A new family of Greek origin maps to the CRD locus for autosomal dominant cone-rod dystrophy on 19q.

Retinal photoreceptor dystrophies (RD) are a highly heterogeneous group of genetic disorders of the retina, representing the most frequently inherited form of visual handicap, affecting approximately 1.5 million people world wide. To date, more than 40 genetic loci have been implicated in RD. One of them, the CORD2 locus, for an autosomal dominant form of cone-rod dystrophy (CRD), maps to chromosome 19q and has previously been reported in a single large family of British origin. We now report a new family with severe early onset CRD, phenotypically very similar to the British family, which also maps to 19q, but is of Greek origin. Haplotype data of the Greek family showed no recombination between and including markers D19S219 and D19S246 and linkage analysis gave a lod score of 2.7 (at theta=0) with marker D19S412, confirming the data obtained in the British family.

Double mutant alleles: are they rare?

The presence of two different mutations carried by the same CF allele has been demonstrated in four out of 44 Bulgarian CF patients during a systematic search of the entire coding sequence of the CFTR gene. Two of the double mutant alleles include one nonsense and one missense mutation and although the nonsense mutation can be considered to be the main defect, the amino acid substitutions are good candidates for disease-causing mutations as well. One double mutant carries two missense mutations whose contribution to the CF phenotype is difficult to evaluate. The findings suggest that double mutant alleles may be more common than expected and could account for some of the problems in phenotype-genotype correlations. Such alleles may have important implications for molecular diagnosis and genetic counselling.

Analysis of 14 cystic fibrosis mutations in five south European populations.

We have analysed five Southern European populations (Albanian, Greek, Italian, Spanish and Yugoslavian) for 14 cystic fibrosis (CF) mutations. The most frequent mutations, apart from delta F508, were G542X (6.04%), R1162X (3.61%) and N1303K (3.24%). Each of the other analysed mutations were present at a frequency of less than 1% (R347P, R334W, S549RA, S549I, G551D, R553X and W1282X), and four mutations (D110H, delta I507, S549RT, and S1255X) were not found in this sample. The data presented here allows the use of mutation analysis in 69.5% of Spanish, 58% of Greek, and 56.5% of Italian CF cases.

Cystic fibrosis in Greece: typing with DNA probes and identification of the common molecular defect.

The relative frequency of the delta F508 mutation in the Greek population is 54.1%; this is similar to that reported in other Southern European populations and contrasts with the considerably higher frequencies encountered in Northern Europe and North America. The low frequency is in agreement with the linkage disequilibrium already reported between cystic fibrosis and haplotype B in this country. In contrast to the common association of pancreatic insufficiency with the homozygous delta F508 genotype, the present study revealed two homozygous children with no evidence of pancreatic failure.

Studies of RFLP closely linked to the cystic fibrosis locus throughout Europe lead to new considerations in populations genetics.

The prenatal diagnosis of cystic fibrosis is now routinely performed by using two probes tightly linked to the CF locus (XV2C and KM19). These probes have been shown to exhibit a strong linkage disequilibrium with the CF locus. Our data (103 families) have been pooled with other French data (237 families). They are consistent with the hypothesis of a unique ancestral mutation initially associated with a B (D1E2) restriction fragment length polymorphism (RFLP) haplotype, subsequently reassociated by cross-over with A, C or D haplotypes. Assuming such an hypothesis, the mutation is supposed to be 3000-6000 years old, depending on generation length and the true recombination ratio between the KM19 and CF loci. Up-to-date Spanish, Danish and Greek data are reported together with other previously published population data in order to discuss the geographic origin and age of the mutation in Europe. The action of selection in terms of heterozygote advantage and distorsion of segregation is discussed.

Haplotypes in cystic fibrosis patients with or without pancreatic insufficiency from four European populations.

We examined the allele and haplotype frequencies of five polymorphic DNA markers in 355 European cystic fibrosis (CF) patients (from Belgium, the German Democratic Republic, Greece, and Italy) who were divided into two groups according to whether they were or not taking supplementary pancreatic enzymes. The level of linkage disequilibrium between each polymorphism and the CF mutation varied among the different populations; there was no significant association between KM.19 and CF in the Greek population. The distributions of alleles and haplotypes derived from the polymorphisms revealed by probes KM.19 and XV.2c were always different in patients with or without pancreatic insufficiency (PI) in all the populations studied. In particular, among 32 patients without PI, only 9 (or 28%) were homozygous for the KM.19-XV.2c = 2-1 haplotype (which was present in 73% of all the CF chromosomes in our sample) compared to 162 of 252 patients (or 64%) with PI. These findings are consistent with the hypothesis that pancreatic insufficiency or sufficiency may be determined by different mutations at the CF locus.