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1.
Medicine (Baltimore) ; 100(17): e25647, 2021 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-33907123

RESUMEN

ABSTRACT: To understand the possible carrier status of genes associated with hereditary hearing loss (HHL) in the general population among local residents and to give genetic counseling for pregnant women.A total of 3541 subjects were recruited. We used multiplex PCR technology combined with next-generation sequencing technology to detect 100 hotspot mutations in 18 common deafness-related genes. The homozygous mutation screening results were verified using Sanger sequencing.Of the 3541 participants, 37 alleles of 8 deafness genes were detected. A total of 145 (4.09%) were found to be GJB2 gene mutation carriers, and the hotspot mutation was c.235delC (1.54%). Twenty three (0.65%) were found to be GJB3 gene mutation carriers. A total of 132 (3.37%) were found to be SLC26A4 gene mutation carriers, and the hotspot mutation was c.919-2A > G (0.49%). Forty four (1.24%) were found to be mitochondrial DNA mutation carriers. Sanger sequencing results verified that 2 cases were homozygous for the c.235delC mutation and that 1 case was homozygous for the c.754T > C mutation.Genetic testing for pregnant women and their partners allows early identification of the molecular etiology of hearing loss (HL). On the one hand, it could give genetic counseling for pregnant women, such as early diagnosis of delayed deafness and drug-susceptible deafness. On the other hand, it could be used to assess hearing conditions during pregnancy, leading to prevention and timely intervention for newborns.


Asunto(s)
Pruebas Genéticas/métodos , Pérdida Auditiva/diagnóstico , Pérdida Auditiva/genética , Diagnóstico Prenatal/métodos , Adulto , Alelos , Grupo de Ascendencia Continental Asiática/genética , China , Conexina 26/genética , Conexinas/genética , Análisis Mutacional de ADN , ADN Mitocondrial/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Recién Nacido , Masculino , Proteínas de la Membrana/genética , Reacción en Cadena de la Polimerasa Multiplex , Mutación , Embarazo , Transportadores de Sulfato/genética
2.
Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi ; 35(3): 229-233;237, 2021 Mar.
Artículo en Chino | MEDLINE | ID: mdl-33794607

RESUMEN

Objective:To identify the pathogenic gene mutation of two patients with non-syndromic deafness(NSHL). Methods:Two patient with NSHL and their parents were selected in the research object. Each participant provided 3-5 mL of peripheral venous blood, which was used to establish a DNA library. Next generation sequencing was used to detect the sequence of the patient's genome, and the sequencing results were compared with the human genome sequence (GRCh)37/hg19. Sanger sequencing was used to verify the parents' genome sequence. Finally the patient's pathogenic gene mutation was confirmed.Amino acid conservatism and single nucleotide polymorphisms of the mutant sites were analyzed using a variety of databases and software. Results:The mutation was located to CDH23 gene in the chromosomal location 10q21-q22. Complex heterozygous mutations consist of c. 1343T>C and c. 7991_7993delTCA. Parents are heterozygous carriers of a single mutation. Conclusion:The next generation sequencing technology were used to screen the pathogenic gene mutation of inherited deafness. Combined with the genetic sequencing results of parents, the specific pathogenic gene mutation of deafness patients can be identified. While the pathogenicity of complex heterozygous mutation were explained by various pathogenicity analysis methods.


Asunto(s)
Sordera , Pérdida Auditiva Sensorineural , Cadherinas/genética , Conexinas/genética , Análisis Mutacional de ADN , Sordera/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación , Linaje
3.
Medicine (Baltimore) ; 100(16): e25463, 2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33879678

RESUMEN

INTRODUCTION: Wilson Disease (WD) is an autosomal recessive inherited metabolic disease caused by mutations in the ATPase copper transporting beta gene (ATP7B). WD can cause fatal neurological and hepatic disorders if not diagnosed and treated. OBJECTIVE: To analyze the disease-causing mutations of 14 Chinese WD children, 11 of whom are diagnosed with hepatic disorders, 2 with neurological degeneration and 1 with both hepatic and neurological disorders. METHODS: All ATP7B coding regions were analyzed by Sanger sequencing. Single nucleotide polymorphisms (SNPs) functional impacts were assessed by combining the results of four bioinformatics tools (Poly-phen-2, SIFT, PANTHER-PSEP and PhD-SNPs) in an index that reflects the combined probability (cPdel) of an amino acid change to be deleterious to the protein function. RESULTS: Two novel variants involved in WD development, c.1448_1455del (p.Arg483SerfsX19) and c.4144G>T (p.Glu1382Stop), and 11 previously reported mutations were detected. Both new variants result in shortened and dysfunctional ATP7B proteins. cPdel score suggests that SNPs may be deleterious to the ATP7B functionality. CONCLUSIONS: This study enriches the library of the ATP7B mutations that lead to WD and can be used as a basis for genetic counseling, for WD prevention and clinical and prenatal diagnosis. Those SNPs that are believed to be harmless to ATP7B protein may be involved in the pathogenesis of WD.


