目的:遗传性球形红细胞增多症(hereditary spherocytosis,HS)是最常见的遗传性红细胞膜缺陷病,主要表现为贫血、黄疸、脾大。由于部分患者临床表现不典型、家族史阴性,加上传统的实验室检查敏感性和特异性均较低,常导致漏诊、误诊。目...目的:遗传性球形红细胞增多症(hereditary spherocytosis,HS)是最常见的遗传性红细胞膜缺陷病,主要表现为贫血、黄疸、脾大。由于部分患者临床表现不典型、家族史阴性,加上传统的实验室检查敏感性和特异性均较低,常导致漏诊、误诊。目前已明确ANK1、SPTB、SPTA1、SLC4A1和EPB42基因突变可引起其对应的编码蛋白质缺失,进而导致红细胞膜缺陷。本研究旨在分析HS基因诊断的可行性和临床应用价值。方法:回顾性收集2018年1月至2021年9月中南大学湘雅二医院血液内科收治的26例中国湖南HS患者的资料,分析其临床表现和实验室检测结果。应用二代测序(next-generation sequencing,NGS)结合Sanger测序,检测HS致病基因突变和胆红素代谢调控关键酶尿苷二磷酸葡萄糖醛酸转移酶1家族多肽A1(uridine diphosphate-glucuronosyl transferase 1 family polypeptide A1,UGT1A1)变异。根据美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics,ACMG)发布的《序列变异解释的标准和指南》进行致病基因变异判读。分析不同基因变异类型患者的临床特征,并对其临床诊断和基因诊断进行对比分析。结果:在26例HS患者中,贫血23例、黄疸25例、脾大24例、胆石症14例;16例有家族史,10例无家族史;25例HS致病基因突变检测结果为阳性,1例阴性。19个家系共检出18个HS致病基因杂合变异,其中14个为致病性变异,1个可能致病性变异,3个意义未明变异。SPTB突变(12个)和ANK1突变(4个)最多。变异类型以无义突变为主(9个)。SPTB突变组与ANK1突变组相比,外周血红细胞参数及溶血指标的差异均无统计学意义(均P>0.05)。ANK1突变组切脾率高于SPTB突变组,差异有统计学意义(χ^(2)=6.970,P=0.014)。不同突变类型(无义突变、移码突变、剪接位点突变及错义突变)组间外周血红细胞参数及溶血指标差异亦均无统计学意义(均P>0.05)。临床确诊的18例患者中,17例与基因诊断一致;临床疑诊患者8例,均经HS致病基因突变检测确诊。24例HS患者行UGT1A1变异检测,5例患者携带UGT1A1变异导致酶活性降低,19例酶活性正常。酶活性降低组较酶活性正常组的总胆红素(total bilirubin,TBIL)水平高,差异具有统计学意义(U=22,P=0.038)。结论:大多数HS患者有贫血、黄疸和脾大,常合并胆石症。中国湖南HS致病基因突变以SPTB和ANK1突变最常见,基因型与临床表型无明显相关性。基因诊断与临床诊断高度一致。UGT1A1酶活性降低可导致HS患者黄疸程度加重。临床联合基因诊断有利于HS的快速、精准诊断;而UGT1A1酶活性相关基因变异检测对HS黄疸评估有重要意义。展开更多
BACKGROUND Neonatal hyperbilirubinemia is one of the common diseases of newborns that typically presents with yellow staining of skin,resulting in sequelaes such as hearing loss,motor and intellectual development diso...BACKGROUND Neonatal hyperbilirubinemia is one of the common diseases of newborns that typically presents with yellow staining of skin,resulting in sequelaes such as hearing loss,motor and intellectual development disorders,and even death.The pathogenic factors of neonatal hyperbilirubinemia are complex.Different cases of hyperbilirubinemia may have a single or mixed etiology.AIM To explore the etiological characteristics of severe hyperbilirubinemia in term newborns of eastern Guangdong of China.METHODS Term newborns with severe hyperbilirubinemia in one hospital from January 2012 to December 2021 were retrospectively analyzed.The etiology was determined according to the laboratory results and clinical manifestations.RESULTS Among 1602 term newborns with hyperbilirubinemia in eastern Guangdong of China,32.20%(580/1602)was severe hyperbilirubinemia.Among the causes of severe hyperbilirubinemia,neonatal hemolysis accounted for 15.17%,breast milk jaundice accounted for 12.09%,infection accounted for 10.17%,glucose-6-phosphate dehydrogenase(G6PD)deficiency accounted for 9.14%,and the coexistence of multiple etiologies accounted for 6.55%,unknown etiology accounted for 41.72%.ABO hemolysis and G6PD deficiency were the most common causes in the 20 cases with bilirubin encephalopathy.94 severe hyperbilirubinemia newborns were tested for uridine diphosphate glucuronosyl transferase 1A1(UGT1A1)*6 variant(rs4148323,c.211G>A,p.Arg71Gly),9 cases were 211 G to A homozygous variant,37 cases were 211 G to A heterozygous variant,and 48 cases were wild genotypes.CONCLUSION The main cause for severe hyperbilirubinemia and bilirubin encephalopathy in eastern Guangdong of China were the hemolytic disease of the newborns,G6PD deficiency and infection.UGT1A1 gene variant was also a high-risk factor for neonatal hyperbilirubinemia.Targeted prevention and treatment according to the etiology may reduce the occurrence of bilirubin encephalopathy and kernicterus.展开更多
