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1.
Anticancer Res ; 40(1): 435-441, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892598

RESUMO

AIM: The purpose of the Imadje study was to confirm the efficacy and safety of imatinib, following resection of kit-positive gastrointestinal stromal tumour (GIST), in the adjuvant setting in the Greek population. PATIENTS AND METHODS: A total of 34 adult patients already receiving imatinib were enrolled. Recurrence-free (RFS) and overall survival, as well as time to treatment failure and safety were assessed. RESULTS: Overall survival could not be estimated in the present study, as no death occurred. Overall, 91.2% of patients were recurrence-free at 36 months, while the median time to treatment failure was 35 months. No new or unexpected safety findings were observed. Mutation analysis in 14 patients showed that the most frequent mutations were located in KIT exon 11 (64.3%) and exon 9 (28.6%). Univariate analysis showed that only surgical resection with a margin classification of R0 was associated with better RFS. CONCLUSION: Adjuvant treatment with imatinib for 3 years in patients with intermediate to high risk of recurrence was proven to prolong RFS, while being well-tolerated and not exhibiting a negative impact on patient compliance with therapy.


Assuntos
Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mesilato de Imatinib/uso terapêutico , Recidiva Local de Neoplasia/patologia , Análise Mutacional de DNA , Intervalo Livre de Doença , Feminino , Grécia , Humanos , Mesilato de Imatinib/efeitos adversos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
2.
Zhonghua Yi Xue Za Zhi ; 100(2): 136-140, 2020 Jan 14.
Artigo em Chinês | MEDLINE | ID: mdl-31937054

RESUMO

Objective: Tuberous sclerosis complex (TSC) is a multi-system disease with TSC1 and TSC2 genes as the pathogenic genes. The purpose of our study was to analyze the gene mutation in patients with TSC with epilepsy as the main clinical manifestation. The relationship between genotype and phenotype, scalp EEG in patients was analyzed. Methods: The peripheral blood was extracted from 43 patients and their families. TSC gene was detected by second-generation sequencing. Long-term video EEG monitoring and MRI examination were performed to determine the onset area, seizure type and location of nodules. Results: 39 patients had TSC gene mutation, 4 patients did not detect the gene mutation.11 had TSC1 mutations and 28 had TSC2 mutations. 22 mutations were de novo. Patients with TSC2 mutations had earlier seizure and more nodules than patients with TSC1 mutations, but no significant difference in intelligence and spasm were observed. 28 patients had focal origin of scalp EEG, of which 85.7% of TSC2 mutations patients had focal origin. Conclusions: Patients of TSC2 mutations always has an early onset age. Although MRI shows multiple nodules, the onset of EEG is mainly focal origin.


Assuntos
Esclerose Tuberosa , Análise Mutacional de DNA , Eletroencefalografia , Genótipo , Humanos , Mutação , Fenótipo , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa
3.
J Clin Pathol ; 73(1): 35-41, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31296605

RESUMO

AIMS: Precision medicine therapy is remodelling the diagnostic landscape of cancer. The success of these new therapies is often based on the presence or absence of a specific mutation in a tumour. The Idylla platform is designed to determine the mutational status of a tumour as quickly and accurately as possible, as a rapid, accurate diagnosis is of the utmost importance for the treatment of patients. This is the first complete prospective study to investigate the robustness of the Idylla platform for EGFR, KRAS and BRAF mutations in non-small cell lung cancer, metastatic colorectal cancer and metastatic melanoma, respectively. METHODS: We compared prospectively the Idylla platform with the results we obtained from parallel high-throughput next-generation sequencing, which is the current gold standard for mutational testing. Furthermore, we evaluated the benefits and disadvantages of the Idylla platform in clinical practice. Additionally, we reviewed all the published Idylla performance articles. RESULTS: There was an overall agreement of 100%, 94% and 94% between the next-generation panel and the Idylla BRAF, KRAS and EGFR mutation test. Two interesting discordant findings among 48 cases were observed and will be discussed together with the advantages and shortcoming of both techniques. CONCLUSION: Our observations demonstrate that the Idylla cartridge for the EGFR, KRAS and BRAF mutations is highly accurate, rapid and has a limited hands-on time compared with next-generation sequencing.


