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A female of Chinese origin carried the codon 43 (GT) (

Patients with the β

The aim of this study was to determine the hematological characteristics in a large group of Hb H (β4) patients with or without a coexisting β-thalassemia (β-thal), identified by a thalassemia screening program in mainland China. A total of 361 patients with Hb H disease were found, including 343 with deletional types and 18 with nondeletional types. β-Thalassemia was found in 28 (7.8%) out of the 361 Hb H cases, and all of the 28 cases had the deletional type of Hb H disease. Lower hemoglobin (Hb) levels were detected in cases with the nondeletional type compared to those in cases with the deletional type. β-Thalassemia significantly increases the Hb levels in Hb H cases. The Hb H and Hb Bart's (γ4) fractions were visible in 270 (85.7%) and 122 (38.7%) out of 315 deletional type cases, respectively, while no Hb H or Hb Bart's fractions were detectable in 28 deletional type cases with β-thal. Therefore, the diagnosis of Hb H disease in a β-thal carrier is challenging. Molecular analysis of α- and β-globin genes is imperative in all cases with a β-thal trait.

We first report a novel β chain variant, Hb Heze [β144(HC1)Lys→Arg; HBB: c.434A>G], in a Chinese family. Heterozygous inheritance of the mutation results in a mild β-thalassemia (β-thal) phenotype, whereas compound heterozygosity of Hb Heze with β0-thal appears as the cause of β-thal intermedia (β-TI) in our case.

Increased Hb A

Kruppel-like factor 1 (KLF1) is a pleiotropic erythroid transcription factor that is a regulator of definitive erythropoiesis. The aim of this study was to detect KLF1 gene variants in α-thalassemia (α-thal) carriers with an increased Hb F level in a Chinese population, and determine the changes of hematological parameters as a result of interactions between KLF1 gene mutations and α-thal. Subjects with α-thal and Hb F levels of ≥1.0% were selected for further investigation. Direct sequencing was used to detect KLF1 gene mutations. Hematological parameters of subjects with α-thal and concomitant KLF1 gene mutations and those with α-thal alone were compared. The KLF1 gene variants were detected in 46 of 275 (16.7%) individuals with α-thal and Hb F levels of ≥1.0%. The detection rate of KLF1 gene mutations rose correspondingly when the Hb F level increased. For α0-thal carriers, significantly lower mean corpuscular volume (MCV) and mean corpuscular hemoglobin (Hb) (MCH) values were observed in KLF1 gene mutation-positive carriers than that in KLF1 gene mutation-free carriers; conversely, significantly higher Hb A2 and Hb F levels were observed in the former condition rather than in the latter condition. The results of this study indicate that KLF1 gene variants are common in Chinese subjects with α-thal and increased Hb F levels, and KLF1 gene mutations decreased the red blood cell (RBC) indices in α-thal carriers as that in normal adults.

A Chinese family with δ-thalassemia (δ-thal) was found, in which the daughter is homozygous for δ-thal (HBD: c.-127TC) with complete deficiency of Hb A

The combination of β-thalassemia (β-thal) and a hemoglobin (Hb) variant is not uncommon in regions with a high prevalence of thalassemia. Although most of the β-globin chain variants will not aggravate the β-thal, some can compromise the accurate molecular diagnosis. In this study, we present a rare case of coinheritance of β-thal and Hb Hornchurch [β43(CD2)Glu→Lys; HBB: c.130G>A], that compromises the molecular diagnosis of homozygous β-thal.

