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Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8
  1. Kaoru Fujinami1,2,3,4,
  2. Rupert W Strauss3,4,5,6,7,
  3. John (Pei-Wen) Chiang8,
  4. Isabelle S Audo9,10,
  5. Paul S Bernstein11,
  6. David G Birch12,
  7. Samantha M Bomotti5,
  8. Artur V Cideciyan13,
  9. Ann-Margret Ervin5,
  10. Meghan J Marino14,
  11. José-Alain Sahel10,15,16,
  12. Saddek Mohand-Said9,10,
  13. Janet S Sunness17,
  14. Elias I Traboulsi14,
  15. Sheila West5,
  16. Robert Wojciechowski5,
  17. Eberhart Zrenner18,19,
  18. Michel Michaelides3,4,
  19. Hendrik P N Scholl20,21,
  20. ProgStar Study Group
  21. On behalf of the ProgStar Study Group
    1. 1 Laboratory of Visual Physiology, Division for Vision Research, National Institute of Sensory Organs, National Hospital Organization, Tokyo Medical Center, Tokyo, Japan
    2. 2 Department of Ophthalmology, Keio University, School of Medicine, Tokyo, Japan
    3. 3 UCL Institute of Ophthalmology, London, UK
    4. 4 Moorfields Eye Hospital, London, UK
    5. 5 Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA
    6. 6 Department of Ophthalmology, Johannes Kepler University Linz, Linz, Austria
    7. 7 Department of Ophthalmology, Medical University of Graz, Graz, Austria
    8. 8 Casey Molecular Diagnostic Laboratory, Portland, Oregon, USA
    9. 9 Institute de la Vision, Sorbonne Université, Paris, France
    10. 10 CHNO des Quinze-Vingts, DHU Sight Restore, Charenton, France
    11. 11 Moran Eye Center, University of Utah, Salt Lake City, Utah, USA
    12. 12 Retina Foundation of the Southwest, Dallas, Texas, USA
    13. 13 Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    14. 14 Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA
    15. 15 Department of Ophthalmology, Fondation Ophtalmologique Rothschild, Paris, France
    16. 16 Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburgh, USA
    17. 17 Richard E Hoover Low Vision Rehabilitation Services, Greater Baltimore Medical Center, Baltimore, Maryland, USA
    18. 18 Center for Ophthalmology, Eberhard-Karls University Hospital, Tuebingen, Germany
    19. 19 Werner Reichardt Centre for Integrative Neuroscience, University of Tuebingen, Tuebingen, Germany
    20. 20 Department of Ophthalmology, University of Basel, Basel, Switzerland
    21. 21 Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland
    1. Correspondence to Professor Hendrik P N Scholl, , Department of Ophthalmology, University of Basel, Universitätsspital Basel, Mittlere Strasse 91, Basel, CH-4031, Switzerland; hendrik.scholl{at}usb.ch; Michel Michaelides, Department of Genetics, University College London, Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, UK; michel.michaelides{at}ucl.ac.uk

    Abstract

    Background/aims To describe the genetic characteristics of the cohort enrolled in the international multicentre progression of Stargardt disease 1 (STGD1) studies (ProgStar) and to determine geographic differences based on the allele frequency.

    Methods 345 participants with a clinical diagnosis of STGD1 and harbouring at least one disease-causing ABCA4 variant were enrolled from 9 centres in the USA and Europe. All variants were reviewed and in silico analysis was performed including allele frequency in public databases and pathogenicity predictions. Participants with multiple likely pathogenic variants were classified into four national subgroups (USA, UK, France, Germany), with subsequent comparison analysis of the allele frequency for each prevalent allele.

    Results 211 likely pathogenic variants were identified in the total cohort, including missense (63%), splice site alteration (18%), stop (9%) and others. 50 variants were novel. Exclusively missense variants were detected in 139 (50%) of 279 patients with multiple pathogenic variants. The three most prevalent variants of these patients with multiple pathogenic variants were p.G1961E (15%), p.G863A (7%) and c.5461-10 T>C (5%). Subgroup analysis revealed a statistically significant difference between the four recruiting nations in the allele frequency of nine variants.

