scholarly journals Analysis of the UGT1A1 Genotype in Hyperbilirubinemia Patients: Differences in Allele Frequency and Distribution

2019 ◽  
Vol 2019 ◽  
pp. 1-9
Author(s):  
Xiao-xiao Mi ◽  
Jian Yan ◽  
Xiao-jie Ma ◽  
Ge-li Zhu ◽  
Yi-dan Gao ◽  
...  
Keyword(s):  
Promoter Region ◽  
Direct Sequencing ◽  
Chinese Patients ◽  
Southeastern China ◽  
Unconjugated Hyperbilirubinemia ◽  
Gilbert Syndrome ◽  
Pathogenic Variants ◽  
Ethnic Populations ◽  
Age Range ◽  
Frequent Allele

Objective. The spectrum of UDP-glucuronyl transferase A1 (UGT1A1) variants in hereditary unconjugated hyperbilirubinemia varies markedly between different ethnic populations. This study evaluated the UGT1A1 genotypes in hyperbilirubinemia patients from southeastern China. Methods. We enrolled 60 patients from southeastern China (44 men and 16 women; age range: 3–76 years) with unconjugated hyperbilirubinemia and performed genetic analysis of the UGT1A1 gene by direct sequencing. Results. For patients with Gilbert syndrome, 85% (47/55) harbored pathogenic variants of UGT1A1⁎60. Both UGT1A1⁎28 and UGT1A1⁎81 were detected in the promoter region of UGT1A1. Additionally, 83% (20/24) of patients with Gilbert syndrome heterozygous for UGT1A1⁎60 had an association with heterozygous variation of UGT1A1⁎28 or UGT1A1⁎81, while 91% (21/23) of Gilbert syndrome patients homozygous for UGT1A1⁎60 had biallelic variations of UGT1A1⁎28 and UGT1A1⁎81. We detected 213 UGT1A1 allelic variants, including six novel variations, with the most frequent allele being the UGT1A1⁎60, followed by UGT1A1⁎28 and UGT1A1⁎6. All of the patients showed multiple sites of variants in UGT1A1; however, variation number was not associated with bilirubin levels (P>0.05). Conclusions. The spectrum of UGT1A1 variants in southeastern Chinese patients was distinct from other ethnic populations. Our findings broaden the knowledge concerning traits associated with UGT1A1 variants and help profile genotype–phenotype correlations in hyperbilirubinemia patients.

scholarly journals Identifying UGT1A1 gene mutations in Vietnamese patients with Gilbert syndrome

2021 ◽  
Vol 63 (2) ◽  
pp. 16-20
Author(s):  
Thi Thanh Hoa Nguyen ◽  
◽  
Quang Lieu Dau ◽  
Dang Ton Nguyen ◽  
Hai Ha Nguyen ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Promoter Region ◽  
Gene Mutations ◽  
Tata Box ◽  
Enzyme Expression ◽  
Ugt1a1 Gene ◽  
Gilbert Syndrome ◽  
Pathogenic Variants ◽  
Bilirubin Metabolism ◽  
Different Populations

Gilbert’s syndrome (GS) is the most common inherited disorder of bilirubin metabolism, non-lethal, affecting 3-12% of the population. The genetic variants of the UDP- glucuronosyltransferase 1A1 (UGT1A1) gene might reduce the gene transcription activity and its enzyme expression, which affects the ability to conjugate glucuronidation in the liver. This study aimed to identify genetic variants of UGT1A1 in two Vietnamese sibling brothers with jaundice manifestations suspected GS. The peripheral blood samples of patients were used to extract genome DNA and sequence the enhancer, promoter, and coding all five exons of UGT1A1. Two pathogenic variants c.-3279T>G located in the phenobarbital responsive enhancer module (gtPBREM) and A(TA)7TAA of the TATA box in the promoter region were identified. They are twice common pathogenic variants that were reported in almost hyperbilirubinemia individuals from different populations. The obtained results improved the accuracy of medical diagnosis and warned the patients to be cautious in case they have to use medical drugs in the future.