Background: Gilbert syndrome (GS) is characterized by an elevated serum bil-irubin due to a polymorphism in Uridine Diphosphate Glucuronosyl Transferase (UGT1A1) gene. Several studies have found high prevalence of Gil...Background: Gilbert syndrome (GS) is characterized by an elevated serum bil-irubin due to a polymorphism in Uridine Diphosphate Glucuronosyl Transferase (UGT1A1) gene. Several studies have found high prevalence of Gilbert Syn-drome in some Asian countries but still haven’t explored in Bangladesh. Aim of this study was to determine the allele frequencies of two different variants of UGT1A1 polymorphisms (UGT1A1 6 and UGT1A1 28) among Bangladeshi population. Materials and method: Total 150 unrelated volunteer from outpa-tient unit of the Central Hospital Limited, and Bangabandhu Sheikh Mujib Medical University, Dhaka were enrolled in this study. Peripheral blood was obtained from each subject and DNA extraction was done by Genomic DNA Isolation Kit. Polymorphisms of UGT1A1*6 (c.211G>A) was genotyped using the TaqMan Assay-on-Demand SNP Typing System and UGT1A1*28 (c.-53_-52TA) promoter repeat number polymorphism was determined by PCR method on an ABI PRISM 3130 Genetic Analyzer. Results: 57.3% of the study participants were male, mean age of them was 4.05 years. Minor allele fre-quency (MAF) was 0.442 (44.2%) for UGT1A1*28 and 0.047 (4.7%) for UGT1A1*6. Conclusion: This is the first ever study conducted among Bangla-deshi population to identify the Gilbert syndrome and found very high prevalence. Drugs those who are conjugated by UGT1A1 may lead to worse adverse event due to UGT1A1 polymorphism. Infants having decreased UGT1A1 enzyme activity develop neonatal jaundice and its further complication like Ker-nicterus. Higher incidence of Gilbert syndrome among Bangladeshi might be the alert for the clinicians treating neonatal jaundice.展开更多
文摘目的:遗传性球形红细胞增多症(hereditary spherocytosis,HS)是最常见的遗传性红细胞膜缺陷病,主要表现为贫血、黄疸、脾大。由于部分患者临床表现不典型、家族史阴性,加上传统的实验室检查敏感性和特异性均较低,常导致漏诊、误诊。目前已明确ANK1、SPTB、SPTA1、SLC4A1和EPB42基因突变可引起其对应的编码蛋白质缺失,进而导致红细胞膜缺陷。本研究旨在分析HS基因诊断的可行性和临床应用价值。方法:回顾性收集2018年1月至2021年9月中南大学湘雅二医院血液内科收治的26例中国湖南HS患者的资料,分析其临床表现和实验室检测结果。应用二代测序(next-generation sequencing,NGS)结合Sanger测序,检测HS致病基因突变和胆红素代谢调控关键酶尿苷二磷酸葡萄糖醛酸转移酶1家族多肽A1(uridine diphosphate-glucuronosyl transferase 1 family polypeptide A1,UGT1A1)变异。根据美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics,ACMG)发布的《序列变异解释的标准和指南》进行致病基因变异判读。分析不同基因变异类型患者的临床特征,并对其临床诊断和基因诊断进行对比分析。结果:在26例HS患者中,贫血23例、黄疸25例、脾大24例、胆石症14例;16例有家族史,10例无家族史;25例HS致病基因突变检测结果为阳性,1例阴性。19个家系共检出18个HS致病基因杂合变异,其中14个为致病性变异,1个可能致病性变异,3个意义未明变异。SPTB突变(12个)和ANK1突变(4个)最多。变异类型以无义突变为主(9个)。SPTB突变组与ANK1突变组相比,外周血红细胞参数及溶血指标的差异均无统计学意义(均P>0.05)。ANK1突变组切脾率高于SPTB突变组,差异有统计学意义(χ^(2)=6.970,P=0.014)。不同突变类型(无义突变、移码突变、剪接位点突变及错义突变)组间外周血红细胞参数及溶血指标差异亦均无统计学意义(均P>0.05)。临床确诊的18例患者中,17例与基因诊断一致;临床疑诊患者8例,均经HS致病基因突变检测确诊。24例HS患者行UGT1A1变异检测,5例患者携带UGT1A1变异导致酶活性降低,19例酶活性正常。酶活性降低组较酶活性正常组的总胆红素(total bilirubin,TBIL)水平高,差异具有统计学意义(U=22,P=0.038)。结论:大多数HS患者有贫血、黄疸和脾大,常合并胆石症。中国湖南HS致病基因突变以SPTB和ANK1突变最常见,基因型与临床表型无明显相关性。基因诊断与临床诊断高度一致。UGT1A1酶活性降低可导致HS患者黄疸程度加重。临床联合基因诊断有利于HS的快速、精准诊断;而UGT1A1酶活性相关基因变异检测对HS黄疸评估有重要意义。
基金Supported by the Natural Science Foundation of Guangdong Province,No.2016A030307035Special Research Plan 2019 of Chaozhou,No.2020xg01High-Level Development Plan of People’s Hospital of Yangjiang,No.G2020007.
