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.

Genetic heterogeneity in two consanguineous families segregating early onset retinal degeneration: The pitfalls of homozygosity mapping

“…Both locus and allelic heterogeneity, which are potential pitfalls in homozygosity mapping, may occur even within the same consanguineous family [Miano et al, 2000]. Similar examples were reported by Ducroq et al 2006, who found allelic heterogeneity in a large consanguineous Arab family segregating cone‐rod dystrophy due to three different mutations of ABCA4 ; by Fendri et al 2006, who found locus heterogeneity in a consanguineous Tunisian family with limb girdle muscular dystrophy; and by Lezirovitz et al 2008, who found both locus and allelic heterogeneity in a large consanguineous Brazilian pedigree segregating deafness. These observations should be taken into account, especially when studying relatively common and highly heterogeneous conditions, such as hereditary retinal degeneration.…”

DFNB86, a novel autosomal recessive non‐syndromic deafness locus on chromosome 16p13.3

“…Under this assumption, a linkage region of 2.0‐Mb extends from the telomere of chromosome 16p to marker D16S3395 . Although unusual, consanguineous families segregating two different mutant alleles have been reported (1, 2). Other possibilities for the haplotype data are that individuals IV:5 and IV:6 have hearing loss because of a mutation at a different locus or are phenocopies.…”

The molecular basis of autosomal recessive diseases among the Arabs and Druze in Israel

“…For instance, cone rod dystrophy is present in Christian families from several localities in the Galilee. In one of the villages, three mutations (c.5460?1G[A, c.5882G[A, c.3607G[A) were characterized in the ABCA4 gene among the Christian patients (Ducroq et al 2006). In the case of metachromatic leukodystrophy, five mutations in ARSA were found in seven different villages from a small geographic area in the lower Galilee among either Muslim or Christian Arab patients (Heinisch et al 1995).…”