新的珠蛋白基因突变引起少见地中海贫血四例报告及文献复习

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

目的:分析4例少见地中海贫血(地贫)患者的DNA序列、临床表型,提高对地贫的认识。方法:对2014年5月至2019年12月4例少见地贫患者的临床及DNA序列特征进行回顾性分析并复习相关文献。结果:地贫基因常规检测显示,例1~3均未检测到常见的3种α株蛋白1/2(HBA1/A2)基因缺失及其3种点突变和16种β株蛋白(HBB)基因点突变,例4检测到αα^(--SEA)缺失。HBA1/A2和HBB基因全序列Sanger测序示:例1~4分别存在HBB:c.347C>A、HBB:c.1A>G、HBB:c.393T>G及HBA2:c.301-1G>A(IVS-II-142 G>A)突变。同时,例2的祖父、父亲和姑姑均为HBB:c.1A>G杂合突变。结论:本研究发现了新的珠蛋白基因突变,HBB:c.347C>A、HBB:c.1A>G和HBB:c.393T>G以及HBA2:c.301-1 G>A(IVS-II-142 G>A)突变在中国地贫患者中为首次报道,HBB:c.393T>G突变为全球首次报道,丰富了地贫基因突变数据库。

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.