title: Clinical phenotypes in carriers of Leber congenital amaurosis mutations.
abstract: OBJECTIVE
  To determine the clinical phenotypes in carriers with probable disease-causing sequence variations in 1 of 6 genes established to cause Leber congenital amaurosis (LCA).
  
  
  METHODS
  Observational prospective comparative study.
  
  
  METHODS
  Thirty carriers with various probable disease-causing sequence variations in 1 of 6 genes known to cause LCA.
  
  
  METHODS
  After the establishment of various disease-causing sequence variations in 37 (33.6%) of 110 patients with LCA, we examined a number of carriers who were either parents or offspring and who were willing to participate in our study. Evaluations included assessment of visual acuity, slit-lamp biomicroscopy, dilated fundus examination, and full-field electroretinogram (ERG) measurements.
  
  
  METHODS
  Dilated fundus examination and full-field ERGs.
  
  
  RESULTS
  Of the 30 carriers with probable disease-causing sequence variations for LCA, 5 (16.7%) carriers had an AIPL1 variation, 4 (13.3%) CRB1, 0 (0%) CRX, 5 (16.7%) GUCY2D, 9 (30%) RPE65, and 7 (23.3%) carriers had a RPGRIP1 variation. Twenty-nine (96.7%) carriers had 20/20 or better visual acuity in their better seeing eye with correction. Drusenlike deposits were more selectively observed in carriers with mutations in the AIPL1, CRB1, RPE65, and RPGRIP1 genes, whereas mild peripheral chorioretinal atrophy was only observed in AIPL1 and RPE65 carriers. A reduced dark-adapted isolated rod ERG response and/or maximal combined cone and rod response was recorded in carriers with mutations in the AIPL1, GUCY2D, and RPGRIP1 genes. A reduced light-adapted ERG response to a single-flash and/or 32-Hz flicker was recorded in carriers with mutations in the AIPL1, CRB1, GUCY2D, and RPGRIP1 genes. Overall, our cohort of LCA carriers did not describe significant subjective visual difficulties, including nyctalopia and/or photosensitivity.
  
  
  CONCLUSIONS
  The variation of phenotypic expression in carriers among 5 LCA genotypes indicates that there is considerable phenotypic overlap. However, phenotypic trends were noted in carriers' fundus findings and ERG responses for each genetic subtype. Observations of phenotypic associations with specific disease-causing sequence variations in carriers have potential practical value for molecular screening strategies of patients with LCA.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Galvin
authors.forename: Gerald A
authors.initials: GA
authors.lastname: Fishman
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Stone
authors.forename: Robert K
authors.initials: RK
authors.lastname: Koenekoop
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000368:Aged; D001766:Blindness / Q000151:congenital / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D003623:Dark Adaptation; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D006162:Guanylate Cyclase / Q000235:genetics; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D011446:Prospective Studies; D011506:Proteins / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D012162:Retinal Degeneration / Q000151:congenital / Q000235:genetics* / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D005136:Eye Proteins; D006162:Guanylate Cyclase; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D011956:Receptors, Cell Surface; D015534:Trans-Activators; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase; C403625:AIPL1 protein, human; C448939:CRB1 protein, human; C415903:RPGRIP1 protein, human; C109288:cone rod homeobox protein; C110715:guanylate cyclase 1