Asunto(s)
ATPasas Transportadoras de Cobre/genética , Degeneración Hepatolenticular/genética , Grupo de Ascendencia Continental Asiática/genética , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Asesoramiento Genético , Pruebas Genéticas , Degeneración Hepatolenticular/sangre , Degeneración Hepatolenticular/diagnóstico , Degeneración Hepatolenticular/prevención & control , Humanos , Masculino , Mutación , Polimorfismo de Nucleótido Simple
4.
Medicine (Baltimore) ; 100(16): e25520, 2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33879691

RESUMEN

RATIONALE: Glycogen storage disease (GSD) type VI is a rare disease caused by the inherited deficiency of liver phosphorylase. PATIENT CONCERNS: The proband, a 61-month-old Chinese boy, manifested intermittent hematochezia, growth retardation, hepatomegaly, damage of liver function, mild hypoglycemia, and hyperlactatemia. The other patient was a 107-month-old Chinese girl with growth retardation, hepatomegaly, mild hypoglycemia, and hyperlactatemia. In order to further confirm the diagnosis, we conducted a liver biopsy and detected blood samples for their gene using IDT exon chip capture and high-throughput sequencing. DIAGNOSES: According to the clinical symptoms, physical examination, laboratory examinations, liver biopsy, and the genetic test finding, the 2 patients were diagnosed GSD VI. INTERVENTIONS: They were treated mainly with uncooked cornstarch. OUTCOMES: There were 2 mutations of PYGL gene in this pedigree. c.2467C>T (p. Q823X) and c.2178-2A>C occurred both in the proband and his second sister. LESSONS: As a novel mutation, c.2178-2A>C enriches the mutation spectrum of PYGL gene. The different degrees of elevated lactate is an unusual phenotype in GSD VI patients. It is not clear if this is caused by the new mutation of c. 2178-2A > C. Long-term complications remains to be observed.


Asunto(s)
Glucógeno Fosforilasa de Forma Hepática/genética , Enfermedad del Almacenamiento de Glucógeno Tipo VI/genética , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo VI/diagnóstico , Enfermedad del Almacenamiento de Glucógeno Tipo VI/patología , Humanos , Hígado/patología , Masculino , Mutación , Linaje
5.
Medicine (Baltimore) ; 100(16): e25527, 2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33879693

RESUMEN

RATIONALE: Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by thrombocytopenia, small platelets, eczema, immunodeficiency, and an increased risk of autoimmunity and malignancies. X-linked thrombocytopenia (XLT), the milder phenotype of WAS, is always limited to thrombocytopenia with absent or slight infections and eczema. Here, we illustrated the clinical and molecular characteristics of 2 unrelated patients with WAS from Chinese minorities. PATIENT CONCERNS: Patient 1, a 13-day-old male newborn of the Chinese Lahu minority, showed a classic WAS phenotype, including thrombocytopenia, small platelets, buttock eczema, and recurrent infections. Patient 2, an 8-year-and 8-month-old boy of the Chinese Zhuang minority, presented an XLT phenotype without eczema and repeated infections. DIAGNOSIS: Next-generation sequencing was performed to investigate the genetic variations. Flow cytometry was used to quantify the expression of WAS protein and analyze the lymphocyte subsets. A novel frameshift WAS mutation (c.927delC, p.Q310Rfs∗135) and a known nonsense WAS mutation (c.1090C>T, p.R364X) were identified in Patient 1 and Patient 2, respectively. Both patients were confirmed to have WAS protein deficiency, which was more severe in Patient 1. Meanwhile, the analysis of lymphocyte subsets revealed an abnormality in Patient 1, but not in Patient 2. Combined with the above clinical data and genetic characteristics, Patient 1 and Patient 2 were diagnosed as classic WAS and XLT, respectively. In addition, many miliary nodules were accidentally found in abdominal cavity of Patient 2 during appendectomy. Subsequently, Patient 2 was confirmed with pulmonary and abdominal tuberculosis through further laboratory and imaging examinations. To our knowledge, there have been only a few reports about WAS/XLT with tuberculosis. INTERVENTIONS: Both patients received anti-infection therapy, platelet transfusions, and intravenous immunoglobulins. Moreover, Patient 2 also received antituberculosis treatment with ethambutol and amoxicillin-clavulanate. OUTCOMES: The clinical symptoms and hematological parameters of these 2 patients were significantly improved. Regrettably, both patients discontinued the treatment for financial reasons. LESSONS: Our report expands the pathogenic mutation spectrum of WAS gene and emphasizes the importance of molecular genetic testing in diagnosing WAS. Furthermore, researching and reporting rare cases of WAS from different populations will facilitate diagnosis and treatment of this disease.