The HKαα (HongKongαα) allele is an unusual rearrangement of the α-globin gene cluster containing both the -α(3.7) (rightward) and ααα(anti 4.2) crossover deletion/duplication. The anti-HKαα (anti-HongKongαα) allele is the reciprocal product containing both the -α(4.2) (leftward) and ααα(anti 3.7) unequal crossover deletion/duplication. In clinical practice of thalassemia screening, gap-polymerase chain reaction (gap-PCR) approaches are used to detect the common -α(3.7) and -α(4.2) deletions of α-thalassemia (α-thal). Because the HKαα and anti-HKαα alleles also contain the single α-globin gene deletion, individuals with these alleles would be misdiagnosed as -α(3.7) or -α(4.2) carriers. This would likely produce misleading or incorrect information in genetic counseling. In this study, we investigated the HKαα and anti-HKαα alleles in Chinese carriers of silent deletional α-thal, and reported their frequencies to be 2.27 and 0.35% in -α(3.7) and -α(4.2) carriers, respectively. Given the rarity of the HKαα and anti-HKαα alleles, a routine screening for these two rearrangements are unlikely to be necessary on most occasions.

The double heterozygosity for α and β chain variants leads to the formation of abnormal heterodimer hybrids, which could render laboratory diagnostics in a routine setting difficult. The following is the first report of a double heterozygosity for Hb Q-Thailand [α74(EF3)Asp→His; HBA1: c.223G>C] with α+-thalassemia (α+-thal) and Hb J-Bangkok [β56(D7)Gly→Asp; HBB: c.170G>A] found in a Chinese family. Both subjects were healthy with normal or borderline hematological parameters. Hemoglobin (Hb) analyses showed a novel variant, Hb Q-Thailand and Hb J-Bangkok. Family studies helped in the initial recognition and in making presumptive diagnoses, but definitive diagnoses of these cases with complex α and β chain variants could only be obtained after DNA analysis.

Hb Zurich-Albisrieden [HBA2: c.178G > C; α59(E8)Gly→Arg (α2)] is a rare nondeletional α-thalassemia (α-thal) that results from a nucleotide substitution at codon 59 of the α2-globin gene. In this report, we present a fetus with cardiomegaly, enlarged placenta and increased middle cerebral artery-peak systolic velocity (MCA-PSV) at 25 weeks’ gestation. Fetal blood sampling revealed the severe anemia [hemoglobin (Hb) level being 5.5 g/dL] and Hb H (β4) disease-like hematological findings with Hb Bart’s (γ4) level of 30.7%. Molecular analysis of the family found that the father was an Hb Zurich-Albisrieden carrier, the mother heterozygous for the – –SEA α0-thal deletion, and the fetus was a compound heterozygote for Hb Zurich-Albisrieden and the – –SEA α0-thal deletion. Therefore, this was a rare case of Hb Bart’s hydrops fetalis associated with Hb Zurich Albisrieden.

We report a novel mutation on the α2-globin gene, Hb Dapu [α17(A15)Val →Phe (α2); HBA2: c.52G > 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. The combination of this mutation with an in cis deletion of a double α-globin gene resulting in a mild form of Hb H (β4) disease, is consistent with a thalassemic phenotype associated with the novel mutation.

Coinheritance of δ-globin variants along with β-globin gene defects can interfere with correct diagnosis of β-thalassemia (β-thal) trait. In this report, we present the coinheritance of a δ-globin variant, Hb A

We have found an example of the mutation at the intronic region of the second intervening sequence of the β-globin gene, IVS-II-705 (T>G) (HBB: c.316-146T>G), in a Chinese family. The two subjects heterozygous for this mutation presented with typical β-thalassemia (β-thal) trait.

Induced pluripotent stem cells (iPSCs) derived from diseased patients behave as a powerful tool for biomedical research and may provide a source for replacement therapies. In this study, we generated iPSCs from amniotic fluid cells of a fetus with Hb Bart's (γ4) disease (- -/- -). The established iPSCs showed pluripotency similar to that of human embryonic stem cells. They were able to differentiate into various somatic cell types and maintained normal karyotypes after long periods of culture in vitro. The patient-specific iPSCs offer a valuable model for advancing α-thalassemia (α-thal) research and early treatment of the affected fetuses.

