scholarly journals Molecular Epidemiology and Hematologic Characterizationof δβ-thalassemia and Hereditary Persistence of Fetal Hemoglobin in 125661 Families of Greater Guangzhou Area, the metropolis of Southern China

2020 ◽  
Author(s):  
FAN JIANG ◽  
Can Liao
Keyword(s):  
Genetic Counseling ◽  
Molecular Epidemiology ◽  
Gene Cluster ◽  
Southern China ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Screening Programs ◽  
Globin Gene Cluster ◽  
Prenatal Diagnostic ◽  
Thalassemia Screening

Abstract Background: Individuals with δβ-thalassemia/HPFH and β-thalassemia usually present with intermedia or thalassemia major. No large-scale survey on HPFH/δβ-thalassemia in southern China has been reported to date. The purpose of this study was to examine the molecular epidemiology and hematologic characteristics of these disorders in Guangzhou, the largest city in Southern China, to offer advice for thalassemia screening programs and genetic counseling. Methods: A total of 125,661 couples participated in pregestational thalassemia screening. 654 subjects with fetal hemoglobin (HbF) level≥5% were selected for further investigation. Gap-PCR combined with Multiplex ligation dependent probe amplification (MLPA) were used to screen for β-globin gene cluster deletions. Gene sequencing for the promoter region of HBG1 /HBG2 gene were performed for all those subjects. Results: A total of 654 individuals had hemoglobin (HbF) levels≥5%, and 0.12% of the couples were found to be heterozygous for HPFH/δβ-thalassemia, including Chinese Gγ(Aγδβ)0-thal, Southeast Asia HPFH (SEA-HPFH), Taiwanese deletion and Hb Lepore–Boston–Washington. The highest prevalence was observed in the Huadu district and the lowest in the Nansha district. Three cases were identified as carrying β-globin gene cluster deletions, which had not been previously reported. Two at-risk couples (0.0015%) were required to receive prenatal diagnosis. We also found 55 cases of nondeletional-HPFH (nd-HPFH), including 54 with Italian nd-HPFH and one with the A γ-197C-T heterozygous state. It is difficult to discriminate between Chinese G γ( A γδβ) 0 -thal and Italian nd-HPFH carriers using hemoglobin (Hb) analysis. Conclusions: This study is the first to describe the familial prevalence of HPFH/δβ-thalassemia and the high-risk rate in in Greater Guangzhou Area, and the findings will support the implementation of thalassemia screening for three common deletions by gap-PCR. We also presented a systematic description of genotype-phenotype relationships which will be useful for genetic counseling and prenatal diagnostic services for β-thalassemia intermedia. Keywords: Prevalence, δβ-thalassemia, HPFH, Guangzhou

scholarly journals Molecular Epidemiology and Hematologic Characterizationof δβ-thalassemia and Hereditary Persistence of Fetal Hemoglobin in 125661 Families of Greater Guangzhou Area, the metropolis of Southern China

2019 ◽  
Author(s):  
FAN JIANG ◽  
Can Liao
Keyword(s):  
Genetic Counseling ◽  
Molecular Epidemiology ◽  
Gene Cluster ◽  
Southern China ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Screening Programs ◽  
Globin Gene Cluster ◽  
Prenatal Diagnostic ◽  
Thalassemia Screening

Abstract Background:Individuals with δβ-thalassemia/HPFH and β-thalassemia usually present with intermedia or thalassemia major. No large-scale survey on HPFH/δβ-thalassemia in southern China has been reported to date. The purpose of this study was to examine the molecular epidemiology and hematologic characteristics of these disorders in Guangzhou, the largest city in Southern China, to offer advice for thalassemia screening programs and genetic counseling. Methods: A total of 125,661 couples participated in pregestational thalassemia screening. 654 subjects with fetal hemoglobin (Hb F) level ≥5% were selected for further investigation. Gap-PCR combined with Multiplex ligation dependent probe amplification (MLPA) were used to screen for β-globin gene cluster deletions. Gene sequencing for the promoter region of HBG1 /HBG2 gene were performed for all those subjects. Results: A total of 654 individuals had hemoglobin (HbF) levels ≥5%, and 0.12% of the couples were found to be heterozygous for HPFH/δβ-thalassemia, including Chinese Gγ(Aγδβ)0-thal, Southeast Asia HPFH (SEA-HPFH), Taiwanese deletion and Hb Lepore–Boston–Washington. The highest prevalence was observed in the Huadu district and the lowest in the Nansha district. Three cases were identified as carrying β-globin gene cluster deletions, which had not been previously reported. Two at-risk couples (0.0015%) were required to receive prenatal diagnosis. We also found 53 cases of nondeletional-HPFH (nd-HPFH), including 52 with Italian nd-HPFH and one with the Aγ-197C-T heterozygous state. It is difficult to discriminate between Chinese Gγ(Aγδβ)0-thal and Italian nd-HPFH carriers using hemoglobin (Hb) analysis. Conclusions: This study is the first to describe the familial prevalence of HPFH/δβ-thalassemia and the high-risk rate in in Greater Guangzhou Area, and the findings will support the implementation of thalassemia screening for three common deletions by gap-PCR. We alsopresented a systematic description of genotype-phenotype relationships which will be useful for genetic counseling and prenatal diagnostic services for β-thalassemia intermedia.Keywords: Prevalence, δβ-thalassemia, HPFH, Guangzhou