Asunto(s)
Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Trombocitopenia/diagnóstico , Proteína del Síndrome de Wiskott-Aldrich/genética , Síndrome de Wiskott-Aldrich/diagnóstico , Grupo de Ascendencia Continental Asiática/genética , Niño , Análisis Mutacional de ADN , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Pruebas Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Recién Nacido , Masculino , Grupos Minoritarios , Trombocitopenia/genética , Síndrome de Wiskott-Aldrich/genética
6.
Anticancer Res ; 41(4): 2133-2140, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813424

RESUMEN

BACKGROUND/AIM: Tumor-infiltrating lymphocytes (TILs) are considered a prognostic marker for triple-negative breast cancer (TNBC). Immune checkpoint inhibitor (ICI)-based treatments are more effective for tumors with PD-L1-positive TILs, suggesting crucial roles of TILs in the local tumor immunity. However, factors attracting TILs are still largely unknown. Focusing on tumor antigenicity, we examined TNBC samples to identify the characteristics of TIL-high tumors. PATIENTS AND METHODS: Nine treatment-naïve TNBCs (TIL-high: five, TIL-low: four) were subjected to next-generation sequencing (NGS). Loss of heterozygosity (LOH) of PTEN was also analyzed. RESULTS: A variety of copy number variations were observed, and no genes differed significantly between TIL-high and -low groups. However, PTEN loss was more frequently observed in the TIL-high group: 60% compared to 25% in TIL-low tumors. NGS correlated well with LOH analysis in identifying PTEN loss. All three tumors with PTEN loss in the TIL-high group showed high PD-L1. All nine samples were microsatellite-stable. CONCLUSION: Frequent PTEN loss and high expression of PD-L1 in TIL-high TNBC suggest that PTEN mutation may be a biomarker for ICIs.


Asunto(s)
Biomarcadores de Tumor/genética , Linfocitos Infiltrantes de Tumor/metabolismo , Neoplasias de la Mama Triple Negativas/diagnóstico , Neoplasias de la Mama Triple Negativas/genética , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Biomarcadores Farmacológicos/análisis , Biomarcadores Farmacológicos/metabolismo , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Variaciones en el Número de Copia de ADN , Análisis Mutacional de ADN/métodos , Regulación Neoplásica de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Pérdida de Heterocigocidad , Recuento de Linfocitos , Linfocitos/metabolismo , Linfocitos/patología , Linfocitos Infiltrantes de Tumor/patología , Persona de Mediana Edad , Mutación , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Polimorfismo de Nucleótido Simple , Pronóstico , Transcriptoma , Resultado del Tratamiento , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo
8.
Am J Hum Genet ; 108(4): 597-607, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33675682

RESUMEN

Each human genome includes de novo mutations that arose during gametogenesis. While these germline mutations represent a fundamental source of new genetic diversity, they can also create deleterious alleles that impact fitness. Whereas the rate and patterns of point mutations in the human germline are now well understood, far less is known about the frequency and features that impact de novo structural variants (dnSVs). We report a family-based study of germline mutations among 9,599 human genomes from 33 multigenerational CEPH-Utah families and 2,384 families from the Simons Foundation Autism Research Initiative. We find that de novo structural mutations detected by alignment-based, short-read WGS occur at an overall rate of at least 0.160 events per genome in unaffected individuals, and we observe a significantly higher rate (0.206 per genome) in ASD-affected individuals. In both probands and unaffected samples, nearly 73% of de novo structural mutations arose in paternal gametes, and we predict most de novo structural mutations to be caused by mutational mechanisms that do not require sequence homology. After multiple testing correction, we did not observe a statistically significant correlation between parental age and the rate of de novo structural variation in offspring. These results highlight that a spectrum of mutational mechanisms contribute to germline structural mutations and that these mechanisms most likely have markedly different rates and selective pressures than those leading to point mutations.