Assuntos
Biomarcadores Tumorais/genética , Análise Mutacional de DNA/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Neoplasias/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Melanoma/genética , Melanoma/secundário , Neoplasias/patologia , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Fluxo de Trabalho
4.
J Clin Pathol ; 73(1): 14-16, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31434698

RESUMO

AIMS: Untranslated regions (UTRs) play an important role in post-transcriptional regulation of gene expression, including by modulating messenger RNA (mRNA) transport out of the nucleus, translation efficiency, subcellular localisation and stability. Any mutation in this region could alter the stability of mRNA and thereby affect protein synthesis. We analysed if a mutation located in the α complex protected region of the α1 globin gene could cause non-deletional α-thalassaemia by affecting post-transcriptional stability (mRNA stability). METHODS: A total of 14 patients without anaemia, normal or slight microcytosis and hypochromia (medium concentration haemoglobin [MCH] <27 pg) were studied. Haemoglobin subtypes were screened using capillary zone electrophoresis and ion-exchange high-performance liquid chromatography (VARIANT II ß-Thalassaemia Short Program). The most common α-globin mutations were identified by multiplex PCR (Alpha-Globin StripAssay kit) and the molecular characterisation by automatic sequencing of alpha globin genes. RESULTS: All of them shown a novel transversion mutation in nt 778 (C>A), which is located in the 3' UTR in the α complex protected region [HBA1: c.*+46C>A]. CONCLUSIONS: This mutation is in the αRNAmin binding site, so a single nucleotide substitution in this region can decrease mRNA stability by potentially compromising the binding of α-complex protein to αRNAmin, favouring the decay of α-globin mRNA via erythroid cell-enriched endoribonuclease cleavage. In this case, it is a non-deletional α-thalassaemia. However, in silico and empirical studies predicted that it could be a silent polymorphism. Functional studies should be carried out to confirm whether it is a pathological mutation or a silent polymorphism.


Assuntos
Regiões 3' não Traduzidas , Mutação , Polimorfismo Genético , Estabilidade de RNA , RNA Mensageiro/genética , alfa-Globinas/genética , Talassemia alfa/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Análise Mutacional de DNA/métodos , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex , Fenótipo , RNA Mensageiro/metabolismo , Fatores de Risco , alfa-Globinas/metabolismo , Talassemia alfa/sangue , Talassemia alfa/diagnóstico
5.
Gene ; 725: 144164, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31639430

RESUMO

Bardet-Biedl syndrome (BBS) is a clinically and genetically heterogeneous ciliopathy with several clinical features including retinitis pigmentosa, obesity, kidney dysfunction, postaxial polydactyly, behavioral dysfunction and hypogonadism with wide spectrum of additional features. With multiple phenotypes and heterogeneous distribution, it is unlikely that BBS is caused by single gene defect. We have performed clinical and genetic diagnosis of two individuals from an Indian family with classical BBS symptoms. Whole exome sequencing identified homozygous missense mutation in BBS10 gene, hemizygous missense AR and homozygous missense PDE6B mutations in the proband and affected sibling with BBS. Identification of BBS10 mutation along with AR and PDE6B gene mutation will expand the genetic and phenotypic spectrum in individuals with BBS.


Assuntos
Síndrome de Bardet-Biedl/genética , Síndrome de Bardet-Biedl/metabolismo , Chaperoninas/genética , Chaperoninas/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética , Análise Mutacional de DNA , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Mutação/genética , Linhagem , Fenótipo , Receptores Androgênicos/genética , Retinite Pigmentosa/genética , Sequenciamento Completo do Exoma/métodos , Adulto Jovem
6.
Medicine (Baltimore) ; 98(50): e18253, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852093

RESUMO

RATIONALE: Molecular mechanism underlying the autosomal recessive non-syndromic hearing loss (ARNSHL) is still plausible. Pathogenic mutations of the gap junction beta 2 protein (GJB2) are reported to be the primary causes of ARNSHL. PATIENT CONCERNS: A propositus was diagnosed as ARNSHL with bilateral congenital profound hearing loss. DIAGNOSIS: With microarray and target gene sequencing testing methods, a novel GJB2 mutant was found to be associated with ARNSHL in this Han Chinese family. INTERVENTIONS/OUTCOMES: Based on the finding in this research, prenatal screening of GJB2 mutation and genetic counseling are recommended to this family for their next pregnancy. Our interventions allow the family to plan informatively. LESSONS: In this family, we discovered 2 heterozygous carriers of c.113T>C variation in the GJB2 gene. The propositus, who had profound hearing loss, had inherited the c.113T>C variation from his normal mother and the c.235delC from his father.