Genome-Wide Studies in Sickle Cell Anemia Show Associations Between SNPs in the Olfactory Receptor Gene Cluster and Fetal Hemoglobin Concentration.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 821-821 ◽  
Author(s):  
Nadia Timofeev ◽  
Jacqueline N. Milton ◽  
Stephen W Hartley ◽  
Richard Sherva ◽  
Paola Sebastiani ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Olfactory Receptor ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Call Rate ◽  
Globin Gene Cluster ◽  
Genome Wide ◽  
A Genome ◽  
Or Genes ◽  
Genome Wide Significance

Abstract Abstract 821 Fetal hemoglobin (HbF) is the major modulator of sickle cell anemia (SCA, homozygosity for HBB glu6val) severity. In a genome-wide association study in African Americans with SCA we sought to identify single nucleotide polymorphisms (SNPs) associated with HbF concentrations. A discovery sample of 848 African American subjects and a primary replication study of 305 subjects were examined. DNA was genotyped with the Illumina Human610-Quad SNP; some replication set samples were genotyped with the Sentrix HumanCNV370 or the 317K array. For quality control we excluded SNPs with a call rate less than 95%; we excluded subjects with a call rate less than 93%; identity by descent measurements were computed to identify related individuals who were removed from analysis; we inferred gender using chromosome X SNPs removing subjects with gender mismatches; a genome-wide principal components analysis found no association between the phenotype and the first 10 principal components, indicating that the results were not affected by population substructure. The association between HbF and the genotype for each SNP was tested with a multiple linear regression analysis adjusting for sex and assuming an additive model using the software PLINK. SCA is a rare disease in developed countries and assembling large data sets is not feasible. Therefore, true associations with limited effect sizes might not reach “genome-wide” significance of 10-08. To identify genes enriched with moderately strong associations, we developed a SNP set enrichment analysis (SSEA) that computes the probability that a set of SNPs is selected as significant by chance and scores each gene by this probability. Two SNPs exceeded the strict genome-wide significance: SNP rs5006884 in a novel region on chromosome 11 upstream of the β-globin gene cluster locus control region (LCR) containing the olfactory receptor (OR) genes OR51B5 and OR51B6; SNP rs766432 in BCL11A, previously found to be associated with HbF in several different populations. Data for SNPs common to the discovery and replication sets were combined and analyzed jointly. Similarity of the regression beta coefficients across datasets and increased significance of the p-values compared with those observed in the analyses of individual datasets provide additional evidence that the associations were consistent in the both datasets. The Q-Q plot and a genomic inflation factor of 1.003 both suggest that the test statistics are not inflated and are distributed appropriately. SSEA identified 2 OR genes (OR51B5, OR51B6) and BCL11A as enriched in both the discovery and replication sets. The most significant SNP in the OR region (rs5006884) and BCL11A (rs766432) explained 15.6% of the variability in HbF. Also, in the interval Xp 22.2-22.3 we found moderate, but not “genome-wide” significance for 1 SNP in Xp22.2. Phylogenetic conservation of some OR genes and their flanking sequences suggests that this region might also have a role in controlling expression within the β-globin gene-like complex. Low linkage disequilibrium between SNPs in the β-globin locus and the OR genes suggests that one or more variants in the OR genes independently regulate HbF. The top SNP in the OR51B5/OR51B6 locus, rs5006884, was still associated with HbF (p = 1.5E-05) in a model adjusting both for sex and rs2071348, a SNP in tight LD with the HBG2 5' -158 C-T SNP, giving further evidence that the OR region provides important information in addition to the SNPs in the β-globin gene-like complex. Polymorphisms in the upstream OR region might conceivably modulate HbF levels by altering chromatin structure within the β-globin gene cluster. Conserved binding sites for the transcription factor CTCF flank the β-globin gene cluster and evidence suggests that these sites function as insulators. Polymorphisms in this region might affect the actions of enhancers, possibly through their effects on CTCF binding its receptors, thereby affecting the interaction of the globin genes with enhancers in the OR regions. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Expression of Human Globin Genes in Transgenic Mice Carrying the ?-Globin Gene Cluster with a Mutation CausingG??+Hereditary Persistence of Fetal Hemoglobin

