title: Three different ABCA4 mutations in the same large family with several consanguineous loops affected with autosomal recessive cone-rod dystrophy.
abstract: A large multiplex family presumably affected with autosomal recessive cone-rod dystrophy (CRD) was ascertained from Israel. In this family of Christian Arab ancestry with six consanguineous loops, linkage analysis failed to identify homozygosity in all six nuclear families at any of the three arCORD loci hitherto reported. 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. Subsequently, with regard to the wide spectrum of autosomal recessive retinal dystrophies related to ABCA4 mutations, the natural history of the disease was revisited in all patients. Although the diagnosis of CRD was confirmed in 8/9 patients, the last one, aged of 34, displayed typical signs of Stargardt disease without extension to the peripheral retina. The results of this study emphasize the pitfalls of homozygosity mapping in highly inbred families when the heterozygote carrier frequency is particularly high in the general population.
authors.affiliation: Unite de Recherches sur les Handicaps Génétiques de l'Enfants, Hôpital Necker-Enfants Malades, INSERM 393, 149 rue de Sèvres, 75743 Paris Cedex 15, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Ducroq
authors.forename: Stavit
authors.initials: S
authors.lastname: Shalev
authors.forename: Aviv
authors.initials: A
authors.lastname: Habib
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Josseline
authors.initials: J
authors.lastname: Kaplan
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Rozet
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D025063:Chromosome Disorders; D003241:Consanguinity; D005260:Female; D005808:Genes, Recessive / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics*
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters