Leber's congenital amaurosis with anterior keratoconus in Pakistani families is caused by the Trp278X mutation in the AIPL1 gene on 17p

Background: Leber's congenital amaurosis (LCA) represents the earliest and severest form of retinal dystrophy leading to congenital blindness. A total of 20% of children attending blind schools have this disease. LCA has a mu ltigenic basis and is proving central to our understanding of the developme nt of the retina. We describe the clinical and molecular genetic features o f four inbred pedigrees from neighbouring remote villages in northern Pakis tan, in which some of the affected members have concurrent keratoconus. Methods: History-taking and physical and eye examinations were performed in the field. Venipuncture, DNA extraction, studies of linkage to known LCA g enes, automated sequencing and polymorphism analyses for haplotype assessme nts were done. Results: We examined 12 affected and 15 unaffected family members. By histo ry, there were an additional nine blind people in the four pedigrees. In ea ch pedigree a consanguineous marriage was evident. We found a homozygous no nsense mutation in the AIPLI gene, which replaces a tryptophan with a stop codon (Trp278X). The phenotype is severe and variable, despite the common m olecular genetic etiology in each family. Affected patients had hand motion to no light perception vision and fundus findings ranging from maculopathy to diffuse pigmentary retinopathy. Three affected members had definite ker atoconus, and two were suspects based on mild cone formation in the cornea of at least one eye. Interpretation: We have identified four Pakistani families with a severe fo rm of LCA that is associated with severe keratoconus in some affected membe rs. The molecular etiology in all four families is a homozygous nonsense mu tation, Trp278X, in the photoreceptor-pineal gene AIPLI. To our knowledge, this is, one of the first phenotype-genotype correlations of AIPLI-associat ed LCA.