Clinical and genetic diagnosis for 26 paitents with hereditary spherocytosis / 中南大学学报(医学版)

OBJECTIVES@#Hereditary spherocytosis (HS) is the most common hereditary defect of the red cell membrane, mainly characterized by anemia, jaundice, and splenomegaly. Due to the atypical clinical manifestations and negative family history of some patients, as well as the low sensitivity and specificity of traditional laboratory examinations, it is easy for it to escape diagnosis or be misdiagnosed. At present, it has been confirmed that the mutation of ANK1, SPTB, SPTA1, SLC4A1 and EPB42 genes can cause the deletion of their corresponding coding proteins, and thus lead to the defect of erythrocyte membrane. This study aims to analyze the feasibility and clinical application value of HS gene diagnosis.@*METHODS@#Data of 26 patients from Hunan, China with HS admitted to the Department of Hematology, Second Xiangya Hospital of Central South University from January 2018 to September 2021 were retrospectively collected, and their clinical manifestations and results of laboratory examinations were analyzed. Next-generation sequencing (NGS) combined with Sanger sequencing were applied. The mutation of HS pathogenic gene and the variation of uridine diphosphate-glucuronosyl transferase 1 family polypeptide A1 (UGT1A1), a key enzyme in the regulation of bilirubin metabolism, were detected. The results of pathogenic gene variations were interpreted pathogenic gene variations in accordance with the Standards and guidelines for the interpretation of sequence variants published by the American College of Medical Genetics and Genomics (ACMG). The clinical characteristics of patients with different gene variants were analyzed, and the clinical diagnosis and genetic diagnosis were compared.@*RESULTS@#Among the 26 patients with HS, there were 23 cases of anemia, 25 cases of jaundice, 24 cases of splenomegaly, and 14 cases of cholelithiasis. There were 16 cases with family history and 10 cases without family history. The results of HS mutation test were positive in 25 cases and negative in 1 case. A total of 18 heterozygous mutations of HS pathogenic genes were detected in 19 families, among which 14 were pathogenic, 1 was likely pathogenic and 3 were of unknown significance. SPTB mutations (12) and ANK1 mutations (4) were the most common. The main variation types were nonsense mutation (9). There were no significant differences in peripheral blood cell parameters and hemolysis indicators between the SPTB mutant group and the ANK1 mutant group (all P>0.05). The rate of splenectomy in ANK1 mutation group was higher than that in SPTB mutation group, and the difference was statistically significant (χ2=6.970, P=0.014). There were no significant differences in peripheral blood cell parameters and hemolysis indicators among different mutation types (nonsense mutation, frameshift mutation, splice site mutation and missense mutation) (all P>0.05). Among the 18 clinically confirmedpatients, there were 17 cases whose diagnosis is consistent with the genetic diagnosis. Eight patients were clinically suspected, and all of them were confirmed by detection of HS gene mutation. Twenty-four patients with HS underwent UGT1A1 mutation detection, among which 5 patients carried UGT1A1 mutation resulting in a decrease in enzyme activity, and 19 patients had normal enzyme activity. The level of total bilirubin (TBIL) in the group with reduced enzyme activity was higher than that in the group with normal enzyme activity, and the difference was statistically significant (U=22, P=0.038).@*CONCLUSIONS@#Most patients with HS have anemia, jaundice and splenomegaly, often accompanied by cholelithiasis. SPTB and ANK1 mutations are the most common mutations in HS pathogenic genes among patients in Hunan, China, and there was no significant correlation between genotype and clinical phenotype. Genetic diagnosis is highly consistent with clinical diagnosis. The decrease of UGT1A1 enzyme activity can lead to the aggravation of jaundice in HS patients. Clinical combined gene diagnosis is beneficial for the rapid and precision diagnosis of HS. The detection of UGT1A1 enzyme activity related gene variation plays an important role in evaluation of HS jaundice.

Research progress in the eXpression of uridine diphosphate－glucuronosyl transferase 1A1 gene polymorphism / 中华实用儿科临床杂志

The uridine diphosphate_glucuronosyl transferase 1A1(UGT1A1)gene mutation can affect the ex_pression of UGT1A1 gene and enzyme activity,and then reduce bilirubin metabolism leading to unconjugated hyperbi_lirubinemia. With the development of molecular biotechnology,more and more studies are trying to identify the patho_genesis of these polymorphisms by analyzing the expression and enzyme activity of UGT1A1 gene polymorphisms. Now, the progresses in the study of the expression of UGT1A1 gene polymorphism were reviewed.