We describe a new β-thalassemic mutation in a Chinese subject. This allele develops by insertion of one nucleotide (+T) between codons 138 and 139 in the third exon of the β-globin gene. The mutation causes a frameshift that leads to a termination codon at codon 139. In the heterozygote, this allele has the phenotype of classical β-thalassemia (β-thal) minor.

Mutations that cause destabilization of the hemoglobin (Hb) tetramer are a rare cause of hemolytic anemia. In contrast to the hemolytic anemia caused by enzyme deficiencies, a dominant mode of inheritance characterizes the unstable Hbs. Hb Alesha [β67(E11)Val→Met; HBB: c.202GA] is caused by a GA mutation at codon 67 of the β-globin gene, resulting in a valine to methionine substitution at helix E11. This replacement disrupts the apolar bonds between valine and the heme group, producing an unstable Hb and severe hemolysis. We report this rare hemoglobinopathy in a Chinese girl with severe hemolytic anemia, splenomegaly and frequent requirement for red blood cell (RBC) transfusions.

The aim of this study was to demonstrate the performance of nondeletional α-thalassemia (α-thal) prevention using a reverse dot-blot method at a Mainland Chinese hospital. A prenatal control program for nondeletional Hb H disease was performed between January 2009 and December 2013. All couples were screened for α-thal trait, and for couples in which one partner tested positive for α(0)-thal, the other was subjected to screening for Hb Constant Spring (Hb CS, HBA2: c.427T > C) and Hb Quong Sze (Hb QS, HBA2: c.377T > C) mutations by reverse dot-blot assay. Prenatal diagnoses were offered in at-risk pregnancies. During the study period, 51,105 couples were found to be carrying α-thal; among these, 35 (0.07%) couples were found to be at-risk of conceiving an offspring with nondeletional Hb H disease, including 25 couples for Hb H-CS and 10 cases for Hb H-QS. Nine fetuses were diagnosed with nondeletional Hb H disease, and eight of the affected pregnancies were terminated. Detection of nondeletional α-thal is necessary for any prenatal diagnosis (PND) programs in Southeast Asian countries. Reverse dot-blot is a relatively simple method for simultaneous typing of common nondeletional α-thal mutations.

α-Thalassemia (α-thal) is common in southern China. Homozygosity for the - -(SEA) (Southeast Asian) α-globin gene deletion is the most common cause of the Hb Bart's (γ4) disease. Occasionally, other α(0)-thal deletions can also be found. In this study, we report a case with an atypical form of Hb Bart's disease. The fetus was a compound heterozygote for the - -(SEA) and - -(THAI) deletions and presented different clinical features from that of traditional Hb Bart's disease with the - -(SEA) deletion in the homozygous state. 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 finding may have potentially important implications for clinical decisions in a program using ultrasonography to identify signs of homozygous α(0)-thal.

The aim of the present study was to report a 3-year experience on the prenatal control of Hb Bart's (γ4) disease in Mainland China. All pregnancies with fetal Hb Bart's disease were included from January 2011 to December 2013. The main clinical characteristics of the affected pregnancies were reviewed, including maternal reproductive history, prenatal care in the current pregnancy, the gestation of pregnancy at the time of booking, the gestation at the time of prenatal diagnosis (PND), and the complications associated with the pregnancy. A total of 246 cases of fetal Hb Bart's disease were identified during the study period; among these, 177 (72.0%) were diagnosed in early gestation (≤24 weeks), and 69 (28.0%) in late gestation. Most (87.0%) of the patients presenting in late pregnancy had late or no prenatal care. Twenty (29.0%) had major obstetrical complications in patients presenting in late pregnancy, and five (5.0%) in patients presenting in relatively early pregnancy. The delay in PND deprived couples of opportunities to make informed decisions early in pregnancy. Efforts for designing and targeting strategies to improve the timeliness of prenatal care are urgently needed.

