Three different ABCA4 mutations in the same large family with several consanguineous loops affected with autosomal
Dominique Ducroq1, Stavit Shalev, Aviv Habib
1Unite de Recherches sur les Handicaps Génétiques de l'Enfants, Hôpital Necker-Enfants Malades, INSERM 393, 149 rue de Sèvres, 75743 Paris Cedex 15, France.
Insights
Genetic linkage analysis in an Israeli family with cone-rod dystrophy (CRD) revealed novel ABCA4 gene mutations. This highlights challenges in homozygosity mapping for autosomal recessive retinal dystrophies in consanguineous populations.
Area of Science:
- Genetics
- Ophthalmology
- Molecular Biology
Background:
- Autosomal recessive cone-rod dystrophy (arCORD) is a group of inherited retinal diseases.
- Genetic linkage analysis is a common method for identifying disease-causing genes.
Purpose of the Study:
- To identify the genetic cause of autosomal recessive cone-rod dystrophy in a large, multiplex Israeli family.
- To investigate the role of the ABCA4 gene in retinal dystrophies within this family.
Main Methods:
- Linkage analysis was performed to identify homozygous regions in affected family members.
- Segregation analysis of haplotypes at the CORD3 locus was conducted.
- Mutation screening of the ABCA4 gene was performed.
Main Results:
- Linkage analysis failed to identify known arCORD loci but suggested the CORD3 locus.
- Three distinct mutations in the ABCA4 gene were identified in the family.
- While most patients had CRD, one presented with Stargardt disease, indicating a spectrum of phenotypes.
Conclusions:
- The study identified novel ABCA4 mutations responsible for retinal dystrophy in the studied family.
- It underscores the difficulties of homozygosity mapping in highly inbred populations with high carrier frequencies.
- Phenotypic variability, including Stargardt disease, can be associated with ABCA4 mutations.
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.
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