Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8

Kaoru Fujinami, Rupert W. Strauss, John Chiang, Isabelle S. Audo, Paul S. Bernstein, David G. Birch, Samantha M. Bomotti, Artur V. Cideciyan, Ann Margret Ervin, Meghan J. Marino, José Alain Sahel, Saddek Mohand-Said, Janet S. Sunness, Elias I. Traboulsi, Sheila K West, Robert Wojciechowski, Eberhart Zrenner, Michel Michaelides, Hendrik P.N. Scholl

Research output: Contribution to journalArticle


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 languageEnglish (US)
JournalBritish Journal of Ophthalmology
Publication statusAccepted/In press - Jun 19 2018



  • genetics
  • macula
  • retina

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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