Journal
BRITISH JOURNAL OF OPHTHALMOLOGY
Volume 103, Issue 3, Pages 390-397Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/bjophthalmol-2018-312064
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Funding
- Foundation Fighting Blindness Clinical Research Institute (FFB CRI)
- U.S. Department of Defense USAMRMC TATRC, Fort Meade, Maryland, USA [W81-XWH-07-1-0720, W81XWH-09-2-0189]
- 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)
- Fund for the Promotion of Joint International Research, Fostering Joint International Research, The Ministry of Education, Culture, Sports, Science and Technology (Japan)
- Specified Disease Research Program on Intractable British Journal of Ophthalmology Diseases, The Ministry of Health Labour and Welfare (Japan)
- National Hospital Organization Network Research Fund (Japan)
- Austrian Science Fund (FWF
- Austria) [J 3383-B23]
- Foundation Fighting Blindness Clinical Research Institute
- National Institutes of Health, Bethesda, Maryland, USA [EY013203, EY09076]
- Research to Prevent Blindness
- Foundation Fighting Blindness
- German Research Council (Center of Excellence 307)
- Tistou and Charlotte Kerstan Foundation
- National Institute for Health (NIH) Research Biomedical Research Centre at Moorfields Eye Hospital National Health Service Foundation Trust
- UCL Institute of Ophthalmology
- Fight For Sight (UK)
- Macular Society (UK)
- Moorfields Eye Hospital Special Trustees
- Moorfields Eye Charity (UK)
- Retinitis Pigmentosa Fighting Blindness
- Shulsky Foundation, New York City, New York, USA
- Ocular Albinism Research Fund (Clark Enterprises)
- Baylor-Johns Hopkins Center for Mendelian Genetics (National Human Genome Research Institute, NHGRI/NIH) [1U54HG006542-01]
- NATIONAL EYE INSTITUTE [P30EY014800] Funding Source: NIH RePORTER
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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 wellcharacterised 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.
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