Gupta R, Shah A, Gupta K, Chandra D, Sharma A, Rahman K, Singh M K, Yadav S, Kashyap R
Department of Hematology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.
Int J Lab Hematol. 2025 Apr;47(2):318-325. doi: 10.1111/ijlh.14419. Epub 2024 Dec 27.
δβ-thalassemia/HPFH is an uncommon hemoglobinopathy characterized by decreased or the total absence of production of δ- and β-globin and increased HbF levels. Both these disorders have variable genotype and phenotype, but significant overlap in the clinical and laboratory findings. Given the lack of literature in this regard, the study aimed to estimate the prevalence of the disease and evaluate its clinical, hematological, and molecular profile in India.
This was a retrospective study where all samples with HbF level ≥ 5% and suspected to be δβ-thalassemia/HPFH, based on the HPLC, were included in the study over 3.5 years. The demographic and clinical details were retrieved from the electronic medical records. Gap-PCR was carried out to characterize the molecular defect for the HbF determinant, while amplification refractory mutation system (ARMS-PCR) was carried out for β-thalassemia genoyping. Clinical and laboratory parameters of heterozygous and homozygous/compound heterozygous δβ thalassemia deletions were compared.
A total of 65 individuals (0.8%) were diagnosed with δβ-thalassemia/HPFH; these included 45 (69%) patients in the heterozygous group and 20 (31%) cases in the homozygous/compound heterozygous subgroup. While all the carrier states were asymptomatic, 80% of the patients in the homozygous/compound heterozygous state were symptomatic with a thalassemia intermedia-like profile. The median Hb levels were 12.3 g/dL (range -9.5-18.2) and 8.0 g/dL (range 3.8-15.1) respectively. Molecular profiling identified heterozygous Asian Indian inversion deletion γ(γδβ) mutation in 50% of cases, heterozygous HPFH-3 (Indian HPFH, 48.5 kb deletion) in 14% cases, and homozygous γ(γδβ)-thalassemia in 21% cases. Compound heterozygous HPFH-3/γ(γδβ) mutation with β-thalassemia was observed in 8.9% and 3.5%, respectively. In one case, the HbF determinant could not be identified. Heterozygous (HBB:c. 92+5G>C), was the most frequent co-inherited β-thalassemia mutation in the compound heterozygous patients.
The study highlights that high HbF determinants, like δβ thalassemia and HPFH, are relatively more frequent in the Indian subcontinent, and their co-inheritance with β-thalassemia results in a moderately severe disease. Accurate identification of molecular defects is important for prenatal diagnosis and genetic counseling.
δβ地中海贫血/遗传性胎儿血红蛋白持续增多症（HPFH）是一种罕见的血红蛋白病，其特征为δ和β珠蛋白生成减少或完全缺失，以及胎儿血红蛋白（HbF）水平升高。这两种疾病都具有可变的基因型和表型，但在临床和实验室检查结果上有显著重叠。鉴于这方面的文献较少，本研究旨在估计该疾病在印度的患病率，并评估其临床、血液学和分子特征。
这是一项回顾性研究，在3.5年期间，所有基于高效液相色谱法（HPLC）检测HbF水平≥5%且疑似为δβ地中海贫血/HPFH的样本均纳入研究。从电子病历中获取人口统计学和临床详细信息。采用缺口聚合酶链反应（Gap-PCR）来鉴定HbF决定簇的分子缺陷，同时采用扩增阻滞突变系统（ARMS-PCR）进行β地中海贫血基因分型。比较了杂合子和纯合子/复合杂合子δβ地中海贫血缺失的临床和实验室参数。
共有65例个体（0.8%）被诊断为δβ地中海贫血/HPFH；其中杂合子组45例（69%），纯合子/复合杂合子亚组20例（31%）。所有携带者状态均无症状，而纯合子/复合杂合子状态的患者中80%表现为中间型地中海贫血样症状。杂合子组和纯合子/复合杂合子组的血红蛋白（Hb）水平中位数分别为12.3g/dL（范围9.5 - 18.2）和8.0g/dL（范围3.8 - 15.1）。分子谱分析发现，50%的病例存在杂合子亚洲印度人倒位缺失γ（γδβ）突变，14%的病例存在杂合子HPFH - 3（印度HPFH，48.5kb缺失），21%的病例存在纯合子γ（γδβ）地中海贫血。分别有8.9%和3.5%的病例观察到复合杂合子HPFH - 3/γ（γδβ）突变合并β地中海贫血。在1例病例中，未能鉴定出HbF决定簇。杂合子（HBB:c. 92+5G>C）是复合杂合子患者中最常见的共遗传β地中海贫血突变。
该研究强调像δβ地中海贫血和HPFH这样的高HbF决定簇在印度次大陆相对更为常见，它们与β地中海贫血的共同遗传会导致中度严重的疾病。准确鉴定分子缺陷对于产前诊断和遗传咨询很重要。