The aim of the present study was to find the most prevalent structural hemoglobin (Hb) variants in southern China and to present hematological and molecular data of abnormal Hbs in the population from southern China. The type and frequency of structural Hb variants and their hematological and molecular characteristics were identified in 131 individuals from 30,848 unrelated partners who were referred to the prenatal clinic of Dongguan MaternalChildren Health Hospital, Dongguan, Guangdong, People's Republic of China (PRC) from 2011 to 2013. α-Globin or β-globin chain variants were screened using a capillary electrophoresis (CE) system, and α-globin or β-globin gene mutations were confirmed using sequencing techniques. The gene frequency of Hb variants was 0.4% (131/30,848). The most common α-globin variants were Hb Constant Spring (Hb CS, HBA2: c.427T C) (0.2%), followed by Hb Q-Thailand (HBA1: c.223G C) and Hb G-Honolulu (HBA2: c.91G C). The most common β-globin variant was Hb E (HBB: c.79G A) (0.09%), followed by Hb New York (HBB: c.341T A). Our results provide a detailed prevalence and molecular characterization of abnormal Hbs in the population of the Dongguan region. These findings have important implications for a region with a high frequency of α- and β-thalassemias.

Hb Hammersmith [β42(CD1)Phe → Ser; HBB: c.128T > C] is a rare, unstable hemoglobin (Hb) variant. In this case report, we describe another male case of Hb Hammersmith. A 39-year-old male had hemolytic anemia, cyanosis and splenomegaly since 6 months after birth. He passed the disease allele to his daughter, a 3-year-old girl, who also had hemolytic anemia and splenomegaly. This mutation was not identified in the parents and two brothers of the father. Early prenatal diagnosis was performed in the second pregnancy in this family. This is the first case of Hb Hammersmith in an adult male patient.

Tyr35β is located at the convergence of the α1β1, α1β2 and α1α2 interfaces of Hb A. We here report a Chinese family in whom the codon 35 (A > G) (HBB: c.107A > G) mutation of the β-globin gene was not associated with the thalassemic phenotype previously described.

Hb Constant Spring [Hb CS, α142, Term→Gln, TAA>CAA (α2)] is a nondeletional form of α-thalassemia (α-thal) that is most prevalent in Southern Chinese and Southeast Asian populations. We previously found that Hb CS trait could efficiently be screened using Sebia Capillarys2. In this study, we report that Hb CS heterozygotes combined with β-thal could not be detected by the Sebia Capillarys2 method due to the very small amount of Hb CS.

Hb Zurich-Albisrieden [HBA2: c.178G C; α59(E8)Gly→Arg (α2)] is a rare nondeletional α-thalassemia (α-thal) that results from a nucleotide substitution at codon 59 of the α2-globin gene. In this report, we present a fetus with cardiomegaly, enlarged placenta and increased middle cerebral artery-peak systolic velocity (MCA-PSV) at 25 weeks' gestation. Fetal blood sampling revealed the severe anemia [hemoglobin (Hb) level being 5.5 g/dL] and Hb H (β4) disease-like hematological findings with Hb Bart's (γ4) level of 30.7%. Molecular analysis of the family found that the father was an Hb Zurich-Albisrieden carrier, the mother heterozygous for the -

The aim of the present study was to determine the cost effectiveness of a noninvasive prenatal diagnosis (PND) program for α-thalassemia (α-thal) using ultrasound scan. During a 5-year period, 1923 pregnancies at-risk for homozygous α0-thal were recruited into the noninvasive PND program. There were 1452 women who avoided invasive testing because of a normal ultrasound scan. The remaining 471 showed abnormal fetal ultrasonographic findings, and invasive testing was recommended. The overall cost of running the noninvasive PND program was US$213,383, while the cost of running the invasive program would have been US$554,810. The total savings were estimated at US$356,499 for women with an unaffected pregnancy with a net saving of US$246 per capita. This study demonstrated that it is cost effective to run a noninvasive PND program for α-thal in an area where the disease is prevalent, and therefore effectively avoiding an invasive test in unaffected pregnancies.

