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S.P. Shankar, A.M. Shire, J.J. S. Laffin, L.M. Streb, C.M. Taylor, H.L. Haines, J.C. Janutka, M.D. Megonigal, V.C. Sheffield, E.M. Stone; ABCA4 Sequence Variations in Somali and North American Populations . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1699.
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Mutations in the ABCA4 gene cause Stargardt macular dystrophy, cone/rod dystrophy, and Retinitis Pigmentosa. In an ethnically diverse population like that in the United States, a large number of different ABCA4 sequence variations can be found in both normal and affected individuals making the estimation of their pathogenic potential challenging. The purposes of this study were 1) to identify additional disease–causing ABCA4 sequence variations in North American patients with Stargardt disease, and 2) to evaluate the pathogenic potential of the Gly1961Glu sequence variation (the most common disease–associated variant in North American Stargardt patients).
A combination of SSCP, restriction digestion and DNA sequencing was used to screen ABCA4 for sequence variations in 852 unrelated probands with Stargardt disease and 91 normal subjects of North American origin. The "estimate of pathogenic probability" (EPP) was determined for each variation observed. In addition, we screened two Somali families with Stargardt disease and 637 normal subjects of Somali origin for the Gly1961Glu sequence variation.
We identified 259 instances of 115 different ABCA4 sequence variations with an EPP suggesting high pathogenic potential among 374 unrelated Stargardt probands from North America. In addition, the Gly1961Glu change was sought in an additional 478 Stargardt probands and was observed in 73/852 North American Stargardt patients (8.6%). This allele was observed in the heterozygous state in 60/637 (9.4%) of normal individuals born in Somalia. It was also observed in the homozygous state in a 25 year old Somali man with normal vision.
We were able to identify ABCA4 sequence variants that seem likely to be high–penetrance recessive disease alleles in 34.6% of the alleles of Stargardt patients living in North America. The most common such variant is Gly1961Glu, which is seen in the heterozygous state in approximately 10% of North American Stargardt patients. The high frequency of this allele in the Somali population (and its homozygosity in one Somali adult with normal vision) suggests that this allele is not likely to cause macular disease in the homozygous state in that population, and raises the possibility that there is a genetic background effect that makes certain ABCA4 alleles more likely to cause disease in people from North America than in people from Somalia.
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