title: Analysis of a large choroideremia dataset does not suggest a preference for inclusion of certain genotypes in future trials of gene therapy.
abstract: BACKGROUND
  Choroideremia (CHM) is an X-linked degeneration of the retinal pigment epithelium, photoreceptors, and choroid, which causes nyctalopia and progressive constriction of visual fields leading to blindness. The CHM gene encodes Rab escort protein 1 (REP-1). In this work, we reviewed the phenotypes and genotypes of affected males with the purpose of understanding the functional effects of CHM mutations and their relationship with the phenotypes.
  
  
  METHODS
  A retrospective review of 128 affected males was performed analyzing the onset of symptoms, visual acuity, and visual fields with respect to their mutations in the CHM gene.
  
  
  RESULTS
  In rank order, reflecting data from this report, the most common mutations found in the CHM gene were nonsense mutations (41%), exon deletions (37%), and splice sites (14%) associated with a loss of functional protein. In the pool of 106 CHM mutations, we discovered four novel missense mutations (c.238C>T; p.L80F, c.819G>T; p.Q273H, c.1327A>G; p.M443V, and c.1370C>T; p.L457P) predicted to be severe changes affecting protein stability and folding with the effect similar to that of other types of mutations. No significant genotype-phenotype correlation was found with respect to the onset of nyctalopia, the onset of other visual symptoms, visual acuity, or width of visual fields.
  
  
  CONCLUSIONS
  There is no evidence to support exclusion of CHM patients from clinical trials based on their genotypes or any potential genotype-phenotype correlations.
authors.affiliation: Department of Ophthalmology and Visual Sciences University of Alberta Edmonton Alberta Canada.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Freund
authors.affiliation: Ophthalmic Genetics and Visual Function Branch National Eye Institute National Institutes of Health Bethesda Maryland.
authors.forename: Yuri V
authors.initials: YV
authors.lastname: Sergeev
authors.affiliation: Department of Ophthalmology and Visual Sciences University of Alberta Edmonton Alberta Canada.
authors.forename: Ian M
authors.initials: IM
authors.lastname: MacDonald
keywords: Choroideremia; Rab escort protein‐1; natural history; retinal dystrophy; visual acuity; visual fields