title: Genotype-phenotype correlation for leber congenital amaurosis in Northern Pakistan.
abstract: OBJECTIVE
  To report the genetic basis of Leber congenital amaurosis (LCA) in northern Pakistan and to describe the phenotype.
  
  
  METHODS
  DNA from 14 families was analyzed using single-nucleotide polymorphism and microsatellite genotyping and direct sequencing to determine the genes and mutations involved. The history and examination findings from 64 affected individuals were analyzed to show genotype-phenotype correlation and phenotypic progression.
  
  
  RESULTS
  Homozygous mutations were found in RPGRIP1 (4 families), AIPL1 and LCA5 (3 families each), and RPE65, CRB1, and TULP1 (1 family each). Six of the mutations are novel. An additional family demonstrated linkage to the LCA9 locus. Visual acuity, severe keratoconus, cataract, and macular atrophy were the most helpful features in predicting the genotype. Many of the phenotypic variables became more prevalent with increasing age.
  
  
  CONCLUSIONS
  Leber congenital amaurosis in northern Pakistan is genetically heterogeneous. Mutations in RPGRIP1, AIPL1, and LCA5 accounted for disease in 10 of the 14 families. This study illustrates the differences in phenotype, for both the anterior and posterior segments, seen between patients with identical or different mutations in the LCA genes and also suggests that at least some of the phenotypic variation is age dependent.
  
  
  CONCLUSIONS
  The LCA phenotype, especially one including different generations in the same family, may be used to refine a molecular diagnostic strategy.
authors.affiliation: Department of Ophthalmology, St. James's University Hospital, Beckett Street, Leeds LS9 7TF, England. martin.mckibbin@leedsth.nhs.uk
authors.forename: Martin
authors.initials: M
authors.lastname: McKibbin
authors.forename: Manir
authors.initials: M
authors.lastname: Ali
authors.forename: Moin D
authors.initials: MD
authors.lastname: Mohamed
authors.forename: Adam P
authors.initials: AP
authors.lastname: Booth
authors.forename: Fiona
authors.initials: F
authors.lastname: Bishop
authors.forename: Bishwanath
authors.initials: B
authors.lastname: Pal
authors.forename: Kelly
authors.initials: K
authors.lastname: Springell
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Raashid
authors.forename: Hussain
authors.initials: H
authors.lastname: Jafri
authors.forename: Chris F
authors.initials: CF
authors.lastname: Inglehearn
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics; D005838:Genotype; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000453:epidemiology / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics; D018895:Microsatellite Repeats; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D010154:Pakistan / Q000453:epidemiology; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D014792:Visual Acuity; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D005136:Eye Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase; C403625:AIPL1 protein, human; C448939:CRB1 protein, human; C522405:LCA5 protein, human; C415903:RPGRIP1 protein, human; C105443:TULP1 protein, human