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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(10): 969-972, 2021 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-34625934

RESUMO

OBJECTIVE: To explore the clinical phenotype and genetic characteristics of two children with developmental epileptic encephalopathy type 66. METHODS: Genomic DNA was extracted from peripheral blood samples of the two children and their parents. Whole exome sequencing (WES) was carried out and suspected variant was verified by Sanger sequencing. RESULTS: The main manifestations of the two children were neonatal onset seizures, hypotonia, global developmental delay, and facial dysmorphisms. Cranial MRI showed delayed myelination in case 1 and cerebellar dysgenesis in case 2. WES has identified a de novo pathogenic variant in the PACS2 gene in both patients, namely c.625G>A (p.Glu209Lys)(NM_001100913.3), which was reported as a pathogenic variant before. This variant was predicted to be pathogenic according to the American College of Medical Genetics and Genomics guideline (PS2+PM2+PP3). The seizures were controlled after combination treatment of sodium valproate and levetiracetam in both cases. At last follow-up, the motor and intellectual development of the 2 cases were improved. Compared with the cases reported, the clinical symptoms and signs of our cases were relatively mild, and the treatment effects were fairly good. CONCLUSION: The variant of c.625G>A (p.Glu209Lys) in PACS2 gene is a hotspot variant of developmental epileptic encephalopathy 66. Gene testing can facilitate the clinical diagnosis and treatment.


Assuntos
Epilepsia Generalizada , Testes Genéticos , Criança , Família , Humanos , Imageamento por Ressonância Magnética , Proteínas de Transporte Vesicular/genética , Sequenciamento Completo do Exoma
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(10): 973-976, 2021 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-34625935

RESUMO

OBJECTIVE: Two brothes with Seckel's syndrome 1(SCKL1) were reported and a literature review was carried to provide clinical and genetic information of this rare disease. