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1 From the Departments of Ophthalmology and 6 Pediatrics, The University of Iowa College of Medicine, Iowa City; 2 Institute of Ophthalmology and Moorfields Eye Hospital, London, United Kingdom; the 3 Department of Ophthalmology, University of Toronto, Canada; 4 Vision Science Research Program, University Health Network, Toronto, Canada; the 5 Department of Electrical Engineering and Computer Science, The University of Iowa, Iowa City; 7 University of Illinois Eye and Ear Infirmary, Chicago; 8 Bascom Palmer Eye Institute, University of Miami, Florida; 9 The Jules Stein Eye Institute, The University of California at Los Angeles; the 10 Department of Ophthalmology, Scheie Eye Institute, Philadelphia, Pennsylvania; 11 The Casey Eye Institute, The Oregon Health Sciences University, Portland; and 12 The Howard Hughes Medical Institute, Iowa City.
PURPOSE. To assess the allelic variation of the ATP-binding transporter protein (ABCA4).
METHODS. A combination of single-strand conformation polymorphism (SSCP) and automated DNA sequencing was used to systematically screen this gene for sequence variations in 374 unrelated probands with a clinical diagnosis of Stargardt disease, 182 patients with age-related macular degeneration (AMD), and 96 normal subjects.
RESULTS. There was no significant difference in the proportion of any single variant or class of variant between the control and AMD groups. In contrast, truncating variants, amino acid substitutions, synonymous codon changes, and intronic variants were significantly enriched in patients with Stargardt disease when compared with their presence in subjects without Stargardt disease (Kruskal–Wallis P < 0.0001 for each variant group). Overall, there were 2480 instances of 213 different variants in the ABCA4 gene, including 589 instances of 97 amino acid substitutions, and 45 instances of 33 truncating variants.
CONCLUSIONS. Of the 97 amino acid substitutions, 11 occurred at a frequency that made them unlikely to be high-penetrance recessive disease-causing variants (HPRDCV). After accounting for variants in cis, one or more changes that were compatible with HPRDCV were found on 35% of all Stargardt-associated alleles overall. The nucleotide diversity of the ABCA4 coding region, a collective measure of the number and prevalence of polymorphic sites in a region of DNA, was found to be 1.28, a value that is 9 to 400 times greater than that of two other macular disease genes that were examined in a similar fashion (VMD2 and EFEMP1).
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