摘要
目的分析血红蛋白(Hb)H病胎儿及患者的血液学、基因型的关系以及相关自然病程发展过程。方法采集2010-2022年在广西壮族自治区妇幼保健院就诊的1252例Hb H病胎儿及患者血样(包括174例胎儿脐带血,1062例>2岁患者外周血,16例罕见基因型Hb H病患者外周血),进行血液学及常规地中海贫血(地贫)基因型分析;另选择0~2岁Hb H 3.7、Hb H 4.2、Hb H CS和Hb H WS病患儿(n=278),采集外周血,检测红细胞发育变化趋势。采用多重探针杂交技术、微阵列比较基因组杂交技术联合一代Sanger测序对疑似罕见地贫患者进行基因突变检测。结果1062例>2岁的Hb H病患者中,基因缺失型(--/-α)占62.34%(662/1062),其中Hb H 3.7(--^(SEA)/-α^(3.7))、Hb H 4.2(--^(SEA)/-α^(42))较为常见,分别占42.28%(449/1062)和19.11%(203/1062);非基因缺失型(--/ααT或αTα/ααT)中,以Hb H CS(--^(SEA)/ααCS)、Hb H WS(--^(SEA)/ααWS)以及α^(CS)α/α^(CS)α为主,分别占16.85%(179/1062)、16.48%(175/1062)、1.98%(21/1062)。81.12%(537/662)的基因缺失型Hb H病患者表现为轻、中度贫血,Hb H病检出率范围为75%~80%。非基因缺失型中,Hb H WS病患者主要表现为轻度贫血(90%的患者血液Hb浓度>95 g/L),而Hb H CS和Hb H QS(--^(SEA)/ααQS)病患者则主要表现为中、重度贫血,患者外周血均能检出Hb H且含量普遍高于其他类型Hb H病患者。除Hb H CS和Hb H QS复合β-地贫时Hb A2值未显著升高外,其他类型Hb H病患者复合β-地贫时Hb A2值均升高(>3.5%)。各种类型Hb H病患者复合β-地贫时,均未检出Hb H峰。红细胞发育变化趋势检测结果显示,Hb H病患者红细胞计数较正常同龄人升高,而Hb、平均红细胞体积(MCV)、平均红细胞血红蛋白含量(MCH)均低于正常同龄人(均P<0.05),并在6个月至1岁时降到最低;贫血程度严重的Hb H CS病患者,其MCV值升高明显(P<0.001)。Hb H病胎儿脐带血的检测结果显示,α^(CS)α/α^(CS)α胎儿宫内贫血严重,其次为Hb H QS和Hb H CS病胎儿;脐带血中Hb Bart’s含量与贫血严重程度呈负相关(rs=-0.58,P<0.001);Hb H病复合β-地贫时,胎儿贫血情况未见明显改善,Hb Bart′s含量未见明显变化(均P>0.05)。此外,基因缺失型罕见Hb H病患者中,以Hb H 21.9(-α21.9kb/--^(SEA))、Hb H 2.4(-α^2.4)/--^(SEA))常见;非基因缺失型罕见Hb H病患者中,ααAmsterdam-A1/--^(SEA)和ααHb G-Georgia/--^(SEA)均为首见。结论不同类型之间及相同类型在不同发育时期的Hb H病患者临床表现具有异质性。当Hb H病患者复合β-地贫时,基因缺失型患者表型有所改善,而非基因缺失型患者未见明显改变。相较于正常人,Hb H病患者血液Hb、MCV、MCH均降低且红细胞生理变化更为急剧。
Objective To analyze the relationship between hematological and genotype characteristics of fetuses and patients with hemoglobin(Hb)H disease and their natural disease progression.Methods From 2010 to 2022,a total of 1252 blood samples from fetuses and patients with Hb H disease who visited the Guangxi Zhuang Autonomous Regional Maternal and Child Health Hospital were collected(including 174 umbilical cord blood samples,1062 peripheral blood samples from patients over 2 years old,and 16 peripheral blood samples from patients with rare cases of genotype Hb H).Additionally,278 peripheral blood samples were collected from patients aged O-2 years old with Hb H 3.7,Hb H 4.2,Hb H CS,and Hb H WS disease for the study of trends in red blood cell development.Multiple probe hybridization and microarray comparative genomic hybridization technology combined with first-generation Sanger sequencing were used for rare mutation detection.Results Among the 1062 Hb H disease patients over 2 years old,62.34%(662/1062)had gene deletion(--/-α),of which Hb H 3.7(--^(SEA)/-α^(3.7))and Hb H 4.2(--^(SEA)/-α^(42))were the most common,accounting for 42.28%(449/1062)and 19.11%(203/1062)of the total,respectively.Among the non-deletion genotypes(--/ααT orα'α/αα'),Hb H CS(--^(SEA)/α),Hb H WS(--^(SEA))αw)andαα/ααaccounted for 16.85%(179/1062),16.48%(175/1062)and 1.98%(21/1062),respectively.The 81.12%(537/662)of patients with deletional Hb H disease showed mild to moderate anemia,with Hb H detection rates ranging from 75%to 