    Conclusions There is a large spectrum of ABCA4 sequence variants, including 50 novel variants, in a well-characterised cohort thereby further adding to the unique allelic heterogeneity in STGD1. Approximately half of the cohort harbours missense variants only, indicating a relatively mild phenotype of the ProgStar cohort. There are significant differences in allele frequencies between nations, although the three most prevalent variants are shared as frequent variants.

    • genetics
    • macula
    • retina

    This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0

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    Footnotes

    • MM and HPNS are joint senior authors.

    • Presented at A part of information of this article was presented at the Annual Meeting of the Association for Research in Vision and Ophthalmology on 10 May 2017 in Baltimore, Maryland, USA, and the American Society of Human Genetics 2017 on 18 October 2017 in Orlando, Florida, USA.

    • Collaborators The ProgStar study is supported by a contract from the FoundationFighting Blindness. The ProgStar studies consist of the Chair’s Office, nine clinics, two resource centers and two affiliated centers with the following members: Chair’s Office: HPNS; RWS; YuliaWolfson, MD; Millena Bittencourt, MD; Syed Mahmood Shah, MD; Mohamed Ahmed, MD;Etienne Schönbach, MD; KF, MD, PhD; Cole Eye Institute, Cleveland, Ohio, USA:EIT, MD; Justis Ehlers, MD; Meghan Marino, MS; Susan Crowe, BS;Rachael Briggs, COA; Angela Borer, BS; Anne Pinter, CRA; Tami Fecko; NikkiBurgnoni, MS; Greater Baltimore Medical Center, Towson, Maryland, USA: Janet S Sunness, MD;Carol Applegate, MLA, COT; Leslie Russell, MAc; Moorfields Eye Hospital,London, UK: MM, MD; Simona Degli Esposti, MD; Anthony Moore, MD;Andrew Webster, MD; Sophie Connor, BSc; Jade Barnfield, BA; Zaid Salchi, MD;Clara Alfageme, MD; Victoria McCudden; Maria Pefkianaki, MD; Jonathan Aboshiha,MA, MB; Gerald Liew, PhD; Graham Holder, PhD; Anthony Robson, PhD; Alexa King,BA; Daniela Ivanova Cajas Narvaez, MSc; Katy Barnard, BS; Catherine Grigg, BSc;Hannah Dunbar, PhD; Yetunde Obadeyi; Karine Girard-Claudon, MST; Hilary Swann,BSc; Avani Rughani, BSc; Charles Amoah, NVQ; Dominic Carrington; Kanom Bibi,BSc; Emerson Tingco, DMD; Mohamed Nafaz Illiyas; Hamida Begum, BSc; Andrew Carter,BSc; Anne Georgiou, PhD; Selma Lewis, BSc; Saddaf Shaheen, PGDip, BSc; HarpreetShinmar, MSc; Linda Burton, BSc; Moran Eye Center, Salt Lake City, Utah, USA: PaulBernstein, MD, PhD; Kimberley Wegner, BS; Briana Lauren Sawyer, MS; BonnieCarlstrom, COA; Kellian Farnsworth, COA; Cyrie Fry, AS, CRA, OCT-C; MelissaChandler, BS, CRC, OCT-a; Glen Jenkins, BS, COA, CRC, OCT-a; Donnel Creel, PhD;Retina Foundation of the Southwest, Dallas, Texas, USA: David Birch, PhD; Yi-Zhong