scholarly journals Rare Germline Variants in Chordoma-Related Genes and Chordoma Susceptibility

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2704
Author(s):  
Sally Yepes ◽  
Nirav N. Shah ◽  
Jiwei Bai ◽  
Hela Koka ◽  
Chuzhong Li ◽  
...  
Keyword(s):  
Internal Control ◽  
Susceptibility Gene ◽  
Copy Number Variants ◽  
Bone Cancer ◽  
Chinese Patients ◽  
European Ancestry ◽  
Unknown Etiology ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
Pathogenic Variants

Background: Chordoma is a rare bone cancer with an unknown etiology. TBXT is the only chordoma susceptibility gene identified to date; germline single nucleotide variants and copy number variants in TBXT have been associated with chordoma susceptibility in familial and sporadic chordoma. However, the genetic susceptibility of chordoma remains largely unknown. In this study, we investigated rare germline genetic variants in genes involved in TBXT/chordoma-related signaling pathways and other biological processes in chordoma patients from North America and China. Methods: We identified variants that were very rare in general population and internal control datasets and showed evidence for pathogenicity in 265 genes in a whole exome sequencing (WES) dataset of 138 chordoma patients of European ancestry and in a whole genome sequencing (WGS) dataset of 80 Chinese patients with skull base chordoma. Results: Rare and likely pathogenic variants were identified in 32 of 138 European ancestry patients (23%), including genes that are part of notochord development, PI3K/AKT/mTOR, Sonic Hedgehog, SWI/SNF complex and mesoderm development pathways. Rare pathogenic variants in COL2A1, EXT1, PDK1, LRP2, TBXT and TSC2, among others, were also observed in Chinese patients. Conclusion: We identified several rare loss-of-function and predicted deleterious missense variants in germline DNA from patients with chordoma, which may influence chordoma predisposition and reflect a complex susceptibility, warranting further investigation in large studies.

scholarly journals Prevalent Pathogenic Variants of ATP7B in Chinese Patients with Wilson’s Disease: Geographical Distribution and Founder Effect

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 336
Author(s):  
Guo-Min Yang ◽  
Rou-Min Wang ◽  
Nan Xia ◽  
Zi-Wei Zheng ◽  
Yi Dong ◽  
...  
Keyword(s):  
Geographical Distribution ◽  
Founder Effect ◽  
Wilson’S Disease ◽  
Autosomal Recessive Disorder ◽  
Wilson's Disease ◽  
Chinese Patients ◽  
Mainland Chinese ◽  
Pathogenic Variants ◽  
Specific Distribution ◽  
The Common

Wilson’s disease (WD) is an autosomal recessive disorder caused by ATP7B pathogenic variants. This study aimed to show the geographical distribution and haplotype spectrum of three prevalent pathogenic variants (p.R778L, p.P992L, p.T935M) in mainland Chinese population and clarify whether the founder effect may account for their origins. We firstly summarized the frequency and geographical distribution of p.R778L, p.P992L and p.T935M in 715 WD patients. Then, to construct haplotypes associated with the three variants, Sanger sequencing and microsatellite typing at three dinucleotide-repeat markers (D13S314, D13S301, D13S316) flanking the ATP7B gene were performed in 102 WD families. An obvious regional-specific distribution feature was found in p.T935M. Linkage disequilibrium at the three markers was shown in all the three variants and we found the common haplotypes specific for p.R778L, p.P992L and p.T935M respectively, represented successively by 10-7-7, 10-9-5 and 12-4-8, which all exhibited great significance vs. the control chromosomes (p < 0.01). Meanwhile, haplotypes for the three variants differed from the studies in other regions to some extent. The common haplotypes we found indicate that three prevalent pathogenic variants emerge due to the founder effect. Furthermore, the study contributes to expand our knowledge of the genetic diversity of WD from a cross-regional perspective.