Assuntos
Conexinas/genética , DNA/genética , Surdez/genética , Grupos Étnicos , Mutação , Adulto , China/epidemiologia , Conexinas/metabolismo , Análise Mutacional de DNA , Surdez/diagnóstico , Surdez/etnologia , Feminino , Humanos , Lactente , Masculino , Emissões Otoacústicas Espontâneas/fisiologia , Linhagem , Prevalência
7.
Zhonghua Xue Ye Xue Za Zhi ; 40(11): 932-938, 2019 Nov 14.
Artigo em Chinês | MEDLINE | ID: mdl-31856443

RESUMO

Objective: To explore the clinical and prognostic values of TP53 gene mutation in patients with acute myeloid leukemia (AML) . Methods: A retrospective analysis of 265 newly diagnosed AML patients with next-generation sequencing (NGS) data in the Hematology Department of Changhai Hospital from January 2010 to January 2019 was performed. Mutation analysis was carried out by targeted sequencing technology including 200 hematological malignancy related genes. The association of TP53 mutation with clinical features was analyzed. Results: Alterations in TP53 were found in 20 (7.5%) patients, including 17 case (6.4%) of missense mutations, 2 cases (0.7%) of frame-shift deletion mutations and 1 case (0.4%) of splicing sites mutation. A total of 23 kinds of TP53 mutations were detected, most of them (16, 69.6%) were located in the DNA binding domain of exon 5-8, 4 in the DNA binding domain of exon 3-4, 2 in exon 10 and 1 in splice site, respectively. The median age of patients with TP53 alterations was higher than those without [52 (26-72) years old vs 45 (14-75) years old, P= 0.008]. The frequency of complex karyotypes was higher in patients with TP53 alterations than those without [45.0% (9/20) vs 6.1% (15/245) , P<0.001]. Median overall survival (OS) of patients with TP53 alterations was shorter than those without[14.1 (95%CI 6.78-21.42) months vs 31.4 (95%CI 13.20-49.59) months, P=0.029]. The OS of patients treated with "Decitabine + CAG" was superior than that of patients treated with "3 + 7" regimen [30.0 (95%CI 27.35-38.84) months vs 12.5 (95%CI 5.80-19.19) months, P=0.018]. Multivariate analysis indicated that TP53, DNMT3A and USH2A alterations, WBC ≥ 12.45×10(9)/L had negative impacts on OS. Conclusion: The frequency of TP53 mutation was 7.5% in our cohort. Most mutations were located in the DNA binding domain. TP53 alterations were strongly associated with older age, complex karyotype and shorter OS. Decitabine-based induction chemotherapy and hematopoietic stem cell transplantation may improve OS, more cases and/or multicenter randomized studies are needed for further confirmation.


Assuntos
Leucemia Mieloide Aguda , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Idoso , Análise Mutacional de DNA , Humanos , Leucemia Mieloide Aguda/genética , Pessoa de Meia-Idade , Mutação , Prognóstico , Estudos Retrospectivos , Adulto Jovem
8.
Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi ; 54(12): 881-887, 2019 Dec 07.
Artigo em Chinês | MEDLINE | ID: mdl-31887812