Prevalencia de síndrome de Gilbert y sus determinantes genéticas en población chilena / Prevalence of Gilbert syndrome and its genetic determinants in Chile

Background: In Europeans the TATA box TA7 repeat promoter variant in the UGT1A1 gene (UGT1A1*28) is the major determinant of bilirubin levels. Aim: To study the prevalence of Gilbert Syndrome (GS) and its genetic determinants in Chile. Material and Methods: Three different studies were conducted. The prevalence of GS in Chile was assessed in 991 subjects with normal liver tests (ALT and GGT) from the 2nd National Health Survey. We defined GS as a total bilirubin (TB) between 1.4-5mg/dL. The second study assessed the genotype prevalence of SNP rs6742078 (in LD with UGT1A1*28) and rs4149056 in 500 DNA samples of non-related Hispanics. Finally, a case-control study was designed to assess the phenotype-genotype correlation. UGT1A1*28 and rs4149056 variants were determined by direct sequencing and allelic discrimination assays (TaqMan), respectively. Results: Prevalence of GS in the general Chilean population was 2.6% (4.5% in males and 0.5% in female). No correlation with age, educational level or home location was found. Genotypes for UGT1A1*28 (TA6/6 50.5%, TA6/7 37.8%, TA7/7 11.7%) and rs4149056 (TT 74.1%, CT 22.8%, and CC 3.1%) variants were similar to Europeans. In the case-control study, most patients with GS were homozygotes for UGT1A1*28 (TA7/7, 74%). Of note, 44% of patients with intermediate TB levels were also TA7/7, compared to 7% in normal subjects. SLCO1B1 genotype was not correlated with TB levels. Conclusions: While the prevalence of GS was lower in Chile compared to Europeans (~5%), the prevalence of UGT1A1*28 homozygotes was similar (~12%). In Chilean Hispanics, the UGT1A1*28 variant explain 75% of GS phenotype.

The application of UGT1A1 28 genotype combined with pharmacokinetics of SN-38 in the detection of irinotecan-based second-line chemotherapy in patients with advanced colorectal cancer / 肿瘤

Objective: This multicenter study was conducted to retrospectively investigate the gene polymorphism of UGT 1A 1 28 (uridine diphosphate glucuronosyl transferase 1A1 28) in patients with advanced colorectal cancer receiving CPT-11 (irinotecan)-based second-line chemotherapy between June 2010 and January 2012. The associations between peak and valley concentrations of SN-38 with the efficacy and adverse effects of these patients carrying genotype (TA)6/(TA)6 or (TA)6/(TA)7 after chemotherapy with CPT-11. Methods: This was a retrospective multicenter study. Sixty-nine patients with advanced colorectal cancer receiving CPT-11 (irinotecan)-based second-line chemotherapy between June 2010 and January 2012 were collected. The frequency of TA repeats in the TATA box region of the UGT 1A 1 gene was detected before chemotherapy and the plasma concentration of SN-38 was detected by HPLC (high-performance liquid chromatography) at 1.5 h and 49.0 h after CPT-11 infusion. The shortterm response and adverse effects were observed. The relationships of the concentration of plasma SN-38 with the short-term response and adverse effects of patients carrying genotype (TA) 6/(TA)6 or (TA)6/(TA)7 were analyzed by stepwise regression analysis. Results: Of sixty-nine patients, (TA) 6/(TA)6 genotype was identified in forty-five patients (65.22%), (TA)6/(TA)7 genotype was identified in twenty-four patients (34.78%), and (TA)7/(TA)7 genotype was identified in none patients. The average plasma peak and valley concentrations of SN-38 after CPT-11 infusion in patients carrying (TA) 6/(TA)7 genotype were both significantly higher than those in patients carrying (TA)6/(TA)6 genotype (P = 0.001, P = 0.000). Stepwise regression analysis showed that for patients carrying (TA)6/(TA)6 genotype, the peak plasma concentration of SN-38 was related with progression-free survival, and the valley plasma concentration of SN-38 was related with short-term response; for patients carrying (TA)6/(TA)7 genotype, the peak plasma concentration of SN-38 was related with bone marrow suppression, and the valley plasma concentration of SN-38 was related with plasma total bilirubin level and delayed diarrhea after CPT-11 infusion. For patients carrying (TA) 6/(TA)6 genotype, the median progression-free survival of patients whose peak plasma concentration of SN-38 was above 43.20 ng/mL and the valley plasma concentration of SN-38 was above 9.41 ng/mL was significantly prolonged as compared with that of the patients whose peak plasma concentration of SN-38 was less than or equal to 43.20 ng/mL (6.0 vs 4.6 months, χ2 = 25.57, P = 0.00) and the valley plasma concentration of SN-38 was less than or equal to 9.41 ng/mL (6.0 vs 5.2 months, χ2 = 6.81, P = 0.01). For patients carrying (TA)6/(TA)7 genotype, the median progression-free survival of patients whose peak plasma concentration of SN-38 was above 50.60 ng/mL and the valley plasma concentration of SN-38 was above 16.29 ng/mL was not significantly prolonged as compared with that of the patients whose peak plasma concentration of SN-38 was less than or equal to 50.60 ng/ mL (7.0 vs 6.0 months, χ2 = 0.18, P = 0.67) and the valley plasma concentration of SN-38 was less than or equal to 16.29 ng/mL (6.0 vs 7.3 months, χ2 = 0.56, P = 0.46); the rates of bone marrow suppression (P = 0.02, P = 0.02) and delayed diarrhea were higher (P = 0.04, P = 0.03). Conclusion: The genotypes of (TA)6/(TA)6 and (TA)6/(TA)7 account for the majority of advanced colorectal cancer. For patients carrying (TA)6/(TA)6 genotype, CPT-11 dosage can be increased gradually to improve the response of patients with peak plasma concentration of SN-38 ≤ 43.20 ng/mL or peak valley concentration of SN-38 ≤ 9.41 ng/mL after CPT-11 infusion; for patients carrying (TA)6/(TA)7 genotype, CPT-11 dosage can be reduced appropriately to reduce serious adverse effects without affecting the response of patients with peak plasma concentration of SN-38 > 50.60 ng/mL or peak valley concentration of SN-38 > 16.29 ng/mL after CPT-11 infusion. Copyright © 2013 by TUMOR.

