First trimester diagnosis of the hemoglobin disorders.
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Anemia, Sickle Cell↗
Biomedical subjects
J M Old
Publications and source records attributed to J M Old.
Prenatal diagnosis of the common haemoglobin disorders.
New techniques of DNA analysis have been applied to the prenatal diagnosis of the common haemoglobin disorders. Currently, it is possible to provide a comprehensive programme for the prevention of these conditions, although this entails the use of several different techniques including globin chain synthesis analysis, direct identification of mutations with restriction enzymes, linkage analysis of restriction fragment length polymorphisms, and the use of oligonucleotide probes. At present, the best combination of these approaches has to be worked out for individual populations, but as the techniques of chorion villus sampling and DNA analysis improve it should be possible to rationalise these prenatal diagnosis programmes and thus make them simpler and less expensive.
Anemia, Sickle Cell↗
Prenatal diagnosis of ornithine carbamoyl transferase deficiency using a gene specific probe.
A gene specific DNA probe has been used to predict the genotype of two fetuses in families at risk for ornithine carbamoyl transferase deficiency. Although the probe does not detect the mutation directly, prediction was possible by examining restriction fragment length polymorphisms of the parents and sibs to identify the X chromosome carrying the mutation. It is suggested that in all pregnancies, regardless of the predicted outcome, the biochemical status of carrier mothers should be monitored because hyperammonaemia and arginine deficiency may have a deleterious effect on the fetus.
Amino Acid Metabolism, Inborn Errors↗
[Prenatal prevention of drepanocytosis: analysis of cellular DNA in 2 cases].
Direct analysis of fetal DNA using restriction endonucleases constitutes a major area of progress in prenatal diagnosis. This recent technology may permit the precise identification of a mutant allele for some diseases, whereas in others it allows the familial segregation of a pathogenic allele to be followed by its linkage to a DNA sequence polymorphism. This type of analysis, available in a few centers, is currently used, among others, for the prenatal diagnosis of hemoglobinopathies such as sickle cell anemia. After fetal cells have been obtained by choriocentesis or amniocentesis, the extracted DNA is exposed to selected restriction enzymes. In the diagnosis of sickle cell anemia the mutant codon responsible for the substitution of glutamic acid by valine in the beta hemoglobin chain is no longer cut by the enzyme Mst II, due to its variance with the normal codon; this difference in fragment length is detected by DNA electrophoresis, and the particular fragments are identified by molecular hybridization with appropriate radioactive probes. Utilizing these methods the genotype of a homozygous normal fetus can be distinguished from that of a homozygote affected or a heterozygote for the sickle mutation of the beta hemoglobin chain. We have recently applied this prenatal methodology to the pregnancies of two couples from Zaire, in which each member was a proven sickle cell carrier. Fetal material was obtained in both cases by amniocentesis at the 16th week of gestation and followed by cell culture. In the first case, a 46, XX fetus, DNA (10 mcg) revealed a heterozygous sickle cell carrier genotype.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
A new DNA polymorphism for prenatal diagnosis of beta-thalassaemia in Mediterranean populations.
The prevalence of a new polymorphism for the restriction enzyme Ava II in the psi beta-gene of the beta-globin gene cluster was determined in Mediterranean families with at least one beta-thalassaemia homozygote. The polymorphic site was absent in 54/115 beta-thalassaemic chromosomes but only in 4/120 normal chromosomes. The difference in frequencies of this polymorphism between normal and thalassaemic chromosomes greatly increases the feasibility of prenatal diagnosis of beta-thalassaemia by DNA analysis in this population.
Asia, Western↗
Population and genetic studies suggest a single origin for the Indian deletion beta thalassaemia.
In a study of beta thalassaemia in the Asian Indian immigrant populations in the U.K., 23 out of 125 beta-thalassaemic chromosomes (18%) were of the Indian deletion beta type (600 bp deletion involving the 3' end). The individuals with beta thalassaemia had originated from various parts of India and Pakistan. However, all those individuals with deletion beta thalassaemia were from Sind and the adjacent area of Gujarat. Analysis of restriction fragment length polymorphisms in the beta globin gene cluster showed that all the 23 deletion beta thalassaemia chromosomes had an identical haplotype. These findings suggest a single origin for the Indian deletion beta thalassaemia.
Chromosome Deletion↗
Characterization of an Indian (delta beta)0 thalassaemia.
The molecular basis of delta beta thalassaemia in an Indian family is shown here to be due to a previously undescribed deletion within the beta globin gene complex. Starting 3 kilobases from the 3' end of the A gamma gene, the deletion removes the delta and beta globin genes and continues to an unknown extent in the 3' direction. Heterozygotes for this deletion have about 25% Hb F with a G gamma:A gamma ratio of 70:30 while interaction with beta+ thalassaemia results in the clinical picture of thalassaemia intermedia.
Child↗
Feasibility of antenatal diagnosis of beta thalassaemia by DNA polymorphisms in Asian Indian and Cypriot populations.
The feasibility of using restriction fragment length polymorphisms ( RFLPs ) for the antenatal diagnosis of beta thalassaemia in the U.K.-resident Cypriot and Asian Indian populations has been determined. Seven polymorphic restriction endonuclease sites in the beta globin gene cluster were analysed in 20 Cypriot and 42 Asian patients and their parents and the combination of polymorphic sites (haplotype) for each chromosome determined. It was found that 76% of the Asian and 35% of the Cypriot families had DNA polymorphisms which would allow antenatal diagnosis of a homozygous beta thalassaemic fetus, and that in the majority of the remaining families there was a 50% chance of a successful diagnosis of either a normal or a heterozygous fetus. These results indicate that RFLP analysis of fetal DNA is a useful method for antenatal diagnosis of beta thalassaemia in families with either a normal or homozygous beta thalassaemia child, especially in the Asian population in the U.K.
