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S. Kohl, V. B. D. Kitiratschky, T. Grau, S. Schaich, B. Wissinger, ABCA4 Clinical Study Group; ABCA4 Gene Analysis in Patients With Autosomal Recessive Cone and Cone Rod Dystrophies. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3098.
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Mutations in ABCA4 have been initially associated with autosomal recessive Stargardt disease, but can also cause other retinal dystrophies including cone-rod dystrophy and retinitis pigmentosa. We have screened 64 unrelated patients and families with autosomal recessive cone (arCD) and cone-rod dystrophy (arCRD) to determine the prevalence and mutation spectrum of ABCA4 gene mutations in these phenotypes.
Initial mutation screening was performed with the ABCR400 microarray (AsperBiotech, Tartu, Estonia). Sequence analysis of ABCA4 was done employing the VariantSEQr Resequencing System and BigDye Sequencing Chemistry (Applied Biosystems, Darmstadt, Germany). Segregation analysis in family members was performed by DNA sequencing of the respective exon(s), and novel sequence variants were evaluated in healthy control individuals by PCR/RFLP analysis.
ABCR400 gene chip analysis identified ABCA4 gene mutations in 20 of 64 unrelated patients. Three of these patients were homo- and ten compound heterozygous for two mutant ABCA4 alleles, and seven patients carried only single heterozygous mutations. By design, the chip only detects known sequence variants and thus misses novel mutations. Sequencing analysis of all coding exons of the ABCA4 gene in the seven patients with only single mutations identified three novel mutations (c.700C>T, c.3539_3554del, and c.4848+2T>C) in three unrelated patients. In total, microarray and the "all-exon-sequencing" approach together identified 36 mutant ABCA4 alleles, representing 24 different sequence variants.
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