Asunto(s)
Familia , Genoma Humano/genética , Células Germinativas , Mutación de Línea Germinal/genética , Tasa de Mutación , Envejecimiento/genética , Trastorno Autístico/genética , Sesgo , Variaciones en el Número de Copia de ADN/genética , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Edad Paterna , Mutación Puntual/genética
9.
Am J Hum Genet ; 108(4): 656-668, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33770507

RESUMEN

Genetic studies in underrepresented populations identify disproportionate numbers of novel associations. However, most genetic studies use genotyping arrays and sequenced reference panels that best capture variation most common in European ancestry populations. To compare data generation strategies best suited for underrepresented populations, we sequenced the whole genomes of 91 individuals to high coverage as part of the Neuropsychiatric Genetics of African Population-Psychosis (NeuroGAP-Psychosis) study with participants from Ethiopia, Kenya, South Africa, and Uganda. We used a downsampling approach to evaluate the quality of two cost-effective data generation strategies, GWAS arrays versus low-coverage sequencing, by calculating the concordance of imputed variants from these technologies with those from deep whole-genome sequencing data. We show that low-coverage sequencing at a depth of ≥4× captures variants of all frequencies more accurately than all commonly used GWAS arrays investigated and at a comparable cost. Lower depths of sequencing (0.5-1×) performed comparably to commonly used low-density GWAS arrays. Low-coverage sequencing is also sensitive to novel variation; 4× sequencing detects 45% of singletons and 95% of common variants identified in high-coverage African whole genomes. Low-coverage sequencing approaches surmount the problems induced by the ascertainment of common genotyping arrays, effectively identify novel variation particularly in underrepresented populations, and present opportunities to enhance variant discovery at a cost similar to traditional approaches.


Asunto(s)
Análisis Mutacional de ADN/economía , Análisis Mutacional de ADN/normas , Variación Genética/genética , Genética de Población/economía , África , Análisis Mutacional de ADN/métodos , Genética de Población/métodos , Genoma Humano/genética , Estudio de Asociación del Genoma Completo , Equidad en Salud , Humanos , Microbiota , Secuenciación Completa del Genoma/economía , Secuenciación Completa del Genoma/normas
10.
BMC Cancer ; 21(1): 240, 2021 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-33678158

RESUMEN

BACKGROUND: Genetic alterations have been proven to be the promising biomarkers for ICI response. However, sex biases in genetic alterations have been often ignored in the field of immunotherapy, which might specially influence the anticancer immunity and immunotherapy efficacy in male or female patients. Here, we have systematically evaluated the effect of the sex biases in somatic mutation of gastric cancer (GC) patients on the anticancer immunity and clinical benefit to immunotherapy. METHODS: Genomic and transcriptomic data of gastric cancer were downloaded from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC). We also obtained the genomic and clinical data of a MSKCC ICI-treated cohort from cbioportal database. GC male and female-derived tumor somatic mutation profiles were compared by maftools R package. Single sample gene set enrichment analysis (ssGSEA) was conducted to calculate the score of the anticancer immunity indicators including IFN-γ signaling, cytolytic activity (CYT) and antigen presenting machinery (APM). RESULTS: ATRX was found to mutate more frequently in female GC patients compared to male patients (FDR = 0.0108). Female GC patients with ATRX mutation manifested significantly more MSI-high subtypes, increased TMB and PDL1 expression as well as higher scores of IFN-γ signaling, CYT and APM. Gene set enrichment analysis (GSEA) has shown that ATRX mutation might enhance the immunogenicity and anticancer immunity through affecting DNA damage repair pathways. In the ICI-treated cohort from MSKCC, GC patients with ATRX mutation were associated with prolonged overall survival. When stratifying the entire ICI-treated cohort by sex, female patients with ATRX mutation obtained significantly better survival benefits than that of ATRX mutant male patients (Female patients, HR of ATRX MT vs WT = 0.636, 95%CI = 0.455-0.890, P = 0.023; Male patients, HR of ATRX MT vs WT = 0.929, 95%CI = 0.596-1.362, P = 0.712). CONCLUSIONS: ATRX mutation might serve as a potential predictive biomarker for favorable clinical benefit to ICI in female GC patients. ATRX mutation could be applied in combination with other biomarkers of ICI response to better identify the female GC patients who will derive greater benefits from ICI therapy.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Gástricas/tratamiento farmacológico , Proteína Nuclear Ligada al Cromosoma X/genética , Anciano , Biopsia , Análisis Mutacional de ADN , Reparación del ADN/inmunología , Conjuntos de Datos como Asunto , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/inmunología , Femenino , Humanos , Estimación de Kaplan-Meier , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Mutación , RNA-Seq , Factores Sexuales , Estómago/inmunología , Estómago/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/mortalidad
11.
BMC Cancer ; 21(1): 282, 2021 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-33726687