Expression of uridine diphosphate glucuronosyl transferase 1 A1 mRNA in mice with chronic liver injury / 中国普通外科杂志

Objective To investigate the effect of chronic liver injury on the expression of uridine diphosphate glucuronosyltransferase(UGT) 1A1 mRNA in mice. Methods Chronic liver injury model was induced by feeding CCl 4 in mice.Thirty mice were randomly divided into three groups:control group,experimental group 1(CCl 4 was given for 1 month),and experimental group 2(CCl 4 was given for 2 months).The liver function was tested;and the expression of UGT1A1 mRNA in the 3groups was analysed by RT-PCR. Results There was significant difference in the expression of UGT1A1 mRNA between the 3 groups(P

Association of Gly71Arg Mutation in Gene of Bilirubin Uridine 5'-Diphosphate-Glucuronosyl Transferase and Neonatal Jaundice / 实用儿科临床杂志

Objective To explore the association of Gly71Arg mutation in gene of bilirubin uridine 5'-diphosphate-glucuronosyltransferase(UGT1A1)and neonatal jaundice in Beijing city Han population.Methods The genotypes and alleles of the Gly71 Arg polymorphism for UGT1A1 gene were identified by polymerase chain reaction-restricted fragment length polymorphism assay in infants of Beijing city Han population of China,including 96 infants with neonatal jaundice[serum bilirubin(307.06?38.5)?mol/L,indirect bilirubin(292.9?35.9)?mol/L] and 101 healthy control infants [serum bilirubin(131.2?42.1)?mol/L,indirect bilirubin(126.3?39.7)?mol/L].The genotypes and allele frequencies of the polymorphism were compared between infants with neonatal jaundice group and healthy infant group(control group).The effect of polymorphism in infants with neonatal jaundice group on serum bilirubin level were analyzed.Results There were significant differences in genotypes distribution in Gly71Arg polymorphism for UGT1A1 gene between the 2 groups(?2=9.47 P=0.002).Compared with control group,neonatal jaundice group had significantly higher Arg allele frequency in the polymorphism for UGT1A1 gene(?2=10.34 P=0.001).There were independent effects of Gly71Arg mutation in the gene on serum bilirubin level in neonatal jaundice group,at the carriers of homozygote of the Arg allele of Gly71Arg polymorphism had higher serum bilirubin levels compared to carriers of heterozygote of the Arg allele of the polymorphism and non-carriers of the Arg allele of the polymorphism(Pa