Chenguang Zheng

Prevalence and genetic analysis of α- and β-thalassemia in Baise region, a multi-ethnic region in southern China.

Thalassemia is one of the most common hereditary blood disorders. Epidemiological data regarding the occurrence and distribution of thalassemia is important for designing appropriate prevention strategies. The objective of this study was to update and reveal the prevalence of thalassemia and mutation spectrum in the Baise region of southern China. We screened 47,500 individuals from Baise region by hematological and genetic analysis. Totally, 11,432 (24.07%) subjects were diagnosed as being carriers and patients of thalassemia, including 7290 (15.35%) subjects with α-thalassemia, 3152 (6.64%) subjects with β-thalassemia and 990 (2.08%) subjects with both α-thalassemia and β-thalassemia. Ten α-thalassemia mutations and 31 genotypes were identified in the α-thalassemia carriers and patients. Meanwhile, 13 β-thalassemia mutations and 26 genotypes were characterized in the β-thalassemia carriers and patients. Furthermore, the true prevalence of nondeletional mutations and Thailand type (-THAI) deletion mutation were first reported in this study. In addition, three cases of αα/ααα3.7, five cases of HKαα/αα and two rare β-globin mutations, -86 (G>C) and CD 121 (G>T) were first identified in the Chinese Zhuang ethnic populations. Our data indicated that there was great heterogeneity and extensive spectrum of thalassemias in the Baise populations. The findings will be useful for genetic counseling and prevention of severe thalassemia in this region.

First Description of a β-Thalassemia Mutation, -86 (C > G) (HBB: c.-136C > G), in a Chinese Family.

Abstract We present the first description of a Chinese family with a β-thalassemia (β-thal) mutation −86 (C > G) (HBB: c.−136C > G). This mutation changes the conserved promoter sequence within the proximal CACCC box of the β-globin gene that leads to a phenotype of β+-thal. The β-globin haplotype analysis revealed that the −86 mutation in our case was linked with haplotype I [+ − − − − + +]. This haplotype was commonly found both in the β-thal mutation and the βA gene. Our results suggest that the −86 mutation possibly does not have a distinct origin.

The association between four SNPs (rs7482144, rs4671393, rs28384513 and rs4895441) and fetal hemoglobin levels in Chinese Zhuang β-thalassemia intermedia patients

Four SNPs (rs7482144, rs4671393, rs28384513 and rs4895441) associated with HbF levels have been identified in different populations worldwide. To explore whether these SNPs modulate HbF expression in Chinese Zhuang population, 436 Chinese Zhuang β-thalassemia intermedia (β-TI) patients were divided into high HbF level group (mean HbF=25.5%, n=218) and low group (mean HbF=6.51%, n=218) for genotyping using PCR-HRM method. Results demonstrated that there was a significantly higher minor allele frequency (MAF=34.2%) of rs4895441 (G) in HMIP in high HbF level group than that in low group (MAF=19.8%) (P=0.001, OR=1.73, 95% CI: 1.24-2.57). The cumulative effects of risk genotypes of these loci for patients carrying any combination of 1, 2 or 3 risk genotype had a gradually increased risk of high HbF level phenotype compared to those without the risk genotypes (OR=1.50-9.06, P=0.0008); Gene-gene interaction of rs7842144 and rs4895441 showed the best model with the smallest prediction error (0.4259) and the greatest consistency of coefficient of variation (P=0.01). We concluded that rs4895441, G on HMIP might be a high-risk modifier variant for high HbF level expression, and HBG2, BCL11A and HMIP genes, as HbF quantitative trait loci (QTL) could have a synergistic effect on increasing the HbF level in Chinese Zhuang β-TI patients.

Genetic Variants at BCL11A and HBS1L-MYB loci Influence Hb F Levels in Chinese Zhuang β-Thalassemia Intermedia Patients

Abstract Increased Hb F levels can ameliorate the symptoms of β-thalassemia (β-thal). Due to the genetic heterogenicity of β-thal, the relationship between genetic variants in modifier genes and Hb F level has been studied in different populations. The Chinese Zhuang has the second largest population in China and has 6.78% prevalence of β-thal. However, the effects of these single nucleotide polymorphism (SNP) variants on the Hb F levels of β-thal intermedia (β-TI) patients in this population have not been reported. To explore the association between modifier loci (β-globin gene cluster, HBS1L-MYB intergenic region and BCL11A) and Hb F levels in Chinese Zhuang β-TI patients, 96 unrelated β-TI patients (50 males and 46 females) with different Hb F levels were recruited and genotyped by mass spectrometry. A total of 13 SNPs were confirmed to be in a significant relationship with Hb F levels in this population. Of these, high-risk genotypes of six Hb F-associated SNPs, rs9376090, rs7776054, rs9399137, rs9389268, rs9402685 in the HBS1L-MYB intergenic region and rs189984760 in the BCL11A locus, showed association with high Hb F levels, especially for SNPs in linkage disequilibrium. One novel Hb F-associated SNP, rs189984760, was identified in our study. Our findings will be of valuable reference for correlation between modifier genes and Hb F in Chinese Zhuang populations and may lead to better understand the modifying mechanisms for β-thal.