Unstable hemoglobin (Hb) variants represent a rare etiology of congenital hemolytic anemia. Correct diagnosis can be a challenge due to the relative rarity or lack of awareness of this disorder. We report an 18-month-old girl, who presented with a long-standing hemolytic anemia. Her diagnosis of unstable Hb Perth [β32(B14)Leu→Pro, HBB: c.98T > C] had not been made until gene sequencing of the β-globin gene was performed.

Nondeletional α-thalassemia (α-thal) is the result of point mutations in critical regions of the α-globin genes, affecting mRNA processing, mRNA translation, or α-globin stability. Hb Constant Spring (Hb CS, HBA2: c.427T > C) is the most common nondeletional α-thal that results from a nucleotide substitution at the termination codon of the α2-globin gene. Hb Quong Sze (Hb QS, HBA2: c.377T > C) is another nondeletional α-thal in South China with the missense mutation at codon 125 of the α2-globin gene making this hemoglobin (Hb) variant highly unstable. Although homozygosity for Hb CS (α(CS)α/α(CS)α) or Hb QS (α(QS)α/α(QS)α) has been reported, clinical pictures vary from severe hemolysis that developed early in life to only mild anemia, no clinical phenotypic data of compound heterozygosity for Hb CS/Hb QS (α(CS)α/α(QS)α) has been described. In this report we describe an adult case with such a compound heterozygosity who presented with a mild α-thal.

β-Thalassemia (β-thal) is one of the most common inherited single gene disorders in the world. The aim of this study was to describe the gestational age at prenatal diagnosis (PND) for β-thal in at-risk women in mainland China. All pregnant women at-risk for β-thal and undergoing PND at a Mainland Chinese tertiary obstetric center between January 2005 and December 2014 were included. Information required for the survey was obtained from prenatal records and delivery charts. In total, 1307 women underwent PND for β-thal. The mean gestational age for the procedure was 18.5 weeks. There were 384 (29.0%) women with fetal diagnosis in early trimester (14 weeks), 715 (55.0%) in early second trimester (14-24 weeks), and 208 (16.0%) in late second trimester or beyond (24 weeks). Although the proportion of patients undergoing early PND increased along with the time span, the mean n gestational age was not decreased significantly during the study period. The delay in PND deprived couples of the opportunity to make informed decisions early in pregnancy.

Hb Constant Spring (Hb CS, HBA2: c.427T > C) is a common nondeletional α-thalassemia (α-thal) that results from a nucleotide substitution at the termination codon of the α2-globin gene. Homozygosity for Hb CS (αCSα/αCSα) is relatively rare, and generally characterized with mild hemolytic anemia, jaundice, and splenomegaly. In this report we present a fetus with cardiomegaly, pericardial effusion, enlarged placenta and increased middle cerebral artery-peak systolic velocity (MCA-PSV) at 24 weeks’ gestation. Fetal blood sampling revealed the severe anemia [hemoglobin (Hb) level being 4.8 g/dL] and Hb H (β4) disease-like hematological findings with Hb Bart’s (γ4) level of 17.9%. DNA sequencing of the α-globin genes found that both partners were Hb CS carriers and the fetus was an Hb CS homozygote. Therefore, this was a rare case of homozygous Hb CS which demonstrated an unusual and serious anemia and hydrops fetalis in utero.

Tyr35β is located at the convergence of the α1β1, α1β2 and α1α2 interfaces of Hb A. We here report a Chinese family in whom the codon 35 (A G) (HBB: c.107A G) mutation of the β-globin gene was not associated with the thalassemic phenotype previously described.

We report a novel case of Hb Phnom Penh [α117(GH5)Phe-Ile-α118(H1)Thr (α1)] detected through cord blood screening for hemoglobinopathies. Sequence analyses identified this in-frame mutation at codons 117/118 (+ATC) in exon 3 of the α1-globin gene. This mutation causes a silent α-thalassemia (α-thal).