Pathogenic variants in nucleoporin TPR (translocated promoter region, nuclear basket protein) cause severe intellectual disability in humans

2021 ◽  
Author(s):  
Nicole J Van Bergen ◽  
Katrina M Bell ◽  
Kirsty Carey ◽  
Russell Gear ◽  
Sean Massey ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Neurological Disorders ◽  
Promoter Region ◽  
Nuclear Pore ◽  
Valuable Insight ◽  
Amino Acid Deletion ◽  
Pathogenic Variants ◽  
Severe Intellectual Disability ◽  
Functional Analyses ◽  
Insight Into

Abstract The nuclear pore complex (NPC) is a multi-protein complex that regulates the trafficking of macromolecules between the nucleus and cytoplasm. Genetic variants in components of the NPC have been shown to cause a range of neurological disorders, including intellectual disability and microcephaly. Translocated promoter region, nuclear basket protein (TPR) is a critical scaffolding element of the nuclear facing interior of the NPC. Here we present two siblings with biallelic variants in TPR who present with a phenotype of microcephaly, ataxia and severe intellectual disability. The variants result in a premature truncation variant, and a splice variant leading to a 12-amino acid deletion respectively. Functional analyses in patient fibroblasts demonstrate significantly reduced TPR levels, and decreased TPR-containing NPC density. A compensatory increase in total NPC levels was observed, and decreased global RNA intensity in the nucleus. The discovery of variants that partly disable TPR function provide valuable insight into this essential protein in human disease, and our findings suggest that TPR variants are the cause of the siblings’ neurological disorder.

scholarly journals Novel SCN5A and GPD1L Variants Identified in Two Unrelated Han-Chinese Patients With Clinically Suspected Brugada Syndrome

2021 ◽  
Vol 8 ◽  
Author(s):  
Meng Yuan ◽  
Yi Guo ◽  
Hong Xia ◽  
Hongbo Xu ◽  
Hao Deng ◽  
...  
Keyword(s):  
Brugada Syndrome ◽  
Missense Variant ◽  
Han Chinese ◽  
Chinese Patients ◽  
Splicing Variant ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Gated Channel ◽  
Life Threatening ◽  
Glycerol 3 Phosphate Dehydrogenase

Brugada syndrome (BrS) is a complexly genetically patterned, rare, malignant, life-threatening arrhythmia disorder. It is autosomal dominant in most cases and characterized by identifiable electrocardiographic patterns, recurrent syncope, nocturnal agonal respiration, and other symptoms, including sudden cardiac death. Over the last 2 decades, a great number of variants have been identified in more than 36 pathogenic or susceptibility genes associated with BrS. The present study used the combined method of whole exome sequencing and Sanger sequencing to identify pathogenic variants in two unrelated Han-Chinese patients with clinically suspected BrS. Minigene splicing assay was used to evaluate the effects of the splicing variant. A novel heterozygous splicing variant c.2437-2A&gt;C in the sodium voltage-gated channel alpha subunit 5 gene (SCN5A) and a novel heterozygous missense variant c.161A&gt;T [p.(Asp54Val)] in the glycerol-3-phosphate dehydrogenase 1 like gene (GPD1L) were identified in these two patients with BrS-1 and possible BrS-2, respectively. Minigene splicing assay indicated the deletion of 15 and 141 nucleotides in exon 16, resulting in critical amino acid deletions. These findings expand the variant spectrum of SCN5A and GPD1L, which can be beneficial to genetic counseling and prenatal diagnosis.

scholarly journals Gilbert Syndrome in a Young Ethiopian Man: First Case Report

2021 ◽  
Vol 31 (1) ◽  
Author(s):  
Amir Sultan ◽  
Kibrewossen Kiflu
Keyword(s):  
Case Report ◽  
Liver Function ◽  
Male Patient ◽  
Liver Function Tests ◽  
Prolonged Fasting ◽  
Unconjugated Hyperbilirubinemia ◽  
Gilbert Syndrome ◽  
Function Tests ◽  
First Case

