title: Identification of three ABCA4 sequence variations exclusive to African American patients in a cohort of patients with Stargardt disease.
abstract: OBJECTIVE
  To describe the clinical and molecular findings in ten unrelated African American patients with Stargardt disease.
  
  
  METHODS
  Retrospective, observational case series.
  
  
  METHODS
  We reviewed the clinical histories, examinations, and genotypes of 85 patients with molecular diagnoses of Stargardt disease. Three ABCA4 sequence variations identified exclusively in African Americans were evaluated in 300 African American controls and by in silico analysis.
  
  
  RESULTS
  ABCA4 sequence changes were identified in 85 patients from 80 families, of which 11 patients identified themselves as African American. Of these 11 patients, 10 unrelated patients shared 1 of 3 ABCA4 sequence variations: c.3602T>G (p.L1201R); c.3899G>A (p.R1300Q); or c.6320G>A (p.R2107H). The minor allele frequencies in the African American control population for each variation were 7.5%, 6.3%, and 2%, respectively. This is comparable to the allele frequency in African Americans in the Exome Variant Server. In contrast, the allele frequency of all three of these variations was less than or equal to 0.05% in European Americans. Although both c.3602T>G and c.3899G>A have been reported as likely disease-causing variations, one of our control patients was homozygous for each variant, suggesting that these are nonpathogenic. In contrast, the absence of c.6320G>A in the control population in the homozygous state, combined with the results of bioinformatics analysis, support its pathogenicity.
  
  
  CONCLUSIONS
  Three ABCA4 sequence variations were identified exclusively in 10 unrelated African American patients: p.L1201R and p.R1300Q likely represent nonpathogenic sequence variants, whereas the p.R2107H substitution appears to be pathogenic. Characterization of population-specific disease alleles may have important implications for the development of genetic screening algorithms.
authors.affiliation: Cole Eye Institute, Cleveland, Ohio.
authors.forename: Virginia Miraldi
authors.initials: VM
authors.lastname: Utz
authors.forename: Aimee V
authors.initials: AV
authors.lastname: Chappelow
authors.forename: Meghan J
authors.initials: MJ
authors.lastname: Marino
authors.forename: Craig D
authors.initials: CD
authors.lastname: Beight
authors.forename: Gwen M
authors.initials: GM
authors.lastname: Sturgill-Short
authors.forename: Gayle J T
authors.initials: GJ
authors.lastname: Pauer
authors.forename: Susan
authors.initials: S
authors.lastname: Crowe
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Hagstrom
authors.forename: Elias I
authors.initials: EI
authors.lastname: Traboulsi
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D001741:Black or African American / Q000235:genetics*; D001483:Base Sequence / Q000235:genetics; D004596:Electroretinography; D005260:Female; D005451:Fluorescein Angiography; D005787:Gene Frequency; D014644:Genetic Variation; D006801:Humans; D008268:Macular Degeneration / Q000175:diagnosis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012189:Retrospective Studies; D000080362:Stargardt Disease; D041623:Tomography, Optical Coherence
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters