Genotype-Phenotype Correlation for Leber Congenital Amaurosis in Northern Pakistan | Genetics and Genomics | JAMA Ophthalmology | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
den Hollander  AIRoepman  RKoenekoop  RKCremers  FPM Leber congenital amaurosis: genes, proteins and disease mechanisms.  Prog Retin Eye Res 2008;27 (4) 391- 419PubMedGoogle ScholarCrossref
Bainbridge  JWSmith  AJBarker  SS  et al.  Effect of gene therapy on visual function in Leber's congenital amaurosis.  N Engl J Med 2008;358 (21) 2231- 2239PubMedGoogle ScholarCrossref
Maguire  AMSimonelli  FPierce  EA  et al.  Safety and efficacy of gene transfer for Leber's congenital amaurosis.  N Engl J Med 2008;358 (21) 2240- 2248PubMedGoogle ScholarCrossref
Mohamed  MDTopping  NCJafri  HRaashed  Y McKibbin  MAInglehearn  CF Progression of phenotype in Leber's congenital amaurosis with a mutation at the LCA5 locus.  Br J Ophthalmol 2003;87 (4) 473- 475PubMedGoogle ScholarCrossref
den Hollander  AIKoenekoop  RKMohamed  MD  et al.  Mutations in LCA5, encoding the ciliary protein lebercilin, cause Leber congenital amaurosis.  Nat Genet 2007;39 (7) 889- 895PubMedGoogle ScholarCrossref
Stone  EM Leber congenital amaurosis—a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture.  Am J Ophthalmol 2007;144 (6) 791- 811PubMedGoogle ScholarCrossref
Damji  KFSohocki  MMKhan  R  et al.  Leber's congenital amaurosis with anterior keratoconus in Pakistani families is caused by the Trp278X mutation in the AIPL1 gene on 17p.  Can J Ophthalmol 2001;36 (5) 252- 259PubMedGoogle Scholar
Dryja  TPAdams  SMGrimsby  JL  et al.  Null RPGRIP1 alleles in patients with Leber congenital amaurosis.  Am J Hum Genet 2001;68 (5) 1295- 1298PubMedGoogle ScholarCrossref
Dharmaraj  SLeroy  BPSohocki  MM  et al.  The phenotype of Leber congenital amaurosis in patients with AIPL1 mutations.  Arch Ophthalmol 2004;122 (7) 1029- 1037PubMedGoogle ScholarCrossref
Hanein  SPerrault  IGerber  S  et al.  Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis.  Hum Mutat 2004;23 (4) 306- 317PubMedGoogle ScholarCrossref
Jacobson  SGCideciyan  AVAleman  TS  et al.  Leber congenital amaurosis caused by an RPGRIP1 mutation shows treatment potential.  Ophthalmology 2007;114 (5) 895- 898PubMedGoogle ScholarCrossref
Simonelli  FZiviello  CTesta  F  et al.  Clinical and molecular genetics of Leber's congenital amaurosis: a multicenter study of Italian patients.  Invest Ophthalmol Vis Sci 2007;48 (9) 4284- 4290PubMedGoogle ScholarCrossref
Galvin  JAFishman  GAStone  EMKoenekoop  RK Evaluation of genotype-phenotype associations in Leber congenital amaurosis.  Retina 2005;25 (7) 919- 929PubMedGoogle ScholarCrossref
Gerber  SHanein  SPerrault  I  et al.  Mutations in LCA5 are an uncommon cause of Leber congenital amaurosis (LCA) type II.  Hum Mutat 2007;28 (12) 1245PubMedGoogle ScholarCrossref
Ramprasad  VLSoumittra  NNancarrow  D  et al.  Identification of a novel splice-site mutation in the Lebercilin (LCA5) gene causing Leber congenital amaurosis.  Mol Vis 2008;14481- 486PubMedGoogle Scholar
Lotery  AJJacobson  SGFishman  GA  et al.  Mutations in the CRB1 gene cause Leber congenital amaurosis.  Arch Ophthalmol 2001;119 (3) 415- 420PubMedGoogle ScholarCrossref
Yzer  SFishman  GARacine  J  et al.  CRB1 heterozygotes with regional retinal dysfunction: implications for genetic testing of Leber congenital amaurosis.  Invest Ophthalmol Vis Sci 2006;47 (9) 3736- 3744PubMedGoogle ScholarCrossref
Yzer  SLeroy  BPDe Baere  E  et al.  Microarray-based mutation detection and phenotypic characterization of patients with Leber congenital amaurosis.  Invest Ophthalmol Vis Sci 2006;47 (3) 1167- 1176PubMedGoogle ScholarCrossref
Thompson  DAGyürüs  PFleischer  LL  et al.  Genetics and phenotypes of RPE65 mutations in inherited retinal degeneration.  Invest Ophthalmol Vis Sci 2000;41 (13) 4293- 4299PubMedGoogle Scholar
Lorenz  BGyürüs  PPreising  M  et al.  Early-onset severe rod-cone dystrophy in young children with RPE65 mutations.  Invest Ophthalmol Vis Sci 2000;41 (9) 2735- 2742PubMedGoogle Scholar
Lotery  AJNamperumalsamy  PJacobson  SG  et al.  Mutation analysis of 3 genes in patients with Leber congenital amaurosis.  Arch Ophthalmol 2000;118 (4) 538- 543PubMedGoogle ScholarCrossref
Fazzi  ESignorini  SGUggetti  CBianchi  PELanners  JLanzi  G Towards improved clinical characterization of Leber congenital amaurosis: neurological and systemic findings.  Am J Med Genet A 2005;132A (1) 13- 19PubMedGoogle ScholarCrossref
Hameed  AAbid  AAziz  AIsmail  MMehdi  SQKhaliq  S Evidence of RPGRIP1 gene mutations associated with recessive cone-rod dystrophy.  J Med Genet 2003;40 (8) 616- 619PubMedGoogle ScholarCrossref
Porto  FBPerrault  IHicks  D  et al.  Prenatal human ocular degeneration occurs in Leber's congenital amaurosis (LCA2).  J Gene Med 2002;4 (4) 390- 396PubMedGoogle ScholarCrossref
Ophthalmic Molecular Genetics
January 2010

Genotype-Phenotype Correlation for Leber Congenital Amaurosis in Northern Pakistan

Author Affiliations

JANEY L.WIGGSMD, PhDAuthor Affiliations: Department of Ophthalmology, St. James's University Hospital (Drs McKibbin and Bishop), and Section of Ophthalmology and Neuroscience, Leeds Institute of Molecular Medicine (Drs McKibbin, Ali, and Inglehearn, Ms Springell, and Mr Jafri) Leeds, St Thomas's Hospital (Dr Mohamed) and Moorfields Eye Hospital (Dr Pal), London, and Royal Eye Infirmary, Plymouth (Dr Booth), England; and Department of Obstetrics and Gynaecology, King Edward Medical University, Lahore, Pakistan (Dr Raashid and Mr Jafri).

Arch Ophthalmol. 2010;128(1):107-113. doi:10.1001/archophthalmol.2010.309

Objectives  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.

Clinical Relevance  The LCA phenotype, especially one including different generations in the same family, may be used to refine a molecular diagnostic strategy.