Fetal hemoglobin and G gamma levels have been correlated with the presence or absence of eight restriction sites within the beta globin gene cluster (haplotypes) for numerous sickle cell anemia patients from Georgia. The most common haplotypes were #19 (Benin) and #20 (CAR); all patients with haplotype combinations 19/19, 20/20, and 19/20 were severely affected with low Hb F and low G gamma levels. A modified #19 beta S chromosome with a -G gamma-G gamma- globin gene arrangement, instead of -G gamma-A gamma-, was present in SS and SC newborn babies with G gamma values above 80%. Haplotype #3 (Senegal) was present among 15% of the beta S chromosomes; the two adult patients with the 3/3 combination were mildly affected with high Hb F and G gamma values. The haplotype AT with the variant A gamma T chain was a rarity. A new haplotype was found in one 17-year-old SS patient and five of his Hb S heterozygous relatives. This haplotype is associated with an increased production of Hb F in heterozygous and homozygous Hb S individuals; this Hb F contained primarily A gamma chains. A comparison was made between the different haplotypes among SS patients and normal Black individuals, and a remarkable similarity was noted in the fetal hemoglobin data for subjects with these different chromosomes.

Over 60 patients from the Luo and Luhya tribes of Western Kenya, aged 1-23 years, with severe sickle cell anaemia were evaluated through haematological and gene mapping analyses. Nearly all (56 of 58 tested) were homozygous for haplotype 20 (Antonarakis et al, 1984) which is also frequently present in SS patients of the Central African Republic. All patients had a severe haemolytic anaemia with low Hb F levels and low levels of G gamma chains. An alpha-thalassaemia-2 heterozygosity (-alpha/alpha alpha; -3.7 kb deletion) was present in 26 of 53 patients tested; one patient was a homozygote [f(-alpha) = 0.255]. The alpha-thal-2 was type I in all but one subject with this deficiency; the one exception had an alpha-thal-2 heterozygosity, type II. Heterozygosity for the alpha-thal-2 did not affect the clinical condition nor the haematology; Hb F levels were somewhat lower in SS patients with -alpha/alpha alpha than in those with alpha alpha/alpha alpha. A high frequency was observed for the absence of an Xba I restriction site 5' to the zeta globin gene; the frequency of this anomaly [f(Xba I-)] was estimated at 0.39 for the chromosome with two alpha globin genes and at 0.74 for that with the alpha-thal-2 deletion. An Apa I restriction site polymorphism was observed in the IVS-II of the alpha 2 globin gene; 13 alpha 2 genes of 53 normal (alpha alpha/) chromosomes had this restriction site which was absent in the hybrid alpha globin gene of the -alpha/chromosome.

Hematological and hemoglobin composition data are presented for seven Arabian SS patients with mild disease and with high Hb F levels varying between 21 and 34%. Four patients were homozygous for a beta S chromosome with a specific haplotype (#31). The data for these four patients were similar to those for three other SS patients (and for five patients reported earlier, Ref. 2) who were heterozygous for the same beta S chromosome (#31) and for a beta S chromosome with another haplotype (mainly #19). These data offer additional evidence indicating that the increased gamma chain production is specific for the beta S chromosome with haplotype #31. The similarities in hematological data and Hb F levels between these two groups of SS patients and the normal Hb F value in Hb S heterozygotes with beta S chromosome (#31) support the suggestion that the increased Hb F production mainly occurs in response to the anemia of the sickle cell disease.

The levels of G gamma chain in the fetal hemoglobin of more than 40 Black and Caucasian females were determined with a sensitive high performance liquid chromatography procedure and were correlated with their haplotypes, defined by the presence or absence of 10 different restriction sites. Blood was collected during the 16th and 31st week of pregnancy because of a slightly elevated level of Hb F which facilitated the isolation of this protein from a relatively small sample. Four distinct G gamma levels were observed, each being associated with a specific haplotype. Homozygosity for sub-haplotype A [- + + - + +] is associated with high G gamma values (60-70%); that for sub-haplotype B [- - - - - +] with low levels (25-30%); and that for sub-haplotype C [+ - - - - -] with very low levels (10-15%) (restriction sites listed are Hinc II at epsilon; Xmn I 5' to G gamma; Hind III at G gamma and A gamma; Hinc II at psi beta and 3' to it). Sub-haplotype D [(14)- + - - +] with a rare polymorphism 5' to epsilon is associated with extremely high G gamma values. Hb F levels were low (less than 2.5%) and were independent of the haplotype. It is speculated that, yet unknown, variations in the DNA of gene activity controlling regions are responsible for the differences in G gamma value.

Fetal hemoglobin analysis and globin gene mapping have identified one type of beta(0)-thalassemia and four different gamma globin gene arrangements among newborn babies from the northern part of Sardinia. The beta(0)-thalassemia with a nonsense mutation at codon 39 was found on two chromosomes, each with a distinct pattern of polymorphic restriction sites; one had the A gamma T (A gamma 75 Ile----Thr) mutation, while the second did not. Four closely related haplotypes were identified for chromosomes with the A gamma T mutation. The gamma-thalassemia heterozygosity with the -GA gamma- hybrid gene fell into two categories. One apparently originated through crossing-over between mismatched chromosomes characterized by the most common haplotype, while the other had polymorphisms resembling those of a less frequently occurring chromosome. Chromosomes with the -G gamma-AG gamma-A gamma- triplication had polymorphic sites to be expected for this condition, being complimentary to the -GA gamma- thalassemias. Of the two additional gamma globin gene variations the -G gamma- G gamma- arrangement was associated with the chromosome with the most commonly occurring haplotype, while the chromosome with the -A gamma-A gamma- arrangement had a haplotype characteristic for that with the A gamma T mutation, which identified an -A gamma-A gamma T- arrangement. The incidental discovery of a silent beta-chain mutant, Hb Hamilton, with the Val----Ile substitution at position beta 11, in five newborns was also reported.