80%.Among non-deletional Hb H disease,Hb H WS disease showed the mild(blood Hb concentration>95 g/L in 90%of patients)phenotype while Hb H CS and Hb H QS(--^(SEA)/αα)patients had moderate to severe anemia,with Hb H detected in peripheral blood at higher levels than in other types of Hb H disease patients.Except for Hb H CS and Hb H QS,which did not show a significant increase in Hb A2 levels when complicated withβ-thalassemia,Hb A2 levels were increased(>3.5%)in all other types of Hb H disease patients.When Hb H disease was complicated withβ-thalassemia,Hb H peaks were not detected in either type of Hb H disease.The results of red blood cell development trend detection showed that erythrocyte counts were elevated in patients with Hb H disease compared to their normal counterparts;whereas,blood Hb,mean erythrocyte volume(MCV)and mean erythrocyte hemoglobin content(MCH)were lower than in their normal counterparts(P<0.05)and decreased to the minimum at 6 months to 1 year of age.Patients with Hb H CS disease,as the most severe form of anemia,had the highest MCV values(P<0.001).The results of fetal cord blood with Hb H disease showed thatαa/&αcaused severe intrauterine anemia,followed by Hb H QS and Hb H CS.The content of Hb Bart's in umbilical cord blood was negatively correlated with the severity of anemia(r,=-0.58,P<0.001).When Hb H disease was complicated withβ-thalassemia,there was no significant improvement in fetal anemia,and the Hb Bart's content did not change significantly(P>0.05)In addition,Hb H 21.9(-α219b/--^(SEA))and Hb H 2.4(-α^(2.4))/--^(SEA))were common in patients with deletion rare Hb H.In patients with non-deletion rare Hb H,αQAmserlam-Al/--^(SEA) andαqHb G-Coari/--^(SEA) were both first reported.Conclusions There is heterogeneity in clinical manifestations of patients with different types of Hb H disease or same type of Hb H disease at diferent developmental stages.When patients with Hb H are complicated withβ-thalassemia,the phenotype of patients with the deletion type is improved,while that of patients with the non-deletion type is not.Compared to normal individuals,patients with Hb H disease have lower blood Hb concentration,MCV and MCH,and more rapid physiological changes in red blood cells.
作者
林丽
左杨瑾
陈碧艳
周超凡
王梁
陈秋莉
罗静思
何升
Lin Li;Zuo Yangjin;Chen Biyan;Zhou Chaofan;Wang Liang;Chen Qiulil;Luo Jingsi;He Sheng(Genetic and Metabolic Central Laboratory,Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region,Nanning 530000,China;Birth Defect Prevention Research Institute,Guangxi Key Laboratory of Reproductive Health and Birth Defects Prevention,Key Laboratory for Birth Defects Prevention and Control,Nanning 530000,China)
出处
《中华地方病学杂志》
CAS
北大核心
2023年第6期459-466,共8页
Chinese Journal of Endemiology
基金
广西卫生适宜技术推广项目(S2021069)
广西壮族自治区卫生健康委员会自筹课题(Z20190692)
广西卫生适宜技术推广项目(S2021071)
广西壮族自治区卫生健康委员会自筹课题(Z20210270)
中央引导地方财政专项基金(桂科Zy1949016)
广西医学高层次骨干人才"139"计划(G202003023)
广西重点实验室运行补助项目(21-220-22)。
