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The 3' untranslated region (3'UTR) is associated with mRNA stability because of its involvement in 3' end processing, polyadenylation, and mRNA capping. Mutations located in this area can cause a phenotype compatible with β

We describe a new α-globin chain variant in a Chinese subject. This novel variant, with a Val→Met substitution at codon 93 of the α-globin chain, has been named Hb Qingcheng (HBA1: c.280G>A) for where the proband was born. A woman with somatic mosaicism for Hb Qingcheng presented with the phenotype of mild α-thalassemia (α-thal).

Genetic recombination between homologous sequences on the human globin gene clusters can lead to the creation of fusion genes. In this study, we report the detection of an α-globin fusion gene by using real-time polymerase chain reaction (qPCR)-based multicolor melting curve analysis (MMCA). The carriers of this fusion gene had a mild α-thalassemia phenotype with a normal hemoglobin (Hb) value and borderline hematological indices. Sequence analysis revealed that the mutant gene was the result of a fusion between the α2 and ψα1 genes. Our results indicate that the MMCA has the ability to detect the fusion gene, which is helpful for genetic counseling in thalassemia prevalent areas.

The −50 (G>A) (HBB: c.-100G>A) mutation was first reported as a β-thalassemia (β-thal) allele in a Chinese family. However, the hematological features of carriers with this variant are not availabl...

Hb Westmead (α122(H5)His>Gln) (HBA2: c.369C>G) is a common α-globin variant causing α-thalassemia (α-thal) in Mainland China. In this study, we report the hematological characteristics in Hb Westme...

Hb Constant Spring (Hb CS) (HBA2: c.427T>C) is a common α-globin variant causing α-thalassemia (α-thal) phenotypes in mainland China. In this study, we evaluated the efficiency of erythrocyte param...

In this study, we report on a compound heterozygote for variants in the key erythroid transcription factor Kruppel-like factor 1 (KLF1) gene in a patient who presented with severe, transfusion-dependent hemolytic anemia. The red cells were normochromic and normocytic, and resembled those seen in patients with congenital nonspherocytic hemolytic anemia (CNSHA). Next generation sequencing (NGS) revealed that the patient was a compound heterozygote for the KLF1 frameshift variant c.519_525dup (p.Gly176ArgfsTer179) and a missense variant c.1012C>A (p.Pro338Thr). This report adds to the wide clinical spectrum of KLF1 gene variants. We suggest that loss of KLF1 should be considered in otherwise unexplained cases of congenital hemolytic anemia.

We have identified a new α chain hemoglobin (Hb) variant in a Chinese subject. Sequencing of the α-globin gene revealed a mutation in exon 1 at nucleotide 55, which results in the replacement of a ...

Increased Hb A2 is considered the most reliable hematological finding for the identification of β-thalassemia (β-thal) carriers. The aim of this study was to determine the underlying genetic factors associated with a high Hb A2 level in a Chinese population. Subjects were recruited from couples preparing for pregnancy who participated in the thalassemia screening program during a 2-year period. DNA analyses were used for diagnosis of β-thal and other genetic factors. A total of 5985 adults who screened positive for β-thal were recruited. Of these, 5933 (99.1%) were detected to have a β-thal mutation. In the remaining 52 (0.9%) individuals without mutations involving the β-globin gene cluster, 16 were found to have Kruppel-like factor 1 (KLF1) gene variants, and two had an α-globin gene triplication. There were still 34 individuals with unknown genetic factors for their raised Hb A2 values. The results of this study indicate that genetic factors other than β-thal can rarely contribute to the elevation of Hb A2. These subjects usually have borderline microcytic red cell indices and Hb A2 values.

A female of Chinese origin carried the codon 43 (G>T) (HBB: c.130G > T) and codons 71/72 (+A) (HBB: c.216_217insA) mutations of the β-globin gene in cis, identified during prenatal thalassemia screening. The double in cis mutations were inherited from her mother. Both of the two carriers behave as a traditional heterozygote for β-thalassemia (β-thal) with microcytosis and a high Hb A2 level. This case report indicates that the possibility of multiple mutations in cis in a fetus with thalassemia trait has to be considered in a prenatal screening program.