RESUMEN

BACKGROUND: Mismatch repair (MMR)/microsatellite instability (MSI) and tumor mutational burden (TMB) are independent biomarkers that complement each other for predicting immune checkpoint inhibitors (ICIs) efficacy. Here we aim to establish a strategy that integrates MSI and TMB determination for colorectal cancer (CRC) in one single assay. METHODS: Surgical or biopsy specimens retrospectively collected from CRC patients were subjected to NGS analysis. Immunohistochemistry (IHC) and polymerase chain reaction (PCR) were also used to determine MMR/MSI for those having enough tissues. The NGS-MSI method was validated against IHC and PCR. The MSI-high (MSI-H) or microsatellite stable (MSS) groups were further stratified based on tumor mutational burden, followed by validation using the The Cancer Genome Atlas (TCGA) CRC dataset. Immune microenvironment was evaluated for each subgroup be profiling the expression of immune signatures. RESULTS: Tissues from 430 CRC patients were analyzed using a 381-gene NGS panel. Alterations in KRAS, NRAS, BRAF, and HER2 occurred at a significantly higher incidence among MSI-H tumors than in MSS patients (83.6% vs. 58.4%, p = 0.0003). A subset comprising 98 tumors were tested for MSI/MMR using all three techniques, where NGS proved to be 99.0 and 93.9% concordant with PCR and IHC, respectively. Four of the 7 IHC-PCR discordant cases had low TMB (1.1-8.1 muts/Mb) and were confirmed to have been misdiagnosed by IHC. Intriguingly, 4 of the 66 MSS tumors (as determined by NGS) were defined as TMB-high (TMB-H) using a cut-off of 29 mut/Mb. Likewise, 15 of the 456 MSS tumors in the TCGA CRC cohort were also TMB-H with a cut-off of 9 muts/Mb. Expression of immune signatures across subgroups (MSS-TMB-H, MSI-H-TMB-H, and MSS-TMB-L) confirmed that the microenvironment of the MSS-TMB-H tumors was similar to that of the MSI-H-TMB-H tumors, but significantly more immune-responsive than that of the MSS-TMB-L tumors, indicating that MSI combined with TMB may be more precise than MSI alone for immune microenvironment prediction. CONCLUSION: This study demonstrated that NGS panel-based method is both robust and tissue-efficient for comprehensive molecular diagnosis of CRC. It also underscores the importance of combining MSI and TMB information for discerning patients with different microenvironment.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Colorrectales/diagnóstico , Inestabilidad de Microsatélites , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Colon/patología , Colon/cirugía , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Análisis Mutacional de ADN , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Mutación , Estadificación de Neoplasias , Recto/patología , Recto/cirugía , Estudios Retrospectivos , Microambiente Tumoral/genética , Adulto Joven
12.
Otol Neurotol ; 42(4): e399-e407, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33710989

RESUMEN

OBJECTIVE: To study the genotype and phenotype of a Dutch family with autosomal dominantly inherited hearing loss. STUDY DESIGN: Genotype-phenotype correlation study. Genetic analysis consisted of linkage analysis, variable number of tandem repeats analysis, and Sanger sequencing. Audiovestibular function was examined. Regression analysis was performed on pure tone audiometry and speech recognition scores and correlated with the age and/or level of hearing loss. SETTING: Tertiary referral center. PATIENTS: A large Dutch family presenting with sensorineural hearing loss. MAIN OUTCOME MEASURES: Identification of the underlying genetic defect of the hearing loss in this family. Results of pure tone and speech audiometry, onset age, progression of hearing loss and vestibular (dys)function. RESULTS: A novel mutation in COCH, c.1312C > T p.(Arg438Cys), cosegregates with hearing loss and a variable degree of vestibular (dys)function in this family. The reported mean age of onset of hearing loss is 33 years (range, 18-49 yr). Hearing loss primarily affects higher frequencies and its progression is relatively mild (0.8 dB/yr). Speech perception is remarkably well preserved in affected family members when compared with other DFNA9 families with different COCH mutations. CONCLUSION: These findings expand the genotypic and phenotypic spectrum of DFNA9. The c.1312C > T mutation, which affects the vWFA2 domain, causes a relatively mild audiovestibular phenotype when compared with other COCH mutations.