Wang,PhD; Luis Rodriguez, BS; Kirsten Locke, BS; Martin Klein, MS; Paulina Mejia,BS; Scheie Eye Institute, Philadelphia, Pennsylvania, USA: Artur V Cideciyan, PhD; Samuel G Jacobson, MD, PhD; Sharon B Schwartz, MS, CGC; Rodrigo Matsui, MD; MichaelaGruzensky, MD; Jason Charng, OD, PhD; Alejandro J Roman, MS; University ofTübingen, Tübingen, Germany: Eberhart Zrenner, PhD; Fadi Nasser, MD; Gesa Astrid Hahn,MD; Barbara Wilhelm, MD; Tobias Peters, MD; Benjamin Beier, BSc; Tilman Koenig;Susanne Kramer, Dipl. Biol.; The Vision Institute, Paris, France: J-AS, MD;SM-S, MD, PhD; IA, MD, PhD; Caroline Laurent-Coriat,MD; Ieva Sliesoraityte, MD, PhD; Christina Zeitz, PhD; Fiona Boyard, BS; MinhHa Tran, BS; Mathias Chapon, COT; Céline Chaumette, COT; Juliette Amaudruz,COT; Victoria Ganem, COT; Serge Sancho, COT; Aurore Girmens, COT; The WilmerEye Institute, Baltimore, Maryland, USA: HPNS, MD; RWS, MD; YuliaWolfson, MD; Syed Mahmood Shah, MD; Mohamed Ahmed, MD; Etienne Schönbach, MD;Robert Wojciechowski, PhD; Shazia Khan, MD; David G Emmert, BA; Dennis Cain,CRA; Mark Herring, CRA; Jennifer Bassinger, COA; Lisa Liberto, COA; Dana CenterData Coordinating Center: Sheila K West, PhD; Ann-Margret Ervin, PhD; BeatrizMunoz, MS; Xiangrong Kong, PhD; Kurt Dreger, BS; Jennifer Jones, BA; Robert Burke,BA; Doheny Image Reading Center: Srinivas Sadda, MD; Michael S Ip, MD; AnamikaJha, MBS; Alex Ho, BS; Brendan Kramer, BA; Ngoc Lam, BA; Rita Tawdros, BS; YongDong Zhou, MD, PhD; Johana Carmona, HS; Akihito Uji, MD, PhD; AmirhosseinHariri, MD; Amy Lock, BS; Anthony Elshafei, BS; Anushika Ganegoda, BS;Christine Petrossian, BS; Dennis Jenkins, MPH; Edward Strnad, BS; ElmiraBaghdasaryan, MD; Eric Ito, OD; Feliz Samson, BS; Gloria Blanquel, BS; HandanAkil, MD, FEBOpht; Jhanisus Melendez, MS; Jianqin Lei, MD; Jianyan Huang, MD,PhD; Jonathan Chau, BS; Khalil G Falavarjani, MD; Kristina Espino, BS; ManfredLi, BS; Maria Mendoza, BS; Muneeswar Gupta Nittala, MPhil Opt; Netali Roded,BS; Nizar Saleh, MD; Ping Huang, MD, PhD; Sean Pitetta, BS; Siva Balasubramanian,MD, PhD; Sophie Leahy, BA; Sowmya J Srinivas, MBBS; Swetha B Velaga, B Opt;Teresa Margaryan, BA; Tudor Tepelus, PhD; Tyler Brown, BS; Wenying Fan, MD;Yamileth Murillo, BA; Yue Shi, MD, PhD; Katherine Aguilar, BS; Cynthia Chan,BS; Lisa Santos, HS; Brian Seo, BA; Christopher Sison, BS; Silvia Perez, BS;Stephanie Chao, HS; Kelly Miyasato, MPH; Julia Higgins, MS; Zoila Luna, MHA;Anita Menchaca, BS; Norma Gonzalez, MA; Vicky Robledo, BS; Karen Carig, BS;Kirstie Baker, HS; David Ellenbogen, BS; Daniel Bluemel, AA; Theo Sanford, BS;Daisy Linares, HS; Mei Tran, BA; Lorane Nava, HS; Michelle Oberoi, BS; MarkRomero, HS; Vivian Chiguil, HS; Grantley Bynum-Bain, BA; Monica Kim, BS;Carolina Mendiguren, MEM; Xiwen Huang, MPH and Monika Smith, HS.