Child↗
The molecular basis for the clinical diversity of beta thalassaemia in Cypriots.
Much of the clinical variability in the course of homozygous beta thalassaemia in the Cypriot population can be accounted for by the interaction of alpha thalassaemia and by the existence of different molecular forms of beta thalassaemia. Most severe forms of the disorder result from the homozygous state for the common Mediterranean type of beta thalassaemia. One particularly mild form of beta thalassaemia, which also occurs in other Mediterranean populations, results from a single base change at position 6 in the first intervening sequence of the beta-globin gene. These observations provide a basis for the development of a programme for first-trimester antenatal diagnosis using oligonucleotide probes.
Adolescent↗
Maturity onset diabetes of the young is not linked to the insulin gene.
Maturity onset diabetes of the young is inherited as an autosomal dominant condition. Two families with the disease were studied to determine whether the inheritance of this type of diabetes was linked to the insulin gene. A cloned insulin gene probe was hybridised to DNA from the family members and the insulin gene on each chromosome identified by a different fragment length polymorphism. The results showed no linkage between the insulin gene and the inheritance of maturity onset diabetes of the young.
Adolescent↗
A new DNA polymorphism in the beta-globin gene cluster can be used for antenatal diagnosis of beta-thalassaemia.
Restriction endonuclease analysis of the human beta-globin gene cluster has revealed a new DNA polymorphism at a Pvu II recognition site approximately 3.5 kilobases from the 3' end of the Agamma-globin gene. In patients from the Mediterranean area, the Pvu II polymorphism was associated equally with both normal and beta-thalassaemia chromosomes. In patients of Indian and Pakistani origin the polymorphism was almost exclusively associated with only the normal chromosome. Therefore this site may prove very useful for the antenatal diagnosis of beta-thalassaemia by acting as a genetic marker for the normal chromosome in linkage analysis of family members.
Chromosome Mapping↗
Globin gene mapping studies in Sardinian patients homozygous for beta zero Thalassaemia.
The genetic factors responsible for the relatively mild clinical phenotypes of some cases of homozygous beta zero thalassaemia (thalassaemia intermedia) in Sardinia have been evaluated. The frequency of deletion forms of alpha thalassaemia was higher in patients with thalassaemia intermedia (6/8) than in those with thalassaemia major (6/17). The beta globin gene clusters were also studied, first to determine whether there were any rearrangements of the gamma genes, and second to see whether the restriction fragment length polymorphism patterns (haplotypes) of the two groups of patients were similar. The structure of the gamma genes was normal in all the patients with the single exception of a thalassaemia major patient with a triplicated gamma gene arrangement. The beta globin gene cluster haplotypes of the two groups of patients were not significantly different. However, the frequency of the various haplotypes in the thalassaemic as compared to the normal (beta A) chromosomes was different. This finding is of potential value in the antenatal diagnosis of homozygous beta thalassaemia in this population.
Child↗
Antenatal diagnosis of the haemoglobin disorders by analysis of foetal DNA.
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Anemia, Sickle Cell↗
First-trimester fetal diagnosis for haemoglobinopathies: three cases.
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Anemia, Sickle Cell↗
Linkage analysis of nondeletion hereditary persistence of fetal hemoglobin.
Nondeletion forms of hereditary persistence of fetal hemoglobin may result from regulatory disorders of globin gene expression. The defects in two such conditions were localized by demonstrating a tight genetic linkage between the disorders and polymorphic restriction endonuclease sites within the beta-like globin gene complex. In one instance, the defect probably occurred outside the region of DNA between the epsilon- and beta-globin genes.
Chromosome Deletion↗
Restriction endonuclease maps of the beta-like globin gene cluster in the British and Greek forms of HPFH, and for one example of G gamma beta + HPFH.
We report here restriction endonuclease maps of the beta-like globin gene cluster for the British form of HPFH and for a case of G gamma beta + HPFH, and also confirm and extend previous reports of the map for the Greek form of HPFH. These results show that all these conditions belong to a group lacking any substantial deletion or rearrangement of DNA sequence in this gene cluster. The absence of any gross disruption of the structure of this region of the genome, together with evidence that the HPFH genotype is either allelic with, or closely linked to, the beta-like globin gene cluster, suggests that the responsible lesions are nearer to being purely regulatory in nature than in forms of HPFH due to substantial deletions. Thus these conditions promise to provide less equivocal evidence about the regulation of beta-like globin gene expression than has so far been available.
Chromosome Mapping↗
A novel rearrangement of the human beta-like globin gene cluster.
The first example of a duplication involving the human beta-like globin genes has been characterised in DNA from a native of Vanuatu. Restriction endonuclease mapping has shown that a 5 kb insert of DNA in the gamma-delta-beta gene cluster is due to duplication of the Ggamma-globin gene and results in a new rearrangement 5'-epsilon-Ggamma-Ggamma-Agamma-delta-beta-3'.
Adult↗
Restriction mapping of a new deletion responsible for G gamma (delta beta)o thalassemia.
DNA from individuals heterozygous for (G)gamma(deltabeta)(o) thalassaemia has been studied by restriction endonuclease analysis. The results reveal a new molecular defect associated with this condition. A total of three defects is now responsible for the one single phenotype, thereby emphasising the complex relationship between genotype and phenotype among the disorders of beta-like globin synthesis in man.
Chromosome Deletion↗