We describe a Chinese woman who was assumed to be heterozygous for both Hb E [β26(B8)Glu→Lys] and α(0)-thalassemia (α(0)-thal) by a high performance liquid chromatography (HPLC) method, but was later also shown to be a Hb New York [β113(G15)Val→Glu] heterozygote by the Sebia CapillaryS2 system. This study suggested that a single test is never sufficient to allow the correct diagnosis of an abnormal hemoglobin (Hb). We also emphasize the importance of a correct diagnosis of interactions between α- and β-thalassemias.

The interaction of the nondeletional α-thalassemia (α-thal) mutations with the Southeast Asian double α-globin gene deletion results in nondeletional Hb H (β4) disease. Hb Constant Spring (Hb CS, α142, TAA>CAA at α2) and Hb Quong Sze [Hb QS, α125, CTG>CCG (α2)] are the most common nondeletional α-thalassemias in the Chinese population. These α-globin structural variants are unstable and undetectable by routine hemoglobin (Hb) electrophoresis. The amount of Hb Bart’s (γ4) in the cord blood of newborns correlates with the number of α-globin genes that are deleted. We determined the quantity of Hb Bart’s in cord blood at birth with the Sebia CapillaryS electrophoresis system. Using Hb Bart’s levels at 0.1-2.5% as a cut-off range for nondeletional α-thal diagnosis, we detected 154 individuals in 6,525 newborns. Of the 154 samples, 12 were found to be Hb CS carriers, 10 Hb QS carriers, and one Hb Westmead [α122, CAC>CAG (α2)] carrier. We present the first report of the prevalence of Hb QS in our population.

We have identified four Chinese individuals from three unrelated families with raised Hb A2 levels. The anti-Lepore hybrid hemoglobin (Hb) variant was amplified using a pair of primers, 5' to the β-globin gene Cap site and 3' to the δ-globin gene polyadenylation site (polyA) region, respectively. Direct sequencing of the βδ fusion products confirmed the anti-Lepore Hong Kong (NG_000007.3: g.63154_70565dup) variant. We found that this anti-Lepore variant is positioned in zone 3 on the capillary electrophoresis system. It may help in differential diagnosis of Hb variants and providing better information in clinical counseling.

α-Thalassemia (α-thal) is one of the most common monogenic diseases worldwide and is widely distributed in southern China. There are two types of this disease at the DNA level: deletional and nondeletional α-thal. Hb Constant Spring [Hb CS, α142, Term→Gln (α2) (α(CS)α/αα)], Hb Quong Sze [Hb QS, α125(H8)Leu→Pro (α2) (α(QS)α/αα/)] and Hb Westmead [α122(H5)His→Gln (α2) (α(122)α/αα)] are the three common nondeletional mutations in the Chinese population. In this study, we developed an optimized protocol for identification of the three point mutations by high-resolution melting (HRM) analysis using a LightScanner. We successfully detected all the mutant samples with α(CS)α/αα, α(CS)α/- -(SEA), α(CS)α/-α(3.7), α(CS)α/-α(4.2), α(QS)α/αα, α(QS)α/- -(SEA), α(QS)α/-α(4.2), α(QS)α/α(QS)α, and α(122)α/αα. High-resolution melting analysis is a time-saving and cost-effective technique, and the method established here could be applied to screen the three common point mutations, especially in individuals whose partners are a carrier of α⁰-thal.

alpha-Thalassemia (alpha-thal) is a common inherited disease in southern China. The severest form is Hb Bart's disease, in which the affected individuals are lethal in utero or shortly after birth, and the pregnancies are at high risk for severe morbidity. A survey by us revealed a total of 68 cases of Hb Bart's disease during the past 7 years at a maternal hospital and none of these showed that a risk of thalassemia had been recognized prior to the development of hydrops fetalis. The number of cases of Hb Bart's disease did not vary significantly during the study period. This means that the prevention program for alpha-thal has not been efficient. More effort is needed to efficiently control this disease in our region.