Asunto(s)
Proteínas de la Matriz Extracelular , Pérdida Auditiva Sensorineural , Adolescente , Adulto , Análisis Mutacional de ADN , Proteínas de la Matriz Extracelular/genética , Pérdida Auditiva Sensorineural/genética , Humanos , Persona de Mediana Edad , Mutación , Linaje , Fenotipo , Adulto Joven
13.
Plant Sci ; 306: 110875, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33775372

RESUMEN

Grapevine is one of the most valuable fruit crops in the world. Adverse environmental conditions reduce fruit quality and crop yield, so understanding the genetic and molecular mechanisms determining crop yield components is essential to optimize grape production. The analysis of a diverse collection of grapevine cultivars allowed us to evaluate the relationship between fruit set-related components of yield, including the incidence of reproductive disorders such as coulure and millerandage. The collection displayed a great phenotypic variation that we surveyed in a genetics association study using 15,309 single nucleotide polymorphisms (SNPs) detected in the sequence of 289 candidate genes scattered across the 19 grapevine linkage groups. After correcting statistical models for population structure and linkage disequilibrium effects, 164 SNPs from 34 of these genes were found to associate with fruit set-related traits, supporting a complex polygenic determinism. Many of them were found in the sequence of different putative MADS-box transcription factors, a gene family related with plant reproductive development control. In addition, we observed an additive effect of some of the associated SNPs on the phenotype, suggesting that advantageous alleles from different loci could be pyramided to generate superior cultivars with optimized fruit production.


Asunto(s)
Frutas/crecimiento & desarrollo , Frutas/genética , Variación Genética , Genotipo , Fenotipo , Vitis/crecimiento & desarrollo , Vitis/genética , Productos Agrícolas/genética , Productos Agrícolas/crecimiento & desarrollo , Análisis Mutacional de ADN , Genes de Plantas , Estudios de Asociación Genética , Haplotipos , Desequilibrio de Ligamiento , Polimorfismo de Nucleótido Simple
14.
Int J Mol Sci ; 22(4)2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33669698

RESUMEN

There is an urgent need to seek new molecular biomarkers helpful in diagnosing and treating breast cancer. In this elaboration, we performed a molecular analysis of mutations and expression of genes within the PI3K/Akt/mTOR pathway in patients with ductal breast cancer of various malignancy levels. We recognized significant correlations between the expression levels of the studied genes. We also performed a bioinformatics analysis of the data available on the international database TCGA and compared them with our own research. Studies on mutations and expression of genes were conducted using High-Resolution Melt PCR (HRM-PCR), Allele-Specific-quantitative PCR (ASP-qPCR), Real-Time PCR molecular methods in a group of women with ductal breast cancer. Bioinformatics analysis was carried out using web source Ualcan and bc-GenExMiner. In the studied group of women, it was observed that the prevalence of mutations in the studied PIK3CA and AKT1 genes was 29.63%. It was stated that the average expression level of the PIK3CA, PIK3R1, PTEN genes in the group of breast cancer patients is lower in comparison to the control group, while the average expression level of the AKT1 and mTOR genes in the studied group was higher in comparison to the control group. It was also indicated that in the group of patients with mutations in the area of the PIK3CA and AKT1 genes, the PIK3CA gene expression level is statistically significantly lower than in the group without mutations. According to our knowledge, we demonstrate, for the first time, that there is a very strong positive correlation between the levels of AKT1 and mTOR gene expression in the case of patients with mutations and without mutations.


Asunto(s)
Neoplasias de la Mama/genética , Regulación Neoplásica de la Expresión Génica , Mutación/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/metabolismo , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Bases de Datos Genéticas , Femenino , Humanos , Persona de Mediana Edad
15.
Medicine (Baltimore) ; 100(10): e24161, 2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33725819

