The ABCA4 2588G>C Stargardt mutation: single origin and increasing frequency from South-West to North-East Europe

Abstract

Inherited retinal dystrophies represent the most important cause of vision impairment in adolescence, affecting approximately 1 out of 3000 individuals. Mutations of the photoreceptor-specific gene ABCA4 (ABCR) are a common cause of retinal dystrophy. A number of mutations have been repeatedly reported for this gene, notably the 2588G4C mutation which is frequent in both patients and controls. Here we ascertained the frequency of the 2588G4C mutation in a total of 2343 unrelated random control individuals from 11 European countries and 241 control individuals from the US, as well as in 614 patients with STGD both from Europe and the US. We found an overall carrier frequency of 1 out of 54 in Europe, compared with 1 out of 121 in the US, confirming that the 2588G4C ABCA4 mutation is one of the most frequent autosomal recessive mutations in the European population. Carrier frequencies show an increasing gradient in Europe from South-West to North-East. The lowest carrier frequency, 0 out of 199 (0%), was found in Portugal; the highest, 11 out of 197 (5.5%), was found in Sweden. Haplotype analysis in 16 families segregating the 2588G4C mutation showed four intragenic polymorphisms invariably present in all 16 disease chromosomes and sharing of the same allele for several markers flanking the ABCA4 locus in most of the disease chromosomes. These results indicate a single origin of the 2588G4C mutation which, to our best estimate, occurred between 2400 and 3000 years ago.European Journal of Human Genetics (2002) 10, 197 ± 203 ã 2002 Nature Publishing Group All rights reserved 1018-4813/02 $25.00 www.nature.com

Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family

“…36 It is worth mentioning that ABCA4 c.2588G4C (p.G863A), the most frequent autosomal recessive mutation in the European population, is disease causative only in combination with a severe ABCA4 mutation, 32 and does not result in a STGD1 phenotype when present bi-allelic or in combination with a mild ABCA4 mutation. Maugeri et al 32 hypothesised the possibility of a carrier advantage due to the high carrier frequency of the 2588C allele in Sweden (1 out of 18), 37 although the incidence of STGD1 is not higher in our country than in the rest of Europe. The same phenomena can also be applied to p.N1868I.…”

Microarray-based mutation analysis of the ABCA4 (ABCR) gene in autosomal recessive cone–rod dystrophy and retinitis pigmentosa

“…Based on a genotype -phenotype correlation model proposed by us and others, individuals carrying two 2588C alleles would not be expected to show retinal pathology since this variant was deemed a mild allele. 33,49 In three of the 2588C carrying haplotypes (in patients 15730 and 16755, Table 1), the 2588C and 2828A variants are not accompanied by the polymorphic variants 4203A, 5603T, and 5682C (data not shown), but might have been linked to a more severe mutation in the 3 0 part of the gene. Also, the 2588C variant has been found in cis with an intragenic deletion spanning exon 14 of the ABCA4 gene in a French RP patient.…”

CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia

“…This predominance of a single mutation is one of very few examples among retinal diseases such as the p.P23H RHO gene mutation in the US patients with autosomal dominant retinitis pigmentosa, 17 the p.R345W EFEMP1 gene mutation in Malattia Leventinese and Doyne honeycomb retinal dystrophy, 18 or the c.2588G4C ABCA4 gene mutation in middle and northern European Stargardt disease patients. 19 In comparable samples, screening for the c.1148delC mutation will enable the molecular diagnosis of almost 40% of all achromatopsia cases with a single assay.…”