Abstract

α-thalassemia is an inherited blood disorder commonly caused by deletions or point mutations involving one or both α-globin genes. Recent studies shed new light on the critical role of upstream enhancers multi-species conserved sequences (MCSs) in the ordered regulation of α-globin gene expression. Herein, we reported two unrelated probands with deletions in α-globin genes and MCSs, respectively. The proband from Family A is a compound heterozygote carrying a known α⁺ mutation (-α^3.7) and a novel 60.2 kb deletion causing the absence of both α-globin genes. The proband from Family B, on the other hand, is a compound heterozygote with a known α⁰ mutation (--^SEA) and a novel deletion involving only upstream regulatory elements MCS-R1, R2 and R3, while the α-globin genes remain intact. Notably, both these two patients suffered varied extent of anemia, indicating that the loss of enhancer elements could equally lead to reduced synthesis of α-globin. Upon these observations, we then confirmed the exact breakpoints of these two novel deletions using a targeted next-generation sequencing (NGS) previously established by our group, which may enable further elucidation of the rearrangement mechanisms on these deletions and functional dissection of MCSs. Taken together, our study reports a reliable NGS-based molecular screening approach for accurate identification of copy number variations (CNVs) in the α-globin cluster and the genetic diagnosis of these two probands may help to extend the spectrum of α-thalassemia mutations in Chinese population.

中文翻译：

---

通过靶向下一代测序表征两个新的Alu元素介导的导致α0地中海贫血的α-珠蛋白基因簇缺失

摘要

α地中海贫血是一种遗传性血液疾病，通常由涉及一个或两个α珠蛋白基因的缺失或点突变引起。最近的研究揭示了上游增强子多物种保守序列（MCSs）在α-珠蛋白基因表达的有序调节中的关键作用。在本文中，我们报道了两个无关的先证者，分别在α-珠蛋白基因和MCSs中缺失。从A族先证者是一个携带已知α的化合物杂合子⁺突变（-α ^3.7）和新颖60.2 kb的缺失导致缺乏既α珠蛋白基因。另一方面，来自B族的先证者是具有已知^α0突变的复合杂合子（^-SEA）和仅涉及上游调控元件MCS-R1，R2和R3的新型缺失，而α-珠蛋白基因保持完整。值得注意的是，这两名患者均患有不同程度的贫血，表明增强子元素的丢失可能同样导致α-珠蛋白合成减少。根据这些观察结果，我们然后使用我们小组先前建立的靶向下一代测序（NGS）确认了这两个新缺失的确切断点，这可能使得能够进一步阐明这些缺失的重排机制和MCS的功能解剖。在一起