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

Br J Ophthalmol. 2019 Mar;103(3):390-397. doi: 10.1136/bjophthalmol-2018-312064. Epub 2018 Jun 20.

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.

Keywords: genetics; macula; retina.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ATP-Binding Cassette Transporters / genetics*
  • Adolescent
  • Adult
  • Age of Onset
  • Aged
  • Child
  • Child, Preschool
  • Cohort Studies
  • DNA Mutational Analysis
  • Databases, Factual
  • Female
  • Gene Frequency
  • Genotyping Techniques
  • Geography
  • Humans
  • Internationality
  • Macular Degeneration / congenital*
  • Macular Degeneration / diagnosis
  • Macular Degeneration / genetics
  • Male
  • Middle Aged
  • Mutation*
  • Polymerase Chain Reaction
  • Stargardt Disease

Substances

  • ABCA4 protein, human
  • ATP-Binding Cassette Transporters

Supplementary concepts

  • Stargardt disease 1