1990 ◽  
Vol 612 (1 Sixth Cooley') ◽  
pp. 167-178 ◽  
Author(s):  
MINORU TANAKA ◽  
JUDITH A. NOLAN ◽  
AJAY K. BHARGAVA ◽  
KIRSTEN ROOD ◽  
FRANCIS S. COLLINS ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Gene Cluster ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Globin Genes ◽  
Globin Gene Cluster ◽  
Hereditary Persistence

scholarly journals Interaction of two different disorders in the beta-globin gene cluster associated with an increased hemoglobin F production: a novel deletion type of (G) gamma + ((A) gamma delta beta)(0)-thalassemia and a delta(0)-hereditary persistence of fetal hemoglobin determinant

Blood ◽  
1991 ◽  
Vol 77 (4) ◽  
pp. 861-867
Author(s):  
M Losekoot ◽  
R Fodde ◽  
EJ Gerritsen ◽  
I van de Kuit ◽  
A Schreuder ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Beta Globin ◽  
Gamma Delta ◽  
Hemoglobin F ◽  
Beta Globin Gene ◽  
Globin Gene Cluster ◽  
Hereditary Persistence

We report two different disorders of the beta-globin gene cluster segregating in a Belgian family: a novel deletion that results in (G) gamma + ((A) gamma delta beta)(0)-thalassemia (thal) and a heterocellular hereditary persistence of foetal hemoglobin of the Swiss type linked to a delta(0)-thal gene (delta (0)-HPFH). Heterozygosity for the heterocellular HPFH brings about a moderate (3.4% to 8.24%) increase of hemoglobin (Hb) F having a G gamma/A gamma ratio of 4:1, whereas carriers of the G gamma + ((A) gamma delta beta)(0)-thal deletion show in their peripheral blood a considerably higher (15%) percentage of Hb F. Both defects interact in the compound heterozygotes for G gamma + ((A) gamma delta beta)(0)-thal and delta(0)-HPFH producing a further increase (up to 24%) of fetal Hb consisting entirely of G gamma chains. Molecular characterization of the (G) gamma + ((A) gamma delta beta)(0)-thal by means of Southern analysis showed that the deletion spans about 50 kb, removing the 3′ end of the A gamma- gene, the psi beta-, delta-, and beta-genes. A number of possible mechanisms leading to the overproduction of Hb F in HPFH and (G) gamma + ((A) gamma delta beta)(0)-thal will be discussed.

Synergistic effect of two β globin gene cluster mutations leading to the hereditary persistence of fetal hemoglobin (HPFH) phenotype

2017 ◽  
Vol 44 (5) ◽  
pp. 413-417 ◽  
Author(s):  
Priya Hariharan ◽  
Madhavi Sawant ◽  
Manju Gorivale ◽  
Ruma Manchanda ◽  
Roshan Colah ◽  
...  
Keyword(s):  
Synergistic Effect ◽  
Gene Cluster ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Globin Gene Cluster ◽  
Hereditary Persistence

scholarly journals The 3' ends of the deletions of Spanish delta beta zero-thalassemia and black HPFH 1 and 2 lie within 17 kilobases

Blood ◽  
1987 ◽  
Vol 70 (2) ◽  
pp. 593-596 ◽  
Author(s):  
C Camaschella ◽  
A Serra ◽  
G Saglio ◽  
M Baiget ◽  
N Malgaretti ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Molecular Mechanisms ◽  
Globin Gene ◽  
Adult Life ◽  
Fetal Hemoglobin ◽  
Large Deletion ◽  
Complete Characterization ◽  
Beta Globin ◽  
Beta Globin Gene ◽  
Globin Gene Cluster

