1 Fujinami K, et al. Br J Ophthalmol 2018;0:1–8. doi:10.1136/bjophthalmol-2018-312064 Clinical science Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8 Kaoru Fujinami, 1,2,3,4 Rupert W Strauss, 3,4,5,6,7 John (Pei-Wen) Chiang, 8 Isabelle S Audo, 9,10 Paul S Bernstein, 11 David G Birch, 12 Samantha M Bomotti, 5 Artur V Cideciyan, 13 Ann-Margret Ervin, 5 Meghan J Marino, 14 José-Alain Sahel, 10,15,16 Saddek Mohand-Said, 9,10 Janet S Sunness, 17 Elias I Traboulsi, 14 Sheila West, 5 Robert Wojciechowski, 5 Eberhart Zrenner, 18,19 Michel Michaelides, 3,4 Hendrik P N Scholl, 20,21 On behalf of the ProgStar Study Group To cite: Fujinami K, Strauss RW, Chiang J(P-Wen), et al. Br J Ophthalmol Epub ahead of print: [please include Day Month Year]. doi:10.1136/ bjophthalmol-2018-312064 ► Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ bjophthalmol-2018-312064). For numbered affliations see end of article. Correspondence to Professor Hendrik P N Scholl, , Department of Ophthalmology, University of Basel, Universitätsspital Basel, Mittlere Strasse 91, Basel, CH-4031, Switzerland; hendrik.scholl@usb.ch and Michel Michaelides, Department of Genetics, University College London, Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, UK; michel.michaelides@ucl.ac.uk †MM and HPNS are joint senior authors. 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. Received 9 February 2018 Accepted 12 April 2018 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 classifed 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 identifed 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 signifcant 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 signifcant differences in allele frequencies between nations, although the three most prevalent variants are shared as frequent variants. INTRODUCTION Stargardt disease 1 (STGD1; MIM 248200) is the most prevalent inherited macular dystrophy, which is an autosomal recessive condition caused by pathogenic sequence variants in the ABCA4 gene (ATP-binding cassette subfamily A member 4; MIM 601691). 1 2 ABCA4 encodes the retina-specific transmembrane protein and is involved in the active transport of retinoids in visual cycle. 1 2 Patients with STGD1 typically presents with bilateral central visual loss, including central scotoma and reduced visual acuity, and with characteristic macular atrophy surrounded by yellow-white flecks at the level of the retinal pigment epithelium. 1 3–6 Highly variable phenotypes, severity and progression of STGD1 have been found in ABCA4-associated retinopathy. 5–16 There is also a very high allelic heterogeneity in ABCA4, with more than 1000 sequence variations reported to date. 1 17–21 The phenotypic variability and the genetic heterogeneity pose marked challenges in attempts to establish genotype–phenotype correla- tions of ABCA4-associated retinopathy. However, comprehensive clinical and genetic investigations of STGD1 in a large cohort based on well-established eligibility criteria are lacking and would likely help to address the aforementioned challenges. There- fore, the international multicentre ‘Natural History of the Progression of Atrophy Secondary to Stargardt Disease (ProgStar)’ studies were established. 3 The purpose of the present study is to describe the detailed genetic characteristics of the large STGD1 cohort enrolled into the ProgStar studies. This study also provides an opportunity to deter- mine geographic differences in the allele frequency of prevalent ABCA4 variants. MATERIAL AND METHODS Patients In ProgStar, patients with STGD1 were enrolled from nine centres in the USA and Europe: The Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland (JHU); Greater Baltimore Medical Centre, Baltimore, Maryland (GBMC); Scheie Eye Institute, University of Philadelphia, Philadelphia, Pennsylvania (PENN); Retina Foun- dation of the Southwest, Dallas, Texas (RFSW); Moran Eye Centre, Salt Lake City, Utah (MEC); Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio (CC); Moorfields Eye Hospital, London, UK (MEH, UK); Université de Paris 06, Institut national de la santé et de la recherche médicale, Paris, France (INSERM, France); and Eberhard-Karls University on 6 July 2018 by guest. Protected by copyright. http://bjo.bmj.com/ Br J Ophthalmol: first published as 10.1136/bjophthalmol-2018-312064 on 20 June 2018. Downloaded from