广西壮族自治区α-珠蛋白基因罕见变异所致血红蛋白病的表型分析

Phenotypic analysis of hemoglobinopathies caused by rare variants of α-globin gene in Guangxi Zhuang Autonomous Region

目的探讨广西壮族自治区(以下简称广西)α-珠蛋白基因罕见变异及其表型谱,为罕见型血红蛋白病防治提供科学依据。方法以2015年1月至2022年12月在广西辖内11个市级妇幼保健院进行地中海贫血(以下简称地贫)检测的人群为研究对象,根据血液学和常规地贫基因检测结果纳入1289例疑似罕见变异携带者。采集血液样本经多重探针杂交法联合一代测序进行罕见地贫基因检测。结果在1289例疑似罕见变异携带者中,共检测到234个α-珠蛋白基因罕见变异等位基因,罕见变异检出率为18.2%;共包括55种罕见变异,其中拷贝数变异(copy number variants,CNVs)、单核苷酸变异(single nucleotide variants,SNVs)及血红蛋白(hemoglobin,Hb)结构性变异分别占30.9%(17/55)、25.5%(14/55)、41.8%(23/55),3种变异类型中检出率最高的罕见变异分别为-α^(2.4)、αα^(IVS-Ⅱ-55)、αα^(Hb J-Wenchang-Wuming);另有1例融合基因,为αα^(fusion gene)。表型分析结果显示,当α-珠蛋白基因罕见变异(ααα^(anti4.2)、αα^(fusion gene))复合β-珠蛋白基因Hb结构性变异(β^(Hb G-Coushatta)、β^(Hb New York))时,血液学表型仅发生轻微改变;2例罕见SNVs(αα^(CD31)、αα^(Int))复合--^(SEA)致Hb H病患者均表现为轻至中度贫血;部分αα^(IVS-Ⅱ-55)携带者表现为红细胞计数、Hb、平均红细胞体积或/和平均红细胞Hb含量的轻度下降;Hb结构性变异(αα^(4.2-Hb Q-Thailand)、αα^(Hb Debao)、αα^(Hb Amsterdam-A1))复合大片段缺失(--^(SEA))时,表现为典型的Hb H病特征。结论广西α-珠蛋白基因罕见变异在表型阳性疑似携带者中有较高检出率,且变异类型多样;罕见变异携带者通常表现为静止型或轻型地贫,复合其他类型珠蛋白基因变异时也可产生复杂表型。

Objective To study the rare variation and phenotype spectrum ofα-globin protein gene in Guangxi Zhuang Autonomous Region(hereinafter referred to as Guangxi),and to provide a scientific basis for prevention and treatment of rare hemoglobinopathies.Methods A total of 1289 suspected carriers of rare variats were included based on the results of hematology and routine gene testing in 11 municipal level maternal and child health hospitals in Guangxi from January 2015 to December 2022.Blood samples were collected for rare thalassemia gene testing by multiplexed probe hybridization combined with one-generation sequencing.Results Among the 1289 suspected carriers of rare variats,a total of 234 rare variant alleles ofα-globin gene were detected,and the detection rate of rare variants was 18.2%.A total of 55 rare variants were included,including copy number variants(CNVs),single nucleotide variants(SNVs)and hemoglobin(Hb)structural variants,accounted for 30.9%(17/55),25.5%(14/55),and 41.8%(23/55),respectively.The rare variants with the highest detection rate among the three types of variants were-α^(2.4),αα^(IVS-Ⅱ-55),andαα^(Hb J-Wenchang-Wuming),respectively.There was also one case of a fusion gene variant,αα^(fusion gene).The results of hematological phenotyping studies showed that when rare variants of theα-globin gene(ααα^(anti4.2),αα^(fusion gene))were compounded with Hb structural variants of theβ-globin gene(β^(Hb G-Coushatta),β^(Hb New York)),the hematologic phenotypes were only slightly altered.Two cases of rare SNVs(αα^(CD31),αα^(Int))complex--^(SEA)induced Hb H disease,and the patients all presented with mild to moderate anemia.Someαα^(IVS-Ⅱ-55)carriers exhibited mild decreases in red blood counts,Hb,mean erythrocyte corpuscular volume and/or mean corpuscular hemoglobin.The Hb structural variants(αα^(4.2-Hb Q-Thailand),αα^(Hb Debao),αα^(Hb Amsterdam-A1))exhibited typical features of Hb H disease when the compound large segment was missing(--^(SEA)).Conclusions The rare variants ofα-globin gene in Guangxi have a high detection rate in suspected carriers with positive phenotype,and the types of variants are diverse.The carriers of rare variants typically exhibit quiescent or mild thalassemia,and complex phenotypes can also occur when combined with other types of globin gene mutations.