RESUMO

Objective: To screen, diagnose and follow up the abnormal mutation in the gene screening of neonatal deafness. Methods: A total of 24161 newborns born in Zhuhai Maternal and Child Health Hospital from February 1, 2015 to January 31, 2008 were screened for hearing and deafness genes, and audiological screening, diagnosis and 1-3 years follow-up were carried out for the newborns with positive gene screening. Results: There were 991 cases of deafness gene mutation (533 males and 458 females), and the rate of abnormal mutation was 4.10%(991/24 161). Among them, 921 cases were single heterozygous mutation, 130 cases were failed in primary hearing screening, 11 cases were failed in secondary hearing screening, 8 cases were abnormal in audiological diagnosis finally. In these 8 cases, 3 were diagnosed as otitis media and passed audiological follow-up after cure, 2 cases of single ear sensorineural injury caused by high-risk factors, passed after close audiological follow-up, and the other 3 cases were closely audiological follow-up while none of them were successfully sequenced. All of them were moderate to severe sensorineural deafness, 1 case was heterozygous mutation at 3 loci of GJB2(c.235delC,c.408C>A,c.134G>A), 1 case was heterozygous mutation at 2 loci of GJB2(c.235delC, c.109G>A), and 1 case was single heterozygous mutation of GJB2(c.235delC). The remaining 913 cases who passed the primary screening, secondary screening or hearing diagnosis were followed up for 1 to 3 years. Three cases of multiple heterozygous mutation were found in gene screening(2 cases were SLC26A4 2168A>G, IVS7-2A>G, 1 case was GJB2 c.176_191del 16bp, c.299_300del AT), all of them passed both primary and secondary hearing screening. In these 3 cases, the final audiological diagnosis was moderate sensorineural deafness in both ears, with no improvement in the follow-up of 1-3 years. There were 9 monogenic homozygous mutations, 7 failed in primary hearing screening, 3 failed in secondary hearing screening and also failed in audiological diagnosis and 1-3 years' audiological follow-up, all of whom were GJB2 c.235 del C homozygous mutations, and one of whom had a definite family history of deafness. The remaining 6 cases of homozygous mutation diagnosed by primary screening, secondary screening or hearing diagnosis were GJB2 c109G>A homozygous mutation, and passed the 1-3 years' hearing follow-up. 58 children with mtDNA mutations, including 2 with 12S rRNA 1494C>T homozygous mutation, 47 with 1555A>G homozygous mutation, and 9 with 1555A>G heterozygous mutation, all passed the primary or secondary hearing screening, and were instructed to ban ototoxic drugs for the whole life, and passed the 1-3 years' hearing follow-up. Conclusions: The audiological follow-up of children with monogenic heterozygous mutations in deafness gene screening is generally normal. In case of abnormality, the influencing factors such as otitis media should be excluded at first. In case of unexplained moderate to severe sensorineural deafness, the whole-gene sequencing should be performed to find possible pathogenic factors. The children with homozygous mutation or compound heterozygous mutation in gene screening, most of whom show different degrees of hearing loss, should be followed up for a long time, and provide parents with scientific and reasonable genetic counseling according to the mutation genes and loci,. The hearing of drug-induced deafness gene carriers is normal after birth. Parents should be advised to strengthen prevention and follow-up is generally enough.


Assuntos
Análise Mutacional de DNA , Surdez , Perda Auditiva , Pré-Escolar , China , Conexina 26 , Conexinas , Feminino , Seguimentos , Testes Genéticos , Perda Auditiva/diagnóstico , Perda Auditiva/genética , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Triagem Neonatal
9.
Medicine (Baltimore) ; 98(50): e18102, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852070

RESUMO

RATIONALE: Intraductal papillary and mucinous neoplasms of the pancreas (IPMN) are preneoplastic lesions diagnosed with an increasing incidence. Recently, several groups have described, in up to 70% of IPMN, activating mutations of the G-protein alpha stimulatory sub-unit (Gsα subunit) gene (GNAS). GNAS-activating somatic, post-zygotic, mutations are also associated with McCune-Albright syndrome (MCAS) characterized by fibrous dysplasia, precocious puberty, and café-au-lait spots. PATIENT CONCERNS: We herein report a patient with McCune Albright Syndrome that presented with malignant IPMN and underwent pancreatic resection. DIAGNOSES AND INTERVENTIONS: Leucocyte and duodenum juice DNA analysis, endoscopically collected from secretin-stimulated pancreatic juice revealed the same (GNAS) activating mutation also found in the invasive pancreatic colloid adenocarcinoma arising from intestinal subtype IPMN. OUTCOMES: Thirty months after surgery, the patient was alive with recurrence (bone only metastasis). LESSONS: In this observation, we show that MCAS should be view as a new genetic predisposition to IPMN associated pancreatic cancer, and consequently a targeted screening in this high-risk population might be proposed.


