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Martin McKibbin, FRCOphth; Manir Ali, PhD; Moin D. Mohamed, FRCS; Adam P. Booth, FRCOphth; Fiona Bishop, FRCOphth; Bishwanath Pal, FRCOphth; Kelly Springell, BSc; Yasmin Raashid, FRCOG; Hussain Jafri, MBA; Chris F. Inglehearn, PhD

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.

Author 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).

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