Restriction endonuclease gene mapping studies of an Indian (A gamma delta beta)zero-thalassaemia, previously identified as G gamma-HPFH.

Restriction endonuclease mapping data are presented for the DNA of a young Indian homozygous patient (and his heterozygous parents) who were identified 10 years ago as having a G gamma-hereditary persistence of fetal haemoglobin (Sukumaran et al, 1972). However, the present results indicate a genetic lesion in these persons which is similar to that observed in another Indian with (A gamma delta beta)0-thalassaemia homozygosity (Amin et al, 1979) and is characterized by two relatively short deletions and an inversion involving the A gamma, delta and beta globin genes (Jones et al, 1981a). Some additional blot hybridization studies have provided further data confirming the deletion-inversion hypothesis.

Gamma thalassemia resulting from the deletion of a gamma-globin gene.

The first example of a deletion of one of the two gamma globin genes has been characterized through an analysis of the DNA of the heterozygous parent of a homozygous newborn, using restriction endonuclease mapping techniques. A deletion of approximately 5 kb was observed which was probably caused by an unequal crossing-over between the -G gamma- and -A gamma- genes resulting in the formation of a -G gamma A gamma- hybrid gene. Data on proportions of G gamma and A gamma chains in newborn babies assumed to be heterozygous for the hybrid and normal genes suggest that this hybrid gene may be producing its A gamma chain at levels normally seen only for the G gamma chain.

Heterogeneity in the molecular basis of three types of hereditary persistence of fetal hemoglobin and the relative synthesis of the G gamma and A gamma types of gamma chain.

Restriction endonuclease analyses of DNA from one Black G gamma A gamma-HPFH homozygote and four Black and one Indian G gamma A gamma-HPFH heterozygotes have identified three different HPFH types which are the result of large deletions including the delta and beta genes. Two of the types are comparable to those characterized previously, but the third, which is present in the Indian heterozygote, shows a distinct difference in the size of the deletion. The 5' end point of the deletion in this type III G gamma A gamma-HPFH extends 0.5-1.0 kb beyond the 5' end point of one of the Black types of HPFH (type I). Each of the three types is associated with a distinct ratio between the G gamma and the A gamma chains, an observation supported by family data. The highest ratio is found in the heterozygote with the Indian type III G gamma A gamma-HPFH, with 69.3% G gamma chains, while the averages for the other types were 50.7% G gamma (type I) and 32.3% G gamma (type II).

Thalassemia in Bombay: the role of medical genetics in developing countries.

This study of 200 families with thalassaemic children in Bombay showed that these children's treatment and needs place a significant, unavoidable and increasing demand on the public health services. At the same time, owing to the potentially large number of patients and the difficulties of long-term management, the situation is characterized by evasion of the problem, failure of planning, no provisions for prevention, and inadequate treatment leading to premature death among the affected children. The burden on such families is greater in developing than in developed countries because, besides caring for the chronically sick child, their lives are dominated by the high costs of treatment, often amounting to 20-30% of the income for many families. Seven mothers with no healthy children and 27 with only one healthy child had been sterilized; 90% of reproductive-age couples felt that prenatal diagnosis was a necessity. Also, ignorance and prejudice in the community led to social isolation for forty families. The experience in Europe shows that improved treatment is the key step in controlling thalassaemia. A well-organized day-transfusion service is cost-effective, soon restoring the children to health and leading to increased optimism. The formation of associations by parents could mobilize community support for improved treatment and prevention, and increase public awareness of the problem. Thus cost-effective management and prevention through screening, genetic counselling, and prenatal diagnosis are at least as important in the developing as in developed countries.

Homozygotes for the hereditary persistence of fetal hemoglobin: the ratio of G gamma to A gamma chains and biosynthetic studies.

Two sons of a previously reported Ghanaian homozygote for the hereditary persistence of fetal hemoglobin (HPFH) (Ringelhann et al., 1970) also are HPFH homozygotes. In addition, another unrelated adult Ghanaian homozygote has been detected. All of these Ghanaian homozygotes as well as three American Black HPFH homozygotes have the G gamma A gamma type of HPFH with a G gamma to A gamma ratio of about 3:2, in contrast to an Asiatic Indian homozygote who has the G gamma type. Globin chain synthesis in HPFH homozygotes is unbalanced, with a gamma/alpha ratio of 0.6 or less, whereas it is balanced in heterozygotes according to most reports.

The occurrence of different levels of G gamma chain and of the A gamma T variant of fetal hemoglobin in newborn babies from several countries.

The gamma chain compositions of the fetal hemoglobins of 2453 newborn babies from East Asian countries (1350 babies), from Italy, Yugoslavia, Bulgaria, and Georgia (417 Caucasian babies), and 686 black babies from Georgia were determined by high pressure liquid chromatography. Unusual results for a limited number of babies were confirmed by chemical analyses, and were evaluated further by family studies. Statistical analyses indicated high gene frequencies for the A gamma T chain in Italian (f = 0.237), Yugoslavian and Bulgarian (f = 0.238), and white Georgia babies (f = 0.224), a lower frequency in Japan (f = 0.178), and India (f = 0.173), and particularly in mainland China (f = 0.079). The A gamma T gene frequency in normal (AA) Black babies was 0.102. When a beta S or beta C mutation was also present this frequency was greatly decreased, particularly in babies with the AC condition (f = 0.036). These results suggest the near absence of the A gamma T mutation on the chromosome also carrying the beta C determinant. Most babies had the expected G gamma values which vary between 60 and 80%, but several (mainly black) babies had higher values (between 80 and 90%), while one normal black baby had a G gamma value of (nearly) 100%. This condition may be a form of A gamma +1-thalassemia and has been discussed in detail elsewhere (Blood 58:491-500, 1981). Thirty-five clinically normal (mainly Chinese, Indian, and Japanese) babies had G gamma values of about 40%. Twenty-six babies had A gamma I values of about 60%, while the remaining nine babies had A gamma T and A gamma I chains in a ratio of either 1 to 2 or 1 to 1. Two additional newborns did not produce any G gamma chains, but had only A gamma I chains or A gamma T chains. Family studies failed to indicate a specific hematological abnormality. These unusual ratios between the G gamma and A gamma (either A gamma I or A gamma T) chains have led to speculations regarding possible genetic abnormalities present in these infants.