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E. I. Traboulsi, Q. Xi, J. Sears, Q. K. Wang; Novel Compound Heterozygous Mutations in Abca4 Cause Severe Progressive Cone-Rod Dystrophy. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3099.
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© ARVO (1962-2015); The Authors (2016-present)
To identify the gene causing a severe form of progressive autosomal recessive cone-rod dystrophy presenting as Stargardt disease and to characterize its clinical features in a U.S. family.
We examined a family with an unusual retinal dystrophy with early clinical features of Stargardt disease and severe progressive cone-rod dysfunction. Family members underwent complete ocular examinations with evaluation of visual acuity, visual fields, fundus examination, fluorescein angiography and electroretinography. Genome-wide linkage analysis of the family was performed using 408 microsatellite markers spanning the entire human genome. Direct DNA sequence analysis was used for mutational analysis of the ABCA4 gene in all exons and exon-intron boundary regions and for testing co-segregation of the mutations with the disease in the family. SSCP analysis was used to determine the presence of the mutations in 200 unrelated normal controls.
The proband presented with a clinical phenotype that was initially compatible with Stargardt disease, only to progress to a severe cone-rod dystrophy over the course of a few years. The disease-causing gene in the family was linked to the ABCA4 locus on chromosomal 1p22. One novel mutation R219X was identified in exon 6 and another novel splicing mutation IVS37+3A>T was identified in intron 37 of ABCA4. The mutations were not present in 200 normal controls. The two affected sisters in this pedigree were compound heterozygotes for the mutations Unaffected family members either did not carry either or had only one of the two mutations.
We identified two novel severe ABCA4 mutations, R219X and IVS37+3A>T. When present as in a compound heretozygous state, the mutations cause an interesting phenotype of retinal dystrophy that initially manifests as Stargardt disease and progresses into a severe cone-rod dystrophy.
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