title: Cone-rod dystrophy, intrafamilial variability, and incomplete penetrance associated with the R172W mutation in the peripherin/RDS gene.
abstract: OBJECTIVE
  To determine the underlying molecular genetic basis of a retinal dystrophy identified in a 5-generation family, and to examine the phenotype and degree of intrafamilial variability.
  
  
  METHODS
  Family genetic study.
  
  
  METHODS
  Nine affected individuals from a nonconsanguineous British family.
  
  
  METHODS
  Ophthalmologic examination, color vision testing, fundus photography, autofluorescence imaging, and electrophysiological assessment were performed. The clinical notes of 2 additional deceased affected family members were also reviewed. Blood samples were taken for DNA extraction, with linkage analysis being performed, and subsequent mutation screening of the peripherin/RDS gene.
  
  
  RESULTS
  Linkage analysis established a disease interval on chromosome 6p, which harbored the retinal candidate gene, peripherin/RDS. The 3 coding exons of the peripherin/RDS gene were subsequently screened for mutations in affected and unaffected family members. A nonconservative missense substitution, Arg172Trp (R172W), segregated uniquely in all affected subjects. The majority of subjects carrying the R172W peripherin/RDS mutation complained of reduced central vision starting in the second or third decade, with subsequent gradual deterioration of visual acuity and color vision. Three affected individuals complained of nyctalopia. A range of macular appearances were seen, varying from a typical granular appearance to extensive macular atrophy. Autofluorescence imaging in the majority of individuals identified a highly characteristic speckled macular appearance. All affected subjects had abnormal pattern electroretinograms (ERGs) consistent with macular dysfunction and 4 subjects showed additional full-field ERG abnormalities, providing evidence of generalized retinal dysfunction. There was marked variation in the clinical phenotype in those individuals who carried the R172W peripherin/RDS mutation, ranging from severe cone-rod dystrophy to asymptomatic individuals with normal retinal function.
  
  
  CONCLUSIONS
  The Arg172Trp (R172W) peripherin/RDS mutation has been previously reported to cause a fully penetrant progressive macular dystrophy with high intrafamilial and interfamilial consistency of phenotype. This is the first report describing marked intrafamilial variation associated with this mutation, including nonpenetrance. These findings are clinically important in relation to advice on prognosis and accurate genetic counseling.
authors: Institute of Ophthalmology, University College London, London, United Kingdom.
authors: Michel
authors: M
authors: Michaelides
authors: Graham E
authors: GE
authors: Holder
authors: Keith
authors: K
authors: Bradshaw
authors: David M
authors: DM
authors: Hunt
authors: Anthony T
authors: AT
authors: Moore
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D004252:DNA Mutational Analysis; D004596:Electroretinography; D005190:Family; D005260:Female; D008040:Genetic Linkage; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D064531:Peripherins; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology*; D012160:Retina / Q000502:physiology; D012162:Retinal Degeneration / Q000235:genetics* / Q000503:physiopathology
chemical_list: D007381:Intermediate Filament Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C578994:PRPH protein, human; C578997:PRPH2 protein, human; D064531:Peripherins