The pedigree analysis and prenatal diagnosis of Hong Kongαα Thalassemia and the sequence analysis of Hong Kongαα Allele
The pedigree analysis and prenatal diagnosis of Hong Kongαα Thalassemia and the sequence analysis of Hong Kongαα Allele
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DOI：
10.1002/mgg3.1285
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发表时间：
2020-05-18
影响因子：
2
通讯作者：
Zhu, Chunjiang
中科院分区：
文献类型：
--
作者：
Wang, Wenjuan;Zheng, Haiqing;Zhu, Chunjiang
研究背景地中海贫血是世界上最常见的单基因溶血性疾病之一。香港阿尔法阿尔法（HK阿尔法阿尔法）地中海贫血症最初发现于中国南方的人。由于HK α α地中海贫血遗传变化的复杂性，我们缺乏HK α α等位基因的精确序列分析。在这里，我们的目的是检测特定的基因型和跟踪这种罕见的genotype.Methods的遗传规律，我们招募了一个前所未有的巨大的家系，其中包含11个人携带HK α α地中海贫血基因和4个非遗传相关的患者患有HK α α从中国南方。对家系进行常规血液学分析和常规遗传筛查，并对每个个体进行HK α α地中海贫血的两轮巢式PCR（聚合酶链反应）。第一代基因测序进行了6个人，包括4个非遗传相关patients.Results，我们发现，5个家庭成员为HK α α等位基因阳性。仅具有HK α α/--（SEA）或HK α α/-α（4.2）的患者II-2、III-1和II-3呈现α-地中海贫血次要性状。携带HK α/-α（3.7）和β（41 - 42）/β（N）的罗马数字1 - 1显示出典型的β地中海贫血特征。单独携带基因型HK α/-α（4.2）的胎儿在出生后不太可能遭受任何有害影响。HK α α等位基因全序列分析显示，6例患者的HK α α等位基因具有较高的相似性，提示所有的HK α α等位基因可能来自同一祖先。此外，家系和测序分析表明，HK α α等位基因含有α α（抗4.2）突变，-α（3.7）突变和α-血红蛋白基因的片段，因此，HK α α等位基因的组成和形成。结论两轮巢式PCR是检测HK α α等位基因的有效方法。本研究首次揭示了HK α α等位基因的序列，证实了HK α α地中海贫血具有同一祖先，丰富了HK α α等位基因的组成和形成机制，为HK α α地中海贫血的诊断和产前咨询开辟了新的可能性。
Background Thalassemia is one of the most common monogenic hemolytic disorders in the world. Hong Kong alpha alpha (HK alpha alpha) thalassemia was initially found among the people of southern China. Because of the complexity of genetic changes in HK alpha alpha thalassemia, we lack a precise sequence analysis of the HK alpha alpha allele. Here we aim to detect the specific genotype and trace the law of inheritance of this rare genotype.Methods We recruited an unprecedented huge pedigree containing 11 individuals carrying the HK alpha alpha thalassemia gene and 4 nongenetic-related patients suffering from HK alpha alpha from south China. Regular hematological analysis and routine genetic screening were performed on the pedigree and two-round nested PCR (polymerase chain reaction) for HK alpha alpha thalassemia were performed on each individual. The first-generation gene sequencing was performed on six individuals, including four nongenetic-related patients.Result We found that five family members were positive for the HK alpha alpha allele. Patients II-2, III-1, and II-3 with only HK alpha alpha/--(SEA) or HK alpha alpha/-alpha(4.2) presented with alpha-thalassemia minor trait. ROMAN NUMERAL ONE-1, the carrier of both HK alpha alpha/-alpha(3.7) and beta(41-42)/beta(N), showed a typical beta-thalassemia trait. Fetus with genotype HK alpha alpha/-alpha(4.2) alone was not likely to suffer from any deleterious effects after birth. The whole sequence of HK alpha alpha allele revealed that HK alpha alpha alleles in the six patients shared a high similarity, implying that all HK alpha alpha alleles are likely from the same ancestor. Moreover, pedigree and sequencing analyses demonstrated that the HK alpha alpha allele contained alpha alpha alpha(anti4.2) mutation, -alpha(3.7) mutation, and a fragment from alpha-hemoglobin gene; thus, the composition and formation of HK alpha alpha allele was revealed. Finally, the high similarity and composition of HK alpha alpha alleles implies that once HK alpha alpha formed, alpha alpha alpha(anti4.2) and -alpha(3.7) mutations tended to be a fusion gene and quite impossible to be inherited separately.Conclusion The two-round nested PCR is an effective method to detect HK alpha alpha allele. Besides, our study for the first time revealed the sequence of the HK alpha alpha allele, the evidence of the same ancestor with HK alpha alpha thalassemia and enriched the composition as well as the formation mechanism of HK alpha alpha allele, and immediately opened up novel potential diagnosis and prenatal counseling for HK alpha alpha thalassemia.