RESUMEN

ABSTRACT: Propionic acidemia is associated with pathogenic variants in PCCA or PCCB gene. We investigated the potential pathogenic variants in PCCA or PCCB genes in Fujian Han population.Two probands and their families of Han ethnicity containing two generations were subject to newborn screening using tandem mass spectrometry, followed by diagnosis using urine gas chromatography mass spectrometry. Sanger sequencing was used to identify potential mutations in PCCA and PCCB genes.Compound heterozygous variants were identified in PCCB gene in two siblings of the first family, the youngest girl showed a novel missense variant c.1381G>C (p.Ala461Pro) in exon 13 and a heterozygous missense variant c.1301C>T (p.Ala434Val) in exon 13, which were inherited respectively from their parents. The oldest boy is a carrier with a novel missense variant c.1381G>C (p.Ala461Pro) in exon 13 which were inherited from his father. In the second family, c.1535G>A homozygous mutations were identified in the baby girl, which were inherited respectively from their parents. In silico analysis, several different types of bioinformatic software were utilized, which predicted that the novel variant c.1381G>C in PCCB gene was damaged. According to ACMG principle, the missense variant c.1381G>C (p.Ala461Pro) in exon 13 was a Variant of Undetermined Significance (VUS).One novel missense variant and two missense variants in PCCB gene were identified in the study. The novel variant of PCCB gene identified VUS was identified for the first time in the Chinese population, which enriched the mutational spectrum of PCCB gene.


Asunto(s)
Ligasas de Carbono-Carbono/genética , Metilmalonil-CoA Descarboxilasa/genética , Acidemia Propiónica/genética , Grupo de Ascendencia Continental Asiática/genética , Análisis Mutacional de ADN , Femenino , Pruebas Genéticas , Heterocigoto , Humanos , Lactante , Recién Nacido , Mutación Missense , Tamizaje Neonatal , Linaje , Acidemia Propiónica/sangre , Acidemia Propiónica/diagnóstico , Espectrometría de Masas en Tándem
16.
Methods Mol Biol ; 2292: 23-33, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33651349

RESUMEN

Urinary cell-free DNA offers an important noninvasive source of material for genomic testing also for nonurological tumors. Its clinical utility in monitoring tumor evolution and treatment failure is promising. Here we describe a method to detect cancer mutations into urine from patients affected by colorectal cancer.


Asunto(s)
Ácidos Nucleicos Libres de Células/genética , Neoplasias Colorrectales/genética , Análisis Mutacional de ADN/métodos , Proteínas Proto-Oncogénicas p21(ras)/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/aislamiento & purificación , Biomarcadores de Tumor/orina , Ácidos Nucleicos Libres de Células/aislamiento & purificación , Ácidos Nucleicos Libres de Células/orina , Neoplasias Colorrectales/orina , Humanos , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos
17.
BMC Cancer ; 21(1): 289, 2021 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-33736612

RESUMEN

BACKGROUND: Cervical cancer is a gynecologic cancer type that develops in the cervix, accounting for 8% mortality of all female cancer patients. Infection with specific human papillomavirus (HPV) types is considered the most severe risk factor for cervical cancer. In the context of our socioeconomic conditions, an increasing burden of this disease and high mortality rate prevail in Bangladesh. Although several researches related to the epidemiology, HPV vaccination, and treatment modalities were conducted, researches on the mutation profiles of marker genes in cervical cancer in Bangladesh remain unexplored. METHODS: In this study, five different genomic regions within the top three most frequently mutated genes (EGFR, KRAS and PIK3CA) in COSMIC database with a key role in the development of cervical cancers were selected to study the mutation frequency in Bangladeshi patients. In silico analysis was done in two steps: nucleotide sequence analysis and its corresponding amino acid analysis. RESULTS: DNA from 46 cervical cancer tissue samples were extracted and amplified by PCR, using 1 set of primers designed for EGFR and 2 sets of primers designed for two different regions of both PIK3CA and KRAS gene. In total, 39 mutations were found in 26 patient samples. Eleven different mutations (23.91%), twenty-four different mutations (52.17%) and four mutations (8.7%) were found in amplified EGFR, PIK3CA and KRAS gene fragments, respectively; among which 1 (EGFR) was common in seven patient samples and 2 (PIKCA) were found in more than 1 patient. Our study shows that except for KRAS, the frequency of observed mutations in our patients is higher than those reported earlier in other parts of the world. Most of the exonic mutations were found only in the PIK3CA and EGFR genes. CONCLUSIONS: The study can be used as a basis to build a mutation database for cervical cancer in Bangladesh with the possibility of targetable oncogenic mutations. Further explorations are needed to establish future diagnostics, personalized medicine decisions, and other pharmaceutical applications for specific cancer subtypes.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias del Cuello Uterino/genética , Adulto , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Bangladesh , Biomarcadores de Tumor/antagonistas & inhibidores , Cuello del Útero/patología , Cuello del Útero/cirugía , Quimioterapia Adyuvante/métodos , Fosfatidilinositol 3-Quinasa Clase I/genética , Toma de Decisiones Clínicas , Simulación por Computador , Análisis Mutacional de ADN , Técnicas de Apoyo para la Decisión , Receptores ErbB/genética , Femenino , Humanos , Histerectomía , Persona de Mediana Edad , Terapia Molecular Dirigida/métodos , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/terapia
18.
Int Heart J ; 62(2): 359-366, 2021 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-33678800

