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.
Original language | English (US) |
---|---|
Pages (from-to) | 390-397 |
Number of pages | 8 |
Journal | British Journal of Ophthalmology |
Volume | 103 |
Issue number | 3 |
DOIs | |
State | Published - Mar 1 2019 |
Keywords
- genetics
- macula
- retina
ASJC Scopus subject areas
- Ophthalmology
- Sensory Systems
- Cellular and Molecular Neuroscience
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Detailed genetic characteristics of an international large cohort of patients with Stargardt disease : ProgStar study report 8. / Fujinami, Kaoru; Strauss, Rupert W.; Chiang, John et al.
In: British Journal of Ophthalmology, Vol. 103, No. 3, 01.03.2019, p. 390-397.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Detailed genetic characteristics of an international large cohort of patients with Stargardt disease
T2 - ProgStar study report 8
AU - Fujinami, Kaoru
AU - Strauss, Rupert W.
AU - Chiang, John
AU - Audo, Isabelle S.
AU - Bernstein, Paul S.
AU - Birch, David G.
AU - Bomotti, Samantha M.
AU - Cideciyan, Artur V.
AU - Ervin, Ann Margret
AU - Marino, Meghan J.
AU - Sahel, José Alain
AU - Mohand-Said, Saddek
AU - Sunness, Janet S.
AU - Traboulsi, Elias I.
AU - West, Sheila
AU - Wojciechowski, Robert
AU - Zrenner, Eberhart
AU - Michaelides, Michel
AU - Scholl, Hendrik P.N.
N1 - Funding Information: 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). Funding Information: 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). Funding Information: 1Laboratory of Visual Physiology, Division for Vision Research, National Institute of Sensory Organs, National Hospital Organization, Tokyo Medical Center, Tokyo, Japan 2Department of Ophthalmology, Keio University, School of Medicine, Tokyo, Japan 3UCL Institute of Ophthalmology, London, UK 4Moorfields Eye Hospital, London, UK 5Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA 6Department of Ophthalmology, Johannes Kepler University Linz, Linz, Austria 7Department of Ophthalmology, Medical University of Graz, Graz, Austria 8Casey Molecular Diagnostic Laboratory, Portland, Oregon, USA 9Institute de la Vision, Sorbonne Université, Paris, France 10CHNO des Quinze-Vingts, DHU Sight Restore, Charenton, France 11Moran Eye Center, University of Utah, Salt Lake City, Utah, USA 12Retina Foundation of the Southwest, Dallas, Texas, USA 13Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA 14Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA 15Department of Ophthalmology, Fondation Ophtalmologique Rothschild, Paris, France 16Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburgh, USA 17Richard E Hoover Low Vision Rehabilitation Services, Greater Baltimore Medical Center, Baltimore, Maryland, USA 18Center for Ophthalmology, Eberhard-Karls University Hospital, Tuebingen, Germany 19Werner Reichardt Centre for Integrative Neuroscience, University of Tuebingen, Tuebingen, Germany 20Department of Ophthalmology, University of Basel, Basel, Switzerland 21Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland 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. Publisher Copyright: © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2019/3/1
Y1 - 2019/3/1
N2 - 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.
AB - 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.
KW - genetics
KW - macula
KW - retina
UR - http://www.scopus.com/inward/record.url?scp=85048874367&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85048874367&partnerID=8YFLogxK
U2 - 10.1136/bjophthalmol-2018-312064
DO - 10.1136/bjophthalmol-2018-312064
M3 - Article
C2 - 29925512
AN - SCOPUS:85048874367
VL - 103
SP - 390
EP - 397
JO - British Journal of Ophthalmology
JF - British Journal of Ophthalmology
SN - 0007-1161
IS - 3
ER -