Sultan Qaboos University and Hospital, Muscat, Oman.
Eur J Haematol. 2013 Aug;91(2):164-9. doi: 10.1111/ejh.12136. Epub 2013 Jun 15.
Coinheritance of α-thalassemia influences the clinical and hematological phenotypes of β-hemoglobinopathies (β-thalassemia and sickle cell disease) and when present together in significant frequency within a population, a spectrum of clinical forms is observed. Precise molecular characterization of α-thalassemia is important in understanding their disease-modifying role in β-hemoglobinopathies and for diagnostic purposes.
Because currently used approaches are labor/cost-intensive, time-consuming, error-prone in certain genotype combinations and not applicable for large epidemiological screening, we developed a systematic stepwise strategy to overcome these difficulties. We successfully applied this to characterize the α-globin gene status in 150 Omani cord blood samples with Hb Barts and 32 patients with HbH disease.
We observed a good correlation between α-globin genotypes and level of Hb Bart's with the Hb Bart's levels significantly higher in both deletional and non-deletional α-globin genotypes. The most common α-globin genotype in HbH cases was α(TSaudi) α/α(TSaudi) α (n = 16; 50%) followed by -α(3.7) /-(MED) (n = 10; 31%). This approach detects also the α-globin gene triplication as exemplified by the study of a family where the β-globin gene defect failed to explain the β-thalassemia intermedia phenotype.
Molecular characterization of α-thalassemia is complex due to high sequence homology between the duplicated α-globin genes and to the existence of a variety of gene rearrangements (small and large deletions of various sizes) and punctual substitutions (non-deletional alleles). The novelty of our strategy resides, not in the individual technical steps per se but in the reasoned sequential order of their use taking into consideration the hematological phenotype as well.
α-地中海贫血的共遗传会影响β-血红蛋白病（β-地中海贫血和镰状细胞病）的临床和血液学表型，当它们在人群中以显著频率共同存在时，就会观察到一系列临床形式。精确的α-地中海贫血分子特征对于理解其在β-血红蛋白病中的疾病修饰作用以及诊断目的非常重要。
由于目前使用的方法劳动/成本密集、耗时、在某些基因型组合中容易出错且不适用于大规模的流行病学筛查，我们开发了一种系统的逐步策略来克服这些困难。我们成功地应用这种方法来描述 150 例携带 Hb Barts 的阿曼脐带血样本和 32 例 HbH 疾病患者的α-珠蛋白基因状态。
我们观察到α-珠蛋白基因型和 HbBart's 水平之间存在良好的相关性，HbBart's 水平在缺失和非缺失α-珠蛋白基因型中均显著升高。HbH 病例中最常见的α-珠蛋白基因型是α(TSaudi)α/α(TSaudi)α（n=16；50%），其次是-α(3.7)/-(MED)（n=10；31%）。这种方法还可以检测到α-珠蛋白基因三倍体，例如在一个家庭的研究中，β-珠蛋白基因缺陷未能解释β-地中海贫血中间型表型。
由于重复的α-珠蛋白基因之间的高度序列同源性以及各种基因重排（大小不同的小和大缺失）和点状替换（非缺失等位基因）的存在，α-地中海贫血的分子特征非常复杂。我们策略的新颖之处不在于个别技术步骤本身，而在于考虑到血液学表型的合理顺序使用它们。