The prevalence and molecular characterization of (δβ)0-thalassemia and hereditary persistence of fetal hemoglobin in the Chinese Zhuang population

To reveal the prevalence and molecular characterization of (δβ)0‐thalassemia [(δβ)0‐thal] and hereditary persistence of fetal hemoglobin (HPFH) in the Chinese Zhuang population.

Molecular characterization of α- and β-thalassemia in the Yulin region of Southern China

Thalassemia is one of the most common hereditary blood disorders. Epidemiological data regarding the prevalence and distribution of mutations is important for planning a thalassemia control program. To reveal the prevalence of thalassemia and mutation spectrum in the Yulin region of southern China, we screened 130,318 individuals from Yulin region by hematological and genetic analysis. Totally, 24,886 (19.10%) subjects were diagnosed with thalassemia, including 16,308 (12.51%) subjects with α-thalassemia alone, 6658 (5.11%) subjects with β-thalassemia alone and 1920 (1.47%) subjects with both α- and β-thalassemia. Ten α-thalassemia mutations were identified in the α-thalassemia subjects, with the common α-thalassemia mutations being --SEA mutation (51.91%), -α3.7 (19.90%), αCSα (10.58%), -α4.2 (8.13%), αWSα (7.67%). Thirteen β-thalassemia mutations and 31 genotypes were characterized in the β-thalassemia subjects. The seven common mutations [CD41-42 (-CTTT) (43.31%), CD17 (A > T) (34.58%), CD26 (G > A) (6.86%), CD71-72 (+A) (4.25%), -28 (A > G) (3.90%), IVS-II-654 (C > T) (3.53%) and IVS-I-1 (G > T) (2.22%)] accounted for 98.65% of all β-thalassemia defects. Furthermore, 6 cases of α-triplication and 3 cases of mutation -α2.4 were first identified in this region. Our data illustrated that there was great heterogeneity and extensive spectrum of thalassemias in the Yulin populations. The findings will contribute an available reference for prevention of thalassemia in this region.

Characterization of Hb Bart’s Hydrops Fetalis Caused by – –SEA and a Large Novel α0-Thalassemia Deletion

Abstract Hb Bart’s hydrops fetalis is the most severe and generally fatal clinical phenotype of α-thalassemia (α-thal), which is due to the deletion of all four functional α-globin genes of hemoglobin (Hb), resulting in no α-globin chain production (– –/– –). Homozygosity for the – –SEA (Southeast Asian) α-globin gene deletion is the main cause of the Hb Bart’s hydrops fetalis in Asia, especially South China. Occasionally, other α0-thal deletions can also be found. In this study, we report a case with an atypical form of Hb Bart’s hydrops fetalis that was caused by – –SEA and a large novel α0-thal deletion (– –GX) (Guangxi). The fetus with Hb Bart’s in our study presented fetal hydrops features in early gestation which was different from that of traditional Hb Bart’s hydrops fetalis with a homozygous – –SEA deletion. The early onset of fetal hydrops is attributed to the decreased formation of embryonic Hb Portland (ζ2γ2), which is proposed as a candidate for reactivation in cases of severe α-thal. Our findings indicated that it was important to characterize new or rare mutations, and highlighted the significance of using ultrasonography to identify signs of Hb Bart’s hydrops fetalis.

A Novel Mutation of the α2-Globin Gene Causing α+-Thalassemia: Hb Nanning (HBA2: c.369_370delinsGA)

Abstract We report a novel mutation on the α2-globin gene, Hb Nanning (HBA2:c.369_370delinsGA) detected in a Chinese family. This mutation gives rise to a previously undescribed hemoglobin (Hb) variant that was undetectable by various separation techniques. Both carriers of the mutation have mean corpuscular volume (MCV) and mean corpuscular Hb (MCH) values that are below normal, as would be predicted for an α+-thalassemia (α+-thal) patient.

A Novel α2-Globin Gene Mutation: Hb Debao [α31(B12)Arg→Trp; HBA2: c.94A>T]

Abstract We report a novel mutation on the α2-globin gene, Hb Debao [α31(B12)Arg→Trp; HBA2: c.94A>T] detected in a Chinese family. This mutation gives rise to a previously undescribed hemoglobin (Hb) variant that was undetectable by electrophoretic or chromatographic methods. Hb Debao was associated with an α+-thalassemia (α+-thal) deletion [−α3.7 (rightward)] producing a mild phenotype with significant microcytosis and hypochromia, while the combination of this mutation with an α0-thal deletion (−−SEA) resulting in a severe form of Hb H (β4) disease, which is consistent with a thalassemic phenotype associated with the novel mutation.

Characterization of a Large Novel α-Globin Gene Cluster Deletion Causing α0-Thalassemia in a Chinese Family

Abstract We report a large novel α-globin cluster deletion that we named – –PG (NG_000006.1: g.93628_542759del450131), in a Chinese family. This large deletion is approximately 450 kb long, spanning from upstream of the PolR3k gene at the 5′ end to the RAB11FIP3 gene at the 3′ end of chromosome 16p13.3. This deletion removes all the globin distal regulatory elements as well as the whole α-globin gene cluster. Patients with heterozygous – –PG/αα had red blood cell (RBC) indices consistent with α-thalassemia (α-thal) trait, but no apparent increase in a cancer tendency or mental disability, microcephaly, relative hypertelorism, unusual facies or genital anomalies.