A novel deletion of approximately 27 kb including the beta-globin gene and the locus control region 3'HS-1 regulatory sequence: beta zero- thalassemia or hereditary persistence of fetal hemoglobin?

Abstract

A novel deletion of approximately 27 kb with the 5′ breakpoint 1.5 to 2.2 kb upstream of the beta-globin gene, and the 3′ breakpoint approximately 24 kb downstream of the beta-globin gene, has been found in five members of two families from Southeast Asia (Vietnam and Cambodia). Six members of another family from China, previously reported from our laboratory, have also been shown to carry this deletion. The patients presented with mild hypochromia and microcytosis, a hemoglobin (Hb) A2 level of approximately 4.0%, and a markedly increased, heterocellularly distributed, Hb F level (14.0 to 26.0%). In vitro globin-chain synthesis showed a mild imbalance with appreciable gamma-chain compensation (alpha/beta + gamma ratio of 1.46). The 3′ end of this deletion includes the 3′HS-1, and we hypothesize that removal of this region results in the loss of its gamma-globin gene-silencing effect, which causes a markedly elevated Hb F level with a modest increase in Hb A2 levels, unlike the situation in other deletional beta zero-thalassemias. The possible influence of particular sequence variations in the locus control region 5′HS-2 and the G gamma promoter, present on the chromosome with this deletion, on the overall gamma-globin gene should also be considered.

Molecular characterization and PCR detection of a deletional HPFH: Application to rapid prenatal diagnosis for compound heterozygotes of this defect with ?-thalassemia in a Chinese family

“…Patients were from Guangdong Province and Hunan Province of mainland China. Of them, two unrelated adult carriers with high Hb F levels (22.2% and 29.1%, respectively) were detected when screened for ␤-thalassemia [14] and were further identified by DNA analysis as patients with deletional HPFH, which was of the same type as previously described in individuals of Southeast Asia [12,13]. The DNA samples from the two patients were used to characterize the breakpoints of this defect and to construct a PCR-based diagnosis method.…”

“…Preliminary testing showed that the proband bore a deletional chromosome inherited from her mother leading to HPFH [12,13] in addition to a 14-15 (+G) frameshift. To get more evidence, family study was carried out by typing the HPFH deletion and by analyzing parameters of red blood cells and composition of Hbs in all the members in three generations of the family from the matrilineal line.…”

“…Most ␦ ␤-thalassemia or HPFHs are caused by a large deletion involving a variable extent of DNA segment on ␤-globin gene cluster. So far, at least forty types of HPFH or ␦ ␤-thalasse-mia deletions have been reported in the world [1][2][3][4][5][6][7], with four types of the two diseases being identified in Chinese cases [8][9][10][11][12].…”

“…The SEA HPFH deletion involving the entire ␤-globin gene and a 26 kb 3Ј region to the ␤-globin gene with a total deletion length of 27 kb [12] or 30 kb [13] has been previously reported in individuals from Vietnam and Cambodia, but the detailed DNA sequence around the breakpoints has not been described yet. To study the molecular background of deletional HPFH in Chinese, we determined our DNA samples from adults with HPFH phenotypes by systematic screening for the SEA HPFH deletion.…”

Molecular analysis of β‐thalassemia in South Vietnam

“…It was also found that types of mutation are ethnic specific [8]. Three different mutations have been previously described in Vietnamese individuals including the 4-bp deletion at codons 41/42, a 27-kb deletion including the ␤-globin gene and the HS-1 site of LCR, and the novel frameshift mutation at codon 95 (+A) [9][10][11]. The first screening for ␤-thalassemia in Vietnam was performed in the North of Vietnam, situated between China in the north and Laos in the northwest [12].…”