Assuntos
Adenocarcinoma Mucinoso/genética , Carcinoma Ductal Pancreático/genética , Cromograninas/genética , Displasia Fibrosa Poliostótica/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Predisposição Genética para Doença , Mutação , Neoplasias Pancreáticas/genética , Adenocarcinoma Mucinoso/diagnóstico , Adenocarcinoma Mucinoso/etiologia , Biópsia por Agulha , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/etiologia , Cromograninas/metabolismo , Análise Mutacional de DNA , DNA de Neoplasias/genética , Endossonografia , Feminino , Displasia Fibrosa Poliostótica/complicações , Displasia Fibrosa Poliostótica/diagnóstico , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Humanos , Pessoa de Meia-Idade , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/etiologia , Tomografia Computadorizada por Raios X
10.
Zhonghua Yan Ke Za Zhi ; 55(11): 806-810, 2019 Nov 11.
Artigo em Chinês | MEDLINE | ID: mdl-31715676

RESUMO

Retinoblastoma, the most frequent malignant intraocular tumor in childhood, is caused by oncogenic mutations in the RB1 tumor suppressor gene. Identification of these mutations in patients is important for genetic counseling and clinical management of relatives at risk, and thus probands are conventionally applied gene detection in developed countries. However, gene diagnosis is still in the elementary period in China. This article reviews the characteristics of retinoblastoma genetics and the current status of genetic testing in China, so as to attract more attention from ophthalmologists and to promote regulated gene diagnosis in clinical work. Not only does good understanding of retinoblastoma genetics support optimal care for retinoblastoma children and their families, but also promotes the development in foundational research. (Chin J Ophthalmol, 2019, 55: 806-810).


Assuntos
Testes Genéticos , Neoplasias da Retina/diagnóstico , Retinoblastoma/diagnóstico , Criança , China , Análise Mutacional de DNA , Genes do Retinoblastoma , Humanos , Mutação , Neoplasias da Retina/genética , Retinoblastoma/genética , Proteínas de Ligação a Retinoblastoma/genética , Ubiquitina-Proteína Ligases/genética
11.
Zhonghua Bing Li Xue Za Zhi ; 48(11): 873-877, 2019 Nov 08.
Artigo em Chinês | MEDLINE | ID: mdl-31775437

RESUMO

Objective: To study common problems in BRAF gene mutation detection, and conditions for repetition testing using thyroid fine needle aspiration specimens. Methods: A total of 8 644 cases of thyroid fine-needle aspiration specimens at China-Japan Friendship Hospital were collected between February, 2012 and July, 2018. BRAF gene mutation was detected by real-time PCR. Repeat testing was performed in 237 cases when the results were inconsistent with clinical or cytological diagnosis or when uncertain results were obtained. Results: The final positive rates of BRAF mutation was 22.0% (1 897/8 625). Nineteen cases were excluded due to inadequate DNA samples. The average Ct value of internal quality control was 16.061, and the average Ct value of the positive samples was 19.147. Among 237 repeat tests, 51.4% (19/37) continued to have poor DNA quality and 48.6% (18/37) had adequate DNA resulting in 1 positive case and 17 negative cases. In 40 repetition of initial negative cases, results were unchanged. In initial positive cases, 40.4% (40/99) with a difference of Ct value (between BRAF gene and internal quality control) between 8 to 12 turned negative after repetition, 69.8% (37/53) of these cases with a difference of more than 12 turned negative after repetition. The sensitivity and specificity of BRAF mutation were 83.97% and 96.94%, respectively. Conclusions: Difference between BRAF gene Ct value and internal quality control Ct value is recommended as a reliability index for the test result. Cases with a difference greater than 8 should be subjected to repeat testing.


Assuntos
Proteínas Proto-Oncogênicas B-raf/genética , Nódulo da Glândula Tireoide/genética , Nódulo da Glândula Tireoide/patologia , Biópsia por Agulha Fina , China , Análise Mutacional de DNA , Humanos , Mutação , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes
12.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(11): 1085-1089, 2019 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-31703131

