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D. Ducroq, S. Shalev, A. Habib, A. Munnich, J. Kaplan, J.–M. Rozet; Three Different ABCA4 Mutations in the Same Large Consanguineous Family Affected With Autosomal Recessive Cone–Rod Dystrophy: Further Evidence for a High Frequency of ABCA4 Heterozygote Carriers . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1698.
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© ARVO (1962-2015); The Authors (2016-present)
To identify the molecular defect responsible for autosomal recessive cone–rod dystrophy segregating in a large multiplex and consanguineous family of Christian–Arab ancestry.
This pedigree was made of six nuclear families gathering ten affected members and six healthy relatives. All family members underwent general and ophthalmologic examinations. Among affected patients, 7/10 displayed typical signs of the so–called cone–rod dystrophy, 1/10 was affected with a typical Stargardt disease. In 2/10 affected patients the exact diagnosis could not be definitely carried with regard to their young age. Each family member’s blood was collected in Afula, Israel,and analyzed in France.A linkage analysis was performed in this pedigree using polymorphic markers flanking each of the three hitherto known arCRD loci: CORD3, CORD8 and CORD9, respectively. Subsequently, all 50 exons of the ABCA4 gene at the CORD3 locus were screened for mutations by direct sequencing.
Linkage analysis failed to identify homozygosity in the six nuclear families of this large pedigree at any of three arCORD loci. However, homozygosity was found at the CORD3 locus for two nuclear families and the segregation of three distinct haplotypes at this locus in the whole pedigree suggested the alteration of the ABCA4 gene. This hypothesis was confirmed by the identification of three distinct mutations leading to either cone–rod dystrophy or Stargardt disease depending of the nature of the mutations carried by affected members.
The results of this study emphasize the trap of homozygosity mapping in highly inbred families when the heterozygote carrier frequency is much higher than the mean frequency of heterozygote individuals in the general population.
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