RESUMEN

Dilated cardiomyopathy (DCM) is a common cause of heart failure. TTN, which encodes titin protein, is a representative causative gene of DCM, and is presented mainly as a truncation variant. However, TTN truncation variants are also found in healthy individuals, and it is therefore important to evaluate the pathogenicity of each variant. In this study, we analyzed 67 cardiomyopathy-associated genes in a male Japanese patient who was hospitalized for recurrent severe heart failure and identified a novel truncation variant, TTN Ser17456Arg fs*14. This TTN truncation variant was located in the A-band region. Moreover, the patient's mother with heart failure harbored the same variant, whereas the father and brother without heart failure did not harbor the variant. To examine the functional changes associated with the truncation variant, H9c2 cells were subjected to genome editing to generate cells with a homologous truncation variant. The cells were differentiated using all-trans-retinoic acid, and the mRNA expression of skeletal actin and cardiac actin were found to be increased and decreased, respectively, consistent with known changes in patients with DCM or heart failure. In contrast, another cell with the titin truncation variant used as a control showed no changes in heart failure-related genes. In summary, we found a novel TTN truncation variant in familial DCM patients and confirmed its functional changes using a relatively simple cell model. The novel truncation variant was identified as a pathogenic and disease-causing mutation.


Asunto(s)
Cardiomiopatía Dilatada/genética , Conectina/genética , ADN/genética , Mutación , Miocitos Cardíacos/metabolismo , Función Ventricular Izquierda/fisiología , Biopsia , Cardiomiopatía Dilatada/metabolismo , Cardiomiopatía Dilatada/patología , Conectina/metabolismo , ADN/metabolismo , Análisis Mutacional de ADN , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Miocitos Cardíacos/patología , Linaje
19.
Int Heart J ; 62(2): 445-447, 2021 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-33731536

RESUMEN

Recessive mutations in the Myosin regulatory light chain 2 (MYL2) gene are the cause of an infantile-onset myopathy, associated with fatal myocardial disease of variable macromorphology. We here present the first Japanese family affected with recessive MYL2 myopathy. Affected siblings manifested typical features and the proband's autopsy findings were compatible with the diagnosis of noncompaction cardiomyopathy. The rapidly progressive clinical course of this recessive MYL2 cardiomyopathy highlights the crucial role of c-terminal tails in MYL2 protein in maintaining cardiac morphology and function.


Asunto(s)
Cardiomiopatías/genética , ADN/genética , Mutación , Miocardio/patología , Proteína de la Leucemia Promielocítica/genética , Cardiomiopatías/diagnóstico , Cardiomiopatías/metabolismo , Análisis Mutacional de ADN , Resultado Fatal , Femenino , Humanos , Lactante , Miocardio/metabolismo , Linaje , Proteína de la Leucemia Promielocítica/metabolismo
20.
Nature ; 592(7854): 438-443, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33690265

RESUMEN

Continued uncontrolled transmission of SARS-CoV-2 in many parts of the world is creating conditions for substantial evolutionary changes to the virus1,2. Here we describe a newly arisen lineage of SARS-CoV-2 (designated 501Y.V2; also known as B.1.351 or 20H) that is defined by eight mutations in the spike protein, including three substitutions (K417N, E484K and N501Y) at residues in its receptor-binding domain that may have functional importance3-5. This lineage was identified in South Africa after the first wave of the epidemic in a severely affected metropolitan area (Nelson Mandela Bay) that is located on the coast of the Eastern Cape province. This lineage spread rapidly, and became dominant in Eastern Cape, Western Cape and KwaZulu-Natal provinces within weeks. Although the full import of the mutations is yet to be determined, the genomic data-which show rapid expansion and displacement of other lineages in several regions-suggest that this lineage is associated with a selection advantage that most plausibly results from increased transmissibility or immune escape6-8.


Asunto(s)
/virología , Mutación , Filogenia , Filogeografía , /aislamiento & purificación , /epidemiología , /transmisión , Análisis Mutacional de ADN , Evolución Molecular , Aptitud Genética , Humanos , Evasión Inmune , Modelos Moleculares , /patogenicidad , Selección Genética , Sudáfrica/epidemiología , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo , Factores de Tiempo
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