RESUMO

OBJECTIVE: To delineate the clinical and genetic features of two pedigrees affected with aromatic L-amino acid decarboxylase (AADC) deficiency. METHODS: The clinical features, family history and results of genetic testing of 2 patients with AADC deficiency were retrospectively analyzed. RESULTS: Both patients featured hypotension, developmental delay and oculogyric crisis during infancy. Genetic testing confirmed that they have respectively carried c.714+ 4 (IVS6) A to T/c.175(exon2)G TO A compound heterozygous variants and c.714+ 4(IVS6)A to T homozygous variant. CONCLUSION: The clinical manifestation of children with AADC deficiency may include hypotonia, developmental delay and paroxysmal oculogyric crisis. The combination of 3-O-methyldopa testing and variant analysis is not only very useful for early diagnosis, but also important for the evaluation of treatment effect and prognosis of the disease. Discovery of the novel variants has enriched the variant spectrum of AADC deficiency.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Descarboxilases de Aminoácido-L-Aromático/deficiência , Descarboxilases de Aminoácido-L-Aromático/genética , Testes Genéticos , Análise Mutacional de DNA , Humanos , Lactente , Linhagem , Estudos Retrospectivos
13.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(11): 1107-1110, 2019 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-31703137

RESUMO

OBJECTIVE: To explore the genetic basis for a pedigree affected with Marfan syndrome (MFS). METHODS: Clinical data of the patients was collected. With genomic DNA extracted from peripheral blood samples, potential mutation was detected by targeted exome sequencing. Candidate variants were validated by Sanger sequencing and bioinformatic analysis. RESULTS: Targeted exome sequencing and Sanger sequencing revealed a missense c.649T to C(p.Trp217Arg) variant in the exon 7 of FBN1 gene, which was unreported previously. Bioinformatics analysis suggested that the variant can cause amino acid replacement and affect the structure and function of fibrillin-1. CONCLUSION: A novel missense variant of the FBN1 gene was identified, which probably underlies the autosomal dominant MFS in this pedigree.


Assuntos
Fibrilina-1/genética , Síndrome de Marfan/genética , Mutação de Sentido Incorreto , Análise Mutacional de DNA , Éxons , Fibrilinas , Humanos , Mutação , Linhagem
14.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(10): 953-956, 2019 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-31598934

RESUMO

OBJECTIVE: To explore the correlation of genetic mutations and clinical features of myelodysplastic syndromes (MDS) with scores of Revised International Prognostic Scoring System (IPSS-R). METHODS: Eighty-seven patients with de novo MDS were enrolled. Mutations of MDS-related genes and clinical features were used to determine the incidence and subtype of mutations. Clinical features and IPSS-R scores of the patients with high frequency mutations involving TET2, TP53, ASXL1, RUNX1 and SF3B1 genes were compared. RESULTS: Fifty-four patients (62.1%) harbored at least one point mutation. The incidences of various mutations were significantly different, with the incidence of MDS-EB-2 being 100% and MDS-SLD being only 38.9%. Compared with the wild types, patients harboring mutations had higher lactate dehydrogenase, higher ß2 microglobulin, higher percentage of bone marrow blast cells and lower hemoglobin levels (P=0.027, <0.01, <0.01, 0.046, respectively). The IPSS-R scores of MDS patients with mutations were significantly higher than the wild types (P<0.01). The IPSS-R scores of the TP53 mutation groups were 7.82±1.83, which was significantly higher than the control group (3.77±1.66, P<0.01). No difference was found between the IPSS-R between patients carrying TET2, ASXL1, RUNX1, and SF3B1 mutations or the wild types (P>0.05). CONCLUSION: Genetic mutations are commonly found in MDS. MDS patients with mutations have unique clinical laboratory characteristics. Although the prognostic value of most genes is controversial, TP53 is an definite indicator of poor prognosis.


Assuntos
Análise Mutacional de DNA , Síndromes Mielodisplásicas/genética , Humanos , Incidência , Mutação , Prognóstico , Proteína Supressora de Tumor p53/genética
15.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(10): 961-964, 2019 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-31598936

RESUMO

OBJECTIVE: To analyze the clinical phenotype of a Chinese pedigree affected with Tuberous sclerosis complex (TSC) and explore pathogenic mutations of TSC1 and TSC2 gene. METHODS: Unique clinical phenotypes,the results of imaging, examination of the proband and special family history, collectively, made the constellation of features of TSC. Genomic DNA was obtained from six affected and eight unaffected members of the family and potential mutations of the TSC1 and TSC2 genes were detected by PCR-amplification of the exons and exon-intron boundaries and direct sequencing. A total of 150 normal unrelated individuals were used as controls. RESULTS: Genetic analysis documented the presence of a heterozygous mutation, c.1781_1782delTG (p.Val594GlyfsX11), in the exon 15 of TSC1 gene within all the patients of the family. This mutation was not observed in the eight unaffected family members or in the 150 unrelated control subjects from the same population , or the Human Gene Mutation Database (HGMD) and had completely co-segregated with the disease phenotype in the family. CONCLUSION: The c.1781_1782delTG mutation of TSC1 gene may be responsible for the tuberous sclerosis complex in this family. The data presented in the present study are of significance to clinicians, as well as genetic counselors, and may provide new clues for molecular diagnosis of this disease..