Patients with the β0/β0 type of β-thalassemia (β-thal) usually present as β-thal major (β-TM), and are transfusion-dependent. However, the clinical and hematological features of β-thal can be modulated by different modifiers, resulting in a wide range of clinical severity even in patients with the same genotypes. We report a Chinese family with twin brothers, both of whom had the same genotype of β0/β0. One twin was diagnosed as β-TM at 4 months of age and had regularly been transfused; conversely the other twin with a KLF1 (Kruppel-like factor 1) gene mutation, behaved as β-thal intermedia (β-TI), and had never been transfused. Our findings indicate that KLF1 mutations have a role in modulating the phenotypic severity of β-thal. The exact investigation of KLF1 modifiers is necessary in areas where globin gene disorders are most prevalent. This will be helpful in genetic counseling and optimizing the guidelines for prenatal diagnosis (PND) programs.

More than 900 abnormal hemoglobin (Hb) β chain variants have now been characterized. The majority are due to point mutations resulting in a single amino acid substitution within the globin gene involved, with nearly twice as many β chain variants identified compared to α chain variants. Although most of these variants are clinically and hematologically silent, they can interact with different thalassemia mutations, which could sometimes render laboratory diagnostics in a routine setting difficult. In this study, we present a case of coinheritance of Hb City of Hope [β69(E13)Gly→Ser; HBB: c.208G>A] and β-thalassemia (β-thal), that compromises the molecular diagnosis of β-thal trait.

Unstable hemoglobin (Hb) variants are a rare etiology of congenital jaundice caused by hemolytic anemia. For infant patients with jaundice this disorder is often under diagnosed or the last consideration. We report a 14-month-old boy, who presented with a long-standing jaundice. His diagnosis of Hb Sabine [β91(F7)Leu→Pro; HBB: c.275T > C] was not revealed until gene sequencing of the β-globin gene was performed.

We report a rare mutation, HBA2: c.184A>T on the α2-globin gene, detected in a Chinese proband who presented with Hb H disease and a mild anemia. This frameshift mutation results in a premature ter...

In this study, we report the experience of a pre gestational thalassemia screening program at a single center in Southern China. Free thalassemia screening, genetic counseling and prenatal diagnosis (PND) for couples planning pregnancy were implemented over a 2-year period. Among a total of 83,062 screened individuals (41,531 couples), the allele frequencies of β-thalassemia (β-thal), - -SEA and - -THAI deletions were 3.79, 5.75 and 0.028%, respectively. Out of the 41,531 couples, 11,039 couples had at least one partner who had a positive screening test; of these, 455 at-risk couples (1.07%) were identified, including 68 (0.16%) for β-thal, 162 (0.39%) for Hb Bart's (γ4) hydrops fetalis, 190 (0.46%) for deletional Hb H (β4) disease and 25 (0.06%) for nondeletional Hb H disease. Of the 455 at-risk couples, 90 were already pregnant and 66 underwent PND at 10-13 weeks' gestation, resulting in 15 affected fetuses. The remaining 355 at-risk couples were still preparing for pregnancy, and they were on the list for follow-up. There is considerable scope for facilitating timely PND through improved organization and screening strategy. The pre pregnancy screening is a feasible and effective approach to thalassemia prevention.

Hb H disease is generally a moderate form of α-thalassemia (α-thal) that rarely requires regular blood transfusions. In this study, two Chinese families with members carrying transfusion-dependent Hb H disease were investigated for rare mutations on the α-globin genes (HBA1, HBA2). In one family, Hb Zurich-Albisrieden [α59(E8)Gly→Arg; HBA1: c.178G>C] in combination with the Southeast Asian (- -SEA) deletion was the defect responsible for the severe phenotype. In another family, a novel hemoglobin (Hb) variant named Hb Sichuan (HBA1: c.393_394insT), causes α-thal and a severe phenotype when associated with the - -SEA deletion. As these two HBA1 mutations can present as continuous blood transfusion-dependent α-thal, it is important to take this point into account for detecting the carriers, especially in couples in which one partner is already a known α0-thal carrier.

A Chinese family with δ-thalassemia (δ-thal) was found, in which the daughter is homozygous for δ-thal (HBD: c.-127T>C) with complete deficiency of Hb A2 and the mother is a heterozygote with low level of Hb A2. The father, however, is a heterozygote with a normal Hb A2 value due to coinheritance of a β-thalassemia (β-thal). Although no abnormal clinical or hematological findings were noted in the individuals with δ-thal, one should keep in mind that β-thal can be missed during routine preliminary screening when β-thal and δ-thal coexist in a subject.

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.

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.