Russian aniridia patients. Methods: 121 unrelated families with congenital aniridia (147 patients) underwent ophthalmic examination and DNA testing: Sanger sequencing and MLPA followed by loss of heterozygosity of STR markers analysis. Results: 16 patients from 10 unrelated families share the same 11p13 0.51.5 Mb deletion affecting PAX6 downstream regulatory regions: 5 familial and 5 sporadic. The frequency of the deletion, 8.3% (10/121), is higher than hotspot c.718CT rate (7/121, 5.7%). Conclusions: The high rate of the deletion in studied cohort suggests a common underlying mechanism of its formation and points to 11p13 genomic region instability. Supported by RFBR grant 17-04-00475.

Poster 38

Ophthalmic Manifestations of Heimler Syndrome Due To PEX6 Mutations - Nutsuchar Wangtiraumnuay, MD, Queen Sirikit Natianal Institute of Child Health Co-Authors: Waleed Abed Alnabi, MD, Wills Eye Hospital Mai Tsukikawa, MD, Sidney Kimmel Medical College at Thomas Jefferson University Jenina Capasso, LCGC, Wills Eye Hospital Reuven Sharony, MD, Meir Medical Center affiliated with the Sackler Faculty of Medicine, Tel Aviv University Chris F Inglehearn, PhD, St. James's University Hospital, University of Leeds Alex V Levin, MD, MHSc, Wills Eye Hospital

Introduction: Pigmentary retinal dystrophy and macular dystrophy have been previously reported in Heimler syndrome due to mutations in PEX1. Here we reported the ocular manifestations in Heimler syndrome due to mutations in PEX6. Methods: Medical records were reviewed to identify patient demographics, ophthalmic and systemic findings, and results of diagnostic testing including whole genome sequencing. Results: Both patients had heterozygous PEX6 mutations. They exhibited pigmentary retinopathy, hyperfluorescent deposits, depletion of photoreceptors with intraretinal cystoid spaces. Full field electroretinograms showed abnormal photopic with abnormal mfERG. Conclusions: Heimler syndrome due to biallelic PEX6 mutations demonstrates a macular dystrophy with characteristic fundus autofluorescence and may be complicated by intraretinal cystoid spaces.