June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Genetic characteristics of an international large cohort with Stargardt disease: The ProgStar study
Author Affiliations & Notes
  • Kaoru Fujinami
    Division for Vision Research, National Institute of Sensory Organs, National Hospital Organization, Tokyo Medical Center, Tokyo, Japan
    Genetics, UCL Institute of Ophthalmology, London, United Kingdom
  • Rupert Wolfgang Strauss
    Medical Retina, Moorfields Eye Hospital, London, United Kingdom
    Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, United States
  • John Chiang
    Casey Molecular Diagnostic Laboratory, Portland, Oregon, United States
  • Isabelle S Audo
    CHNO des QuinzeVingts, DHU Sight Restore, INSERMDHOS CIC 1423, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, Paris, France
  • Paul S Bernstein
    Moran Eye Center, University of Utah, Salt Lake City, Utah, United States
  • David G Birch
    Retina Foundation of the Southwest, Dallas, Texas, United States
  • Samuel G Jacobson
    Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Brian C Mansfield
    Foundation Fighting Blindness, Columbia, Maryland, United States
  • Meghan J Marino
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States
  • Jose Alain Sahel
    CHNO des QuinzeVingts, DHU Sight Restore, INSERMDHOS CIC 1423, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, Paris, France
  • Saddek Mohand-Said
    CHNO des QuinzeVingts, DHU Sight Restore, INSERMDHOS CIC 1423, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, Paris, France
  • Janet S Sunness
    Richard E Hoover Low Vision Rehabilitation Services, Greater Baltimore Medical Center, Baltimore, Maryland, United States
  • Elias I Traboulsi
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States
  • Eberhart Zrenner
    Center for Ophthalmology, Eberhard-Karls University Hospital, Tuebingen, Germany
  • Michel Michaelides
    Medical Retina, Moorfields Eye Hospital, London, United Kingdom
    Genetics, UCL Institute of Ophthalmology, London, United Kingdom
  • Hendrik P Scholl
    Department of Ophthalmology, University of Basel, Basel, Switzerland
    Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, United States
  • Footnotes
    Commercial Relationships   Kaoru Fujinami, None; Rupert Strauss, None; John Chiang, Molecular Vision Laboratory (E); Isabelle Audo, None; Paul Bernstein, None; David Birch, None; Samuel Jacobson, None; Brian Mansfield, Foundation Fighting Blindness (E); Meghan Marino, None; Jose Sahel, None; Saddek Mohand-Said, None; Janet Sunness, None; Elias Traboulsi, None; Eberhart Zrenner, None; Michel Michaelides, None; Hendrik Scholl, Acucela Inc.:Code F (F), Boehringer Ingelheim Pharma GmbH & Co. KG (C), Daiichi Sankyo, Inc. (C), Genentech Inc./F. Hoffmann-La Roche Ltd. (C), Gensight Biologics (C), Genzyme Corp./Sanofi (R), Gerson Lehrman Group (C), Guidepoint (C), Intellia Therapeutics, Inc. (C), NightstaRx Ltd. (F), QLT, Inc. (F), ReNeuron Group Plc/Ora Inc. (R), Shire (C), Vision Medicines, Inc. (C)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 4638. doi:
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      Kaoru Fujinami, Rupert Wolfgang Strauss, John Chiang, Isabelle S Audo, Paul S Bernstein, David G Birch, Samuel G Jacobson, Brian C Mansfield, Meghan J Marino, Jose Alain Sahel, Saddek Mohand-Said, Janet S Sunness, Elias I Traboulsi, Eberhart Zrenner, Michel Michaelides, Hendrik P Scholl; Genetic characteristics of an international large cohort with Stargardt disease: The ProgStar study. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4638.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : We describe the genetic characteristics of the cohort enrolled in the international multi-center progression of Stargardt disease type 1 (STGD1) study (ProgStar) and determine ethnic features based on the allele frequency

Methods : 275 subjects with a clinical diagnosis of STGD1 and harboring multiple pathogenic ABCA4 variants were enrolled from 9 centers in the USA and Europe (ProgStar retrospective and prospective studies; Strauss et el. Ophthalmology 2016). Subjects were classified into four ethnic subgroups (European/Middle Eastern, African, Asian, and Other/Unknown) based on questionnaire responses, then comparison analysis of the allele frequency was performed with categorical testing of the independence of each prevalent allele.

Results : 195 pathogenic sequence variants were identified in the total cohort, including missense (123), splice site alteration (32), frame shift (19), stop (19), in-frame deletion (1), and large exonic deletion (1). 46 variants were novel. Exclusively missense variants were detected in 136 patients (49.5%). There were 196 European/Middle Eastern patients, 18 African (by descent), 14 Asian and 47 with other/unknown ethnicity. The three most prevalent variants in the total cohort were p.G1961E (15.3%), p.G863A (7.3%), and c.5461-10 T>C (4.9%). The three most prevalent variants in each subgroup were: p.G1961E (15.3%), p.G863A (7.9%), c.5461-10 T>C (5.9%) in European/Middle Eastern; p.R2107H (13.9%), p.V989A (8.3%), p.G991R (8.3%), p.V643M (8.3%) in African; and p.G1961E (39.3%), c.4253+4C>T (7.1%), p.S95P (7.1%) in Asian, respectively. The subgroup analysis revealed a statistically significant ethnic difference in the allele frequency of p.G1961E, p.R2107H, p.V989A, p.G991R, p.V643M, c.4253+4C>T, and p.S95P.

Conclusions : The spectrum of ABCA4 variants has now been documented in a well-characterized large cohort with STGD1. Approximately half of the cohort harbors only missense variants, which is in keeping with the relatively mild phenotype of the ProgStar cohort; since the inclusion criteria of well-demarcated macular atrophy does not include patients with very severe phenotypes such as extended atrophy. Subgroup analysis reveals the distinct prevalent alleles in each ethnicity, although the number of subjects for some subgroups is limited.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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