    • Contributors HPNS and MM have full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: KF, RWS, MM, HPNS. Acquisition, analysis or interpretation of data: all authors. Drafting of the manuscript: KF, RWS, EIT, MM, HPNS. Critical revision of the manuscript for important intellectual content: KF, RWS, DGB, SMB, AVC, A-ME, EIT, MM, HPNS. Statistical analysis: KF. Obtained funding: KF, RWS, IA, PSB, DGB, EZ, MM, HPNS. Administrative, technical or material support: KF, RWS, JC, MM, HPNS. Study supervision: KF, RWS, MM, HPNS.

    • Funding The ProgStar studies are supported by the Foundation Fighting Blindness Clinical Research Institute (FFB CRI) and a grant to FFB CRI by the U.S. Department of Defense USAMRMC TATRC, Fort Meade, Maryland, USA (grant nos: W81-XWH-07-1-0720 and W81XWH-09-2-0189); KF is supported by a Foundation Fighting Blindness Career Development Award Clinical Research Fellowship Program, The Great Britain Sasakawa Foundation, Butterfield Awards for UK-Japan collaboration in medical research and public health Practice (UK), Grant-in-Aid for Young Scientists (A) and Fund for the Promotion of Joint International Research, Fostering Joint International Research, The Ministry of Education, Culture, Sports, Science and Technology (Japan), The Specified Disease Research Program on Intractable British Journal of Ophthalmology Diseases, The Ministry of Health Labour and Welfare (Japan) and National Hospital Organization Network Research Fund (Japan). RWS is supported by the Austrian Science Fund (FWF; Project number: J 3383-B23; Austria), the Foundation Fighting Blindness Clinical Research Institute and National Institutes of Health, Bethesda, Maryland, USA (grant no: EY013203). PSB is supported by unrestricted grants by Research to Prevent Blindness. DGB is supported by Foundation Fighting Blindness and National Institutes of Health, Bethesda, Maryland, USA (EY09076). EZ is supported by a grant from the German Research Council (Center of Excellence 307) and Tistou and Charlotte Kerstan Foundation. MM is supported by grants from the National Institute for Health (NIH) Research Biomedical Research Centre at Moorfields Eye Hospital National Health Service Foundation Trust and UCL Institute of Ophthalmology, Fight For Sight (UK), The Macular Society (UK), Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity (UK), the Foundation Fighting Blindness (including Career Development Award) and Retinitis Pigmentosa Fighting Blindness. HPS is supported by the Shulsky Foundation, New York City, New York, USA; Ocular Albinism Research Fund (Clark Enterprises); unrestricted grant to the Wilmer Eye Institute from Research to Prevent Blindness; Baylor-Johns Hopkins Center for Mendelian Genetics (National Human Genome Research Institute, NHGRI/NIH; identification no: 1U54HG006542-01).

    • Competing interests KF is a a paid consultant of Astellas Pharma, Kubota Pharmaceutical Holdings. DGB is a consultant for NightStaRX, AGTC, Shire, Ionis and Genentech. EZ is a member of the Data Monitoring and Safety Board/Committee of the following entities: ReNeuron Group/Ora, NightStaRx, RD-CURE Consortium and principal investigator in clinical trials sponsored by QLT, SHIRE and FFB at the University of Tuebingen, Institute for Ophthalmic Research. HPNS is a paid consultant of the following entities: Boehringer Ingelheim Pharma, Daiichi Sankyo, Gerson Lehrman Group; Guidepoint and Shire. HPNS is member of the Scientific Advisory Board of the Astellas Institute for Regenerative Medicine; Gensight Biologics; Vision Medicines and Intellia Therapeutics. HPNS is member of the Data Monitoring and Safety Board/Committee of the following entities: Genentech/F. Hoffmann-La Roche and ReNeuron Group/Ora. These arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. Johns Hopkins University and Bayer Pharma have an active research collaboration and option agreement. These arrangements have also been reviewed and approved by the University of Basel (Universitätsspital Basel, USB) in accordance with its conflict of interest policies. HPNS is principal investigator of grants at the USB sponsored by the following entity: Acucela; NightstaRx; QLT. Grants at USB are negotiated and administered by the institution (USB) which receives them on its proper accounts.

    • Patient consent Not required.

    • Ethics approval NHS National Research Ethics Service.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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