BACKGROUND፡ Gilbert syndrome is a well-recognized condition causing unconjugated hyperbilirubinemia with otherwise normal transaminases and liver function tests. CASE: A 21 year old male patient presented with recurrent episodes of jaundice over four years. The episodes were preceded by stressful conditions and intercurrent illnesses. All laboratory prameters were normal except an unconjugated hyperbilirubinemia. A diagnosis of Gilbert syndrome was made after careful clinical evaluation.CONCLUSION: Recognizing Gilbert syndrome has important clinical implicaitions by avoiding uncessary and expensive workup of patients with jaundice. Mangement entails avoiding stressful conditions and prolonged fasting. 

Phenotype Analysis and Genetic Study of Chinese Patients With Treacher Collins Syndrome

2021 ◽  
pp. 105566562110375
Author(s):  
Meng Lu ◽  
Bin Yang ◽  
Zixiang Chen ◽  
Haiyue Jiang ◽  
Bo Pan
Keyword(s):  
Rare Variants ◽  
Clinical Care ◽  
Treacher Collins Syndrome ◽  
Chinese Patients ◽  
Pathogenic Variants ◽  
Premature Termination Codons ◽  
Whole Exome ◽  
Exome Aggregation Consortium ◽  
Phenotype Analysis ◽  
Sporadic Cases

Objective The aim of this study was to confirm the pathogenic variants, explore the genotype–phenotype correlation and characteristics of Chinese patients with Treacher Collins syndrome (TCS). Design Clinical details of 3 TCS family cases and 2 sporadic cases were collected and analyzed. Whole-exome sequencing and Sanger sequencing were conducted to detect causative variants. Setting Tertiary clinical care. Patients This study included 8 patients clinically diagnosed with TCS who were from 3 familial cases and 2 sporadic cases. Main Outcome Measures When filtering the database, variants were saved as rare variants if their frequency were less than 0.005 in the 1000 Genomes Project Database, the Exome Aggregation Consortium (ExAC) browser, and the Novogene database, or they would be removed as common ones. The pathogenic variants identified were verified by polymerase chain reaction. The sequencing results were analyzed by Chromas 2.1 software. Results Two novel pathogenic variants (NM_000356.3: c.537del and NM_000356.3: c.1965_1966dupGG) and 2 known pathogenic variants (NM_000356.3: c.1535del, NM_000356.3: c.4131_4135del) were identified within TCOF1 which are predicted to lead to premature termination codons resulting in a truncated protein. There was a known missense SNP (NM_015972.3: c.139G>A) within POLR1D. No phenotype–genotype correlation was observed. Instead, these 8 patients demonstrated the high genotypic and phenotypic heterogeneity of TCS. Conclusions This study expands on the pathogenic gene pool of Chinese patients with TCS. Besides the great variation among patients which is similar to international reports, Chinese patients have their own characteristics in clinical phenotype and pathogenesis mutations.

The Investigation of JAK2 and C-MPL Mutations of Myeloproliferative Disorders Patiens

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5261-5261
Author(s):  
Jun Xia ◽  
Yunfeng Shen ◽  
Jianyong Li
Keyword(s):  
Polymerase Chain Reaction ◽  
Direct Sequencing ◽  
Myeloproliferative Disorders ◽  
Jak2v617f Mutation ◽  
Chinese Patients ◽  
Chain Reaction ◽  
Cell Counts ◽  
Allele Specific ◽  
Polymerase Chain ◽  
White Blood Cell Counts