文摘BACKGROUND Neonatal hyperbilirubinemia is one of the common diseases of newborns that typically presents with yellow staining of skin,resulting in sequelaes such as hearing loss,motor and intellectual development disorders,and even death.The pathogenic factors of neonatal hyperbilirubinemia are complex.Different cases of hyperbilirubinemia may have a single or mixed etiology.AIM To explore the etiological characteristics of severe hyperbilirubinemia in term newborns of eastern Guangdong of China.METHODS Term newborns with severe hyperbilirubinemia in one hospital from January 2012 to December 2021 were retrospectively analyzed.The etiology was determined according to the laboratory results and clinical manifestations.RESULTS Among 1602 term newborns with hyperbilirubinemia in eastern Guangdong of China,32.20%(580/1602)was severe hyperbilirubinemia.Among the causes of severe hyperbilirubinemia,neonatal hemolysis accounted for 15.17%,breast milk jaundice accounted for 12.09%,infection accounted for 10.17%,glucose-6-phosphate dehydrogenase(G6PD)deficiency accounted for 9.14%,and the coexistence of multiple etiologies accounted for 6.55%,unknown etiology accounted for 41.72%.ABO hemolysis and G6PD deficiency were the most common causes in the 20 cases with bilirubin encephalopathy.94 severe hyperbilirubinemia newborns were tested for uridine diphosphate glucuronosyl transferase 1A1(UGT1A1)*6 variant(rs4148323,c.211G>A,p.Arg71Gly),9 cases were 211 G to A homozygous variant,37 cases were 211 G to A heterozygous variant,and 48 cases were wild genotypes.CONCLUSION The main cause for severe hyperbilirubinemia and bilirubin encephalopathy in eastern Guangdong of China were the hemolytic disease of the newborns,G6PD deficiency and infection.UGT1A1 gene variant was also a high-risk factor for neonatal hyperbilirubinemia.Targeted prevention and treatment according to the etiology may reduce the occurrence of bilirubin encephalopathy and kernicterus.
文摘Background: Gilbert syndrome (GS) is characterized by an elevated serum bil-irubin due to a polymorphism in Uridine Diphosphate Glucuronosyl Transferase (UGT1A1) gene. Several studies have found high prevalence of Gilbert Syn-drome in some Asian countries but still haven’t explored in Bangladesh. Aim of this study was to determine the allele frequencies of two different variants of UGT1A1 polymorphisms (UGT1A1 6 and UGT1A1 28) among Bangladeshi population. Materials and method: Total 150 unrelated volunteer from outpa-tient unit of the Central Hospital Limited, and Bangabandhu Sheikh Mujib Medical University, Dhaka were enrolled in this study. Peripheral blood was obtained from each subject and DNA extraction was done by Genomic DNA Isolation Kit. Polymorphisms of UGT1A1*6 (c.211G>A) was genotyped using the TaqMan Assay-on-Demand SNP Typing System and UGT1A1*28 (c.-53_-52TA) promoter repeat number polymorphism was determined by PCR method on an ABI PRISM 3130 Genetic Analyzer. Results: 57.3% of the study participants were male, mean age of them was 4.05 years. Minor allele fre-quency (MAF) was 0.442 (44.2%) for UGT1A1*28 and 0.047 (4.7%) for UGT1A1*6. Conclusion: This is the first ever study conducted among Bangla-deshi population to identify the Gilbert syndrome and found very high prevalence. Drugs those who are conjugated by UGT1A1 may lead to worse adverse event due to UGT1A1 polymorphism. Infants having decreased UGT1A1 enzyme activity develop neonatal jaundice and its further complication like Ker-nicterus. Higher incidence of Gilbert syndrome among Bangladeshi might be the alert for the clinicians treating neonatal jaundice.
