Compound Heterozygosity for HKααand anin CisDeletion of DoubleαGenes Presents asα-Thalassemia Trait

Wu, Man-Yu; Li, Jian; Li, Shu-Chen; Li, Ru; Liao, Can; Li, Dong-Zhi

doi:10.3109/03630269.2015.1039026

Cited by 5 publications

(3 citation statements)

References 16 publications

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“…This allele contains an intact a2 gene and a a1-a2 fusion gene (-a 3.7 ) with neither decreased nor enhanced aglobin gene dosage. We have confirmed that compound heterozygosity for HKaa and an in cis deletion of double a genes presents as a-thalassemia trait [11]. It can also be speculated that carriers of b-thalassemia trait are unlikely to suffer any more deteriorative effects when combined with the HKaa allele since its imbalanced a/b ratio is unchanged.…”

supporting

confidence: 75%

The Frequency of α-Globin Gene Triplication in a Southern Chinese Population

Zhang

et al. 2015

Indian J Hematol Blood Transfus

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supporting

confidence: 75%

The Frequency of α-Globin Gene Triplication in a Southern Chinese Population

Zhang

et al. 2015

Indian J Hematol Blood Transfus

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“…As shown in Figure 3 , Integrative Genomics Viewer plots of HKαα allele reveal that there is virtually no deletion or duplication of the gene. Therefore, individuals with HKαα/αα presented a normal hematological phenotype, and this structural variant does not aggravate the clinical phenotype of patients even when combined with other α/β-mutations, which is consistent with previously reported results ( 7 , 8 , 11 , 19 , 21 ). Although the carrier rate of the HKαα allele is low and the carriers do not have any clinical manifestations, its molecular diagnosis has important clinical significance.…”

Section: Discussionsupporting

confidence: 92%

“…Several studies have reported that individuals with the HKαα allele present with normal hematological phenotype (8)(9)(10). Individuals with compound heterozygote of HKαα and --SEA showed a typical α-thalassemia trait (11). Although the HKαα allele does not have any deleterious effect on the clinical phenotype of carriers, genetic testing of the HKαα allele has important implications for genetic counseling and prenatal diagnosis.…”

Section: Original Articlementioning

confidence: 99%

Accurate genotype diagnosis of Hong Kongαα thalassemia based on third-generation sequencing

Li¹,

Ye²,

Zhang³

et al. 2022

Ann Transl Med

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Background: The Hong Kongαα (HKαα) allele is a complex structural rearrangement of the α-globin gene containing -α 3.7 and ααα anti 4.2 crossover junctions. Clinically, individuals carrying the HKαα allele are often misdiagnosed or missed using conventional thalassemia gene detection technology. This study aims to identify and validate different HKαα thalassemia subtypes using third-generation sequencing (TGS) technology.Methods: Between January 2015 and June 2021, 32 patients suspected of having HKαα thalassemia were included in this study. Genomic DNA was extracted, and gap-polymerase chain reaction (PCR), two-round nested PCR, multiplex ligation-dependent probe amplification (MLPA), and TGS were used for thalassemia gene detection. Results:The results of HKαα/αα and HKαα/-α 3.7 were similar to -α 3.7 /αα using the gap-PCR method. Tworound nested PCR could be used to verify the HKαα gene, but could not distinguish the subtypes of HKαα thalassemia. The MLPA assay was used to detect the change in the copy number of the α-globin gene, but it could not determine whether -α 3.7 and ααα anti 4.2 were in cis or in trans. Long-read TGS technology could accurately detect the HKαα allele and distinguish the genotypes of HKαα/αα, HKαα/-α 3.7 , HKαα/-α 4.2 , and HKαα/--SEA without pedigree analysis. The contiguous sequence of the HKαα allele was detected using the TGS approach. This study also demonstrated that individuals with HKαα/αα and β N /β N genotypes tended to have normal hematological phenotypes.Conclusions: Long-read TGS is a reliable and efficient approach for accurate detection of HKαα thalassemia, which can be widely used in clinical practice. Accurate molecular diagnosis of HKαα thalassemia will benefit clinical genetic counseling and prenatal diagnosis.

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The pedigree analysis and prenatal diagnosis of Hong Kongαα Thalassemia and the sequence analysis of Hong Kongαα Allele

Wang

Zheng

Zhang

et al. 2020

Molec Gen & Gen Med

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BackgroundThalassemia is one of the most common monogenic hemolytic disorders in the world. Hong Kongαα (HKαα) thalassemia was initially found among the people of southern China. Because of the complexity of genetic changes in HKαα thalassemia, we lack a precise sequence analysis of the HKαα allele. Here we aim to detect the specific genotype and trace the law of inheritance of this rare genotype.MethodsWe recruited an unprecedented huge pedigree containing 11 individuals carrying the HKαα thalassemia gene and 4 nongenetic‐related patients suffering from HKαα from south China. Regular hematological analysis and routine genetic screening were performed on the pedigree and two‐round nested PCR (polymerase chain reaction) for HKαα thalassemia were performed on each individual. The first‐generation gene sequencing was performed on six individuals, including four nongenetic‐related patients.ResultWe found that five family members were positive for the HKαα allele. Patients Ⅱ‐2, Ⅲ‐1, and Ⅱ‐3 with only HKαα/‐‐SEA or HKαα/‐α4.2 presented with α‐thalassemia minor trait. Ⅰ‐1, the carrier of both HKαα/‐α3.7 and β41‐42/βN, showed a typical β‐thalassemia trait. Fetus with genotype HKαα/‐α4.2 alone was not likely to suffer from any deleterious effects after birth. The whole sequence of HKαα allele revealed that HKαα alleles in the six patients shared a high similarity, implying that all HKαα alleles are likely from the same ancestor. Moreover, pedigree and sequencing analyses demonstrated that the HKαα allele contained αααanti4.2 mutation, ‐α3.7 mutation, and a fragment from α‐hemoglobin gene; thus, the composition and formation of HKαα allele was revealed. Finally, the high similarity and composition of HKαα alleles implies that once HKαα formed, αααanti4.2 and ‐α3.7 mutations tended to be a fusion gene and quite impossible to be inherited separately.ConclusionThe two‐round nested PCR is an effective method to detect HKαα allele. Besides, our study for the first time revealed the sequence of the HKαα allele, the evidence of the same ancestor with HKαα thalassemia and enriched the composition as well as the formation mechanism of HKαα allele, and immediately opened up novel potential diagnosis and prenatal counseling for HKαα thalassemia.

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Compound Heterozygosity for HKααand anin CisDeletion of DoubleαGenes Presents asα-Thalassemia Trait

Cited by 5 publications

References 16 publications

The Frequency of α-Globin Gene Triplication in a Southern Chinese Population

The Frequency of α-Globin Gene Triplication in a Southern Chinese Population

Accurate genotype diagnosis of Hong Kongαα thalassemia based on third-generation sequencing

The pedigree analysis and prenatal diagnosis of Hong Kongαα Thalassemia and the sequence analysis of Hong Kongαα Allele

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