Abstract Most studies have shown that JAK2V617F was found in nearly all the patients with polycythemia vera (PV) and half of patients with essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). However, JAK2 exon 12 mutations in JAK2V61F-negetive PV patiens and MPLW515L/K mutations in IMF patiens implied other pathogenesis in these myeloproliferative disorders (MPD). Two parts were included in our research to investigate the JAK2 and c-MPL mutations of MPD patients. Firstly, to evaluate the JAK2 exon 12 mutations and its clinical significance in patients with PV, polymerase chain reaction was used to amply the region of JAK2 exon 12 and direct sequencing was performed to detect mutations of JAK2 exon 12. Clinical features of the PV patients with JAK2 exon 12 mutations and JAK2V617F mutation were retrospectively reviewed. The results showed that the JAK2 exon 12 mutations were detected in 3 of 12 JAK2V617F-negtive PV patients (25.0%). Three JAK2 exon 12 mutations were H538QK539L, K539L and N542-E543del respectively. The patients carrying the mutations of JAK2 exon 12 displayed higher hemoglobin(223.6±15.0 vs190.3±20.2g/l, P&lt;0.05), lower white blood cell counts (7.8±2.3 vs16.2±6.7 *109/l, P&lt;0.05)compared with JAK2V617F-positive PV patients (n=31). Secondly, allele specific polymerase chain reaction (AS-PCR) and gene sequencing were used to detected JAK2V617F, MPLW515L and four types of JAK2 exon 12 mutations (F537-K539delinsL, H538QK539L, K539L, N542-E543del) in 30 IMF patients. Results showed that 15 of 30 (50.0%) patients had JAK2V617F mutation and 2 of 30 (6.7%) patients had MPLW515L mutation. JAK2 exon 12 mutations were not detected in IMF patients. Literature reviews show that this is the first report of JAK2 and c-MPL mutations in a number of Chinese patients with BCR/ABL-negative MPD. It is concluded that the JAK2 exon 12 mutations exist in PV patient and the patients with JAK2 exon 12 mutations are characterized by isolated erythrocytosis. The frequency of MPLW515L mutations is high in IMF, which supports recent studies.

scholarly journals A Promoter Region Polymorphism inPDCD-1Gene Is Associated with Risk of Rheumatoid Arthritis in the Han Chinese Population of Southeastern China

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
CuiPing Liu ◽  
JueAn Jiang ◽  
Li Gao ◽  
XiaoHan Hu ◽  
FengMing Wang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Chinese Population ◽  
Direct Sequencing ◽  
Han Chinese ◽  
Chinese Patients ◽  
Sequencing Analysis ◽  
Healthy Controls ◽  
Han Chinese Population ◽  
Increased Risk

Objective. Programmed cell death 1 (PD-1) induces negative signals to T cells during interaction with its ligands and is therefore a candidate gene in the development of autoimmune diseases such as rheumatoid arthritis (RA). Herein, we investigate the association ofPDCD-1polymorphisms with the risk of RA among Chinese patients and healthy controls.Methods. Using the PCR-direct sequencing analysis, 4PDCD-1SNPs (rs36084323, rs11568821, rs2227982, and rs2227981) were genotyped in 320 RA patients and 309 matched healthy controls. Expression of PD-1 was determined in peripheral blood lymphocytes by flow cytometry and quantitative real-time reverse transcriptase polymerase chain reaction.Results. We observed that the GG genotype of rs36084323 was associated with a increased risk for developing RA (OR 1.70, 95% 1.11–2.61,P=0.049). Patients carrying G/G genotype displayed an increased mRNA level of PD-1(P=0.04)compared with A/A genotype and healthy controls. Meanwhile, patients homozygous for rs36084323 had induced basal PD-1 expression on activated CD4+ T cells.Conclusion. ThePDCD-1polymorphism rs36084323 was significantly associated with RA risk in Han Chinese population. This SNP, which effectively influenced the expression of PD-1, may be a biomarker of early diagnosis of RA and a suitable indicator of utilizing PD-1 inhibitor for treatment of RA.

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