Abstract Spanish delta beta zero-thalassemia, a mild thalassemic condition characterized by increased level of hemoglobin (Hb) F production during adult life, is known to be due to a large deletion starting within the beta globin gene cluster and extending beyond the 3′ breakpoint of any other similar deletional defects so far identified. By molecular cloning and by genomic mapping we now demonstrate that the deletion of Spanish delta beta zero-thalassemia ends at approximately 11 and 17 kilobases (kb) downstream to the 3′ endpoints of black hereditary persistence of fetal hemoglobin (HPFH) type 1 and 2, respectively. As suggested by the complete characterization of this and other deletional defects involving the beta globin gene cluster, the 5′ and 3′ breakpoints of several deletions cluster in rather restricted DNA areas, further strengthening the idea that common molecular mechanisms may operate in causing these deletions.

scholarly journals Two independent genetic factors in the beta-globin gene cluster are associated with high G gamma-levels in the HbF of SS patients

Blood ◽  
1984 ◽  
Vol 64 (2) ◽  
pp. 452-457 ◽  
Author(s):  
JG Gilman ◽  
TH Huisman
Keyword(s):  
Gene Cluster ◽  
Restriction Site ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Beta Globin ◽  
Beta Globin Gene ◽  
Globin Gene Cluster ◽  
Polymorphic Restriction Site ◽  
Polymorphic Restriction ◽  
Beta Gene

The gamma-chains of fetal hemoglobin (HbF) of newborn babies are composed of about 70% G gamma and 30% A gamma. In most babies, the G gamma value declines postnatally to 40%, but in about 20% of black SS patients from Georgia, 5 years and older, the G gamma level remains high at 60%. Moreover, some 3% to 4% of black newborns have high G gamma values of 85%. PstI digestion of DNA of one such high G gamma baby and of one normal newborn showed the former to be heterozygous for the -G gamma-G gamma- and -G gamma-A gamma-chromosomes. Only about one fourth of high G gamma SS patients were such heterozygotes, while three fourths were -G gamma-A gamma-/-G gamma-A gamma-homozygotes. Analysis of DNA of 38 SS patients without the -G gamma-G gamma-chromosome showed a correlation of G gamma values with genotype at one polymorphic restriction site: at the HincII site in the psi beta gene, all -G gamma- A gamma-/-G gamma-A gamma-homozygotes with high G gamma were +/- or +/+, while low G gamma individuals were all -/-. Family studies, involving analyses at four polymorphic sites (HindIII sites in the G gamma and A gamma genes and HincII sites in the psi beta gene and 3′ to it), suggested the association of an unidentified high G gamma genetic determinant with haplotype + - + +. This indicates that a genetic factor causing high G gamma levels in SS patients is closely linked to the -G gamma-A gamma-psi beta region of the beta-globin gene cluster.

scholarly journals Interaction of two different disorders in the beta-globin gene cluster associated with an increased hemoglobin F production: a novel deletion type of (G) gamma + ((A) gamma delta beta)(0)-thalassemia and a delta(0)-hereditary persistence of fetal hemoglobin determinant

Blood ◽  
1991 ◽  
Vol 77 (4) ◽  
pp. 861-867 ◽  
Author(s):  
M Losekoot ◽  
R Fodde ◽  
EJ Gerritsen ◽  
I van de Kuit ◽  
A Schreuder ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Beta Globin ◽  
Gamma Delta ◽  
Hemoglobin F ◽  
Beta Globin Gene ◽  
Globin Gene Cluster ◽  
Hereditary Persistence

Abstract We report two different disorders of the beta-globin gene cluster segregating in a Belgian family: a novel deletion that results in (G) gamma + ((A) gamma delta beta)(0)-thalassemia (thal) and a heterocellular hereditary persistence of foetal hemoglobin of the Swiss type linked to a delta(0)-thal gene (delta (0)-HPFH). Heterozygosity for the heterocellular HPFH brings about a moderate (3.4% to 8.24%) increase of hemoglobin (Hb) F having a G gamma/A gamma ratio of 4:1, whereas carriers of the G gamma + ((A) gamma delta beta)(0)-thal deletion show in their peripheral blood a considerably higher (15%) percentage of Hb F. Both defects interact in the compound heterozygotes for G gamma + ((A) gamma delta beta)(0)-thal and delta(0)-HPFH producing a further increase (up to 24%) of fetal Hb consisting entirely of G gamma chains. Molecular characterization of the (G) gamma + ((A) gamma delta beta)(0)-thal by means of Southern analysis showed that the deletion spans about 50 kb, removing the 3′ end of the A gamma- gene, the psi beta-, delta-, and beta-genes. A number of possible mechanisms leading to the overproduction of Hb F in HPFH and (G) gamma + ((A) gamma delta beta)(0)-thal will be discussed.

Sign in / Sign up

Export Citation Format

Share Document