Assuntos
Proteína 1 do Complexo Esclerose Tuberosa/genética , Esclerose Tuberosa/genética , Análise Mutacional de DNA , Humanos , Mutação , Linhagem , Proteína 2 do Complexo Esclerose Tuberosa
16.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(10): 980-984, 2019 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-31598940

RESUMO

OBJECTIVE: To develop a system for rapid detection of JAK2 V617F mutation among patients with myeloproliferative diseases. METHODS: Specific primers and TagMan probes were designed for the mutant and wild type alleles based on the principle of real-time PCR. A complete system including the method for detection and product for quality control were established through the evaluation of sensitivity and accuracy of the method, double-blind trial, and preparation of negative and positive controls through site-directed mutagenesis and molecular cloning. RESULTS: A system for rapid detection of the JAK V617F mutation has been developed. Compared with Sanger sequencing, the sensitivity and specificity of the method have both reached 100%. Meanwhile, 1000 normal samples and 1 case with the JAK2 V617F mutation were detected, which gave a population rate of 1‰. CONCLUSION: The system was fast, accurate, cheap, high throughput, and easy to use. It can be utilized as a routine test. Although the JAK2 V617F mutation is rare in the population, it should be screened among myeloproliferative neoplasm patients.


Assuntos
Janus Quinase 2/genética , Transtornos Mieloproliferativos/genética , Alelos , Análise Mutacional de DNA , Método Duplo-Cego , Humanos , Mutação , Reação em Cadeia da Polimerase em Tempo Real , Sensibilidade e Especificidade
17.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(10): 972-976, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31642429

RESUMO

OBJECTIVE: To study the types and characteristics of TUBB1 mutation in children with congenital hypothyroidism (CH) and thyroid dysgenesis (TD) in Shandong, China. METHODS: Mutations of the whole coding region of the TUBB1 gene were analyzed for 289 children with CH and TD in Shandong. Whole-genome DNA was extracted from peripheral blood leukocytes. PCR multiplication was performed for the whole coding region of the TUBB1 gene. Sanger sequencing was performed for the PCR products, and a biological information analysis was performed. RESULTS: Among the 289 children with CH and TD, 4 (1.4%) were found to have a c.952C>T(p.R318W) heterozygous mutation in the TUBB1 gene, resulting in the change of tryptophan into arginine at codon 318 of TUBB1 protein. This mutation was evaluated as "potentially pathogenic" based on the classification criteria and guidelines for genetic variation by American College of Medical Genetics and Genomics. CONCLUSIONS: A novel mutation is detected in the exon of the TUBB1 gene in children with CH and TD in Shandong, suggesting that the TUBB1 gene may be a candidate pathogenic gene for CH children with TD.


Assuntos
Hipotireoidismo Congênito , Disgenesia da Tireoide , Tubulina (Proteína)/genética , Criança , China , Hipotireoidismo Congênito/genética , Análise Mutacional de DNA , Humanos , Mutação , Disgenesia da Tireoide/genética
18.
Medicine (Baltimore) ; 98(42): e17594, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626133

