[Rare thalassemia caused by novel nucleotide variants in the globin gene: four case reports and literature review]

Abstract

Objective: To analyze the DNA sequences and clinical phenotypes of four cases with rare thalassemia to improve its recognition and accurate diagnosis. Methods: The DNA sequence characteristics of four cases with rare thalassemia diagnosed from May 2014 to December 2019 were retrospectively analyzed, and related literature was reviewed. Results: The results of the routine gene test for thalassemia indicated that the common three type of deletion and three point mutations in hemoglobin alpha 1/2 (HBA1/A2) , and 16 point mutations in hemoglobin beta (HBB) gene were unable to be detected in cases 1-3, and case 4 was--SEA. However, the results of HBA1/A2 and HBB whole-genome sequencing revealed that the four cases had a point mutation of HBB:c.347C>A, HBB:c.1A>G, HBB:c.393T>G, and HBA2: c.301-1G>A (IVS II-142 G>A) , respectively. Meanwhile, the father, aunt, and grandfather of case 2 carried the HBB:c.1 A>G heterozygous point mutation. Conclusion: The novel mutations in HBB and HBA2 genes, resulting in a rare thalassemia, were revealed. Among them, the HBB:c.347C>A, HBB:c.1A>G, and HBA2:c.301-1G>A (IVS II-142 G>A) mutations were first reported in Chinese patients with thalassemia. Contrarily, HBB:c.393T>G mutation has not yet been recorded in the databases of human hemoglobin variants and thalassemia. The discovery of these novel nucleotide variants in this study would enrich the DNA mutation gene database of thalassemia.

Keywords: DNA sequencing; Gene mutation; Globin; Thalassemia.

图1. 4例少见地中海贫血类型突变基因测序结果（红色箭头示突变位点，黑色箭头示碱基C/T杂合子）

A：例1 HBB:c. 347C>A突变；B：例2 HBB:c.1A>G突变；C：例3HBB：c.393T>G突变；D：例4 HBA2：c.301-1G>A突变

图2. 罕见地中海贫血病例2家系图