RESUMO

RATIONALE: Idiopathic pulmonary arterial hypertension (IPAH) is characterized by intense remodeling of small pulmonary arteries. Loss-of-function mutation of bone morphogenetic protein receptor II (BMPR2) gene and exaggerated activation of transforming growth factor (TGF)-ß signaling play a critical role in this process. PATIENT CONCERNS AND DIAGNOSIS: We report a novel frameshift mutation (c.117InsT, p.Y40fsX48) of the BMPR2 gene identified in a 19-year-old IPAH patient with syncope. Despite BMPR2 mutation, the phosphorylation of Smad2/3 and Samd1/5/8 was increased in the patient's peripheral blood mononuclear cells, and this event was accompanied by the upregulation of bone morphogenetic protein (BMP) signaling target genes, but not TGF-ß signaling target genes. Moreover, we observed an increased expression of other BMPRs, that is, anti-Mullerian hormone type-2 receptor and the activin receptor-like kinases (ALK) 1, ALK3, and ALK6. INTERVENTIONS AND OUTCOMES: The patient was prescribed a combination of macitentan, sildenafil, and nifedipine, which successfully controlled her symptom of syncope and normalized N-terminal pro-brain natriuretic peptide level after 3 months of medication. LESSONS: In light of these results, we propose a new pathogenetic mechanism for IPAH, based on enhanced BMP signaling via the functional replacement of mutated BMPR2 by other BMP receptors.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Proteínas Morfogenéticas Ósseas/genética , DNA/genética , Hipertensão Pulmonar Primária Familiar/genética , Mutação da Fase de Leitura , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Análise Mutacional de DNA , Hipertensão Pulmonar Primária Familiar/metabolismo , Feminino , Humanos , Transdução de Sinais , Adulto Jovem
19.
Nature ; 574(7779): 538-542, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31645727

RESUMO

The most common causes of chronic liver disease are excess alcohol intake, viral hepatitis and non-alcoholic fatty liver disease, with the clinical spectrum ranging in severity from hepatic inflammation to cirrhosis, liver failure or hepatocellular carcinoma (HCC). The genome of HCC exhibits diverse mutational signatures, resulting in recurrent mutations across more than 30 cancer genes1-7. Stem cells from normal livers have a low mutational burden and limited diversity of signatures8, which suggests that the complexity of HCC arises during the progression to chronic liver disease and subsequent malignant transformation. Here, by sequencing whole genomes of 482 microdissections of 100-500 hepatocytes from 5 normal and 9 cirrhotic livers, we show that cirrhotic liver has a higher mutational burden than normal liver. Although rare in normal hepatocytes, structural variants, including chromothripsis, were prominent in cirrhosis. Driver mutations, such as point mutations and structural variants, affected 1-5% of clones. Clonal expansions of millimetres in diameter occurred in cirrhosis, with clones sequestered by the bands of fibrosis that surround regenerative nodules. Some mutational signatures were universal and equally active in both non-malignant hepatocytes and HCCs; some were substantially more active in HCCs than chronic liver disease; and others-arising from exogenous exposures-were present in a subset of patients. The activity of exogenous signatures between adjacent cirrhotic nodules varied by up to tenfold within each patient, as a result of clone-specific and microenvironmental forces. Synchronous HCCs exhibited the same mutational signatures as background cirrhotic liver, but with higher burden. Somatic mutations chronicle the exposures, toxicity, regeneration and clonal structure of liver tissue as it progresses from health to disease.


Assuntos
Células Clonais/citologia , Células Clonais/patologia , Fibrose/genética , Fibrose/patologia , Fígado/citologia , Fígado/metabolismo , Mutação , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Células Clonais/metabolismo , Análise Mutacional de DNA , Hepatócitos/citologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Filogenia , Células-Tronco/citologia , Células-Tronco/metabolismo , Células-Tronco/patologia
20.
Nature ; 574(7779): 532-537, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31645730

RESUMO

The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions that lead to cancer1. However, our understanding of the earliest phases of colorectal neoplastic changes-which may occur in morphologically normal tissue-is comparatively limited, as for most cancer types. Here we use whole-genome sequencing to analyse hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed; some of these were ubiquitous and continuous, whereas others were only found in some individuals, in some crypts or during certain periods of life. Probable driver mutations were present in around 1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium. Colorectal cancers exhibit substantially increased mutational burdens relative to normal cells. Sequencing normal colorectal cells provides quantitative insights into the genomic and clonal evolution of cancer.


Assuntos
Colo/citologia , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Mutação , Sintomas Prodrômicos , Reto/citologia , Adenoma/genética , Adenoma/patologia , Idoso , Proteína Axina/genética , Carcinoma/genética , Carcinoma/patologia , Transformação Celular Neoplásica , Células Clonais/citologia , Células Clonais/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Feminino , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Células-Tronco/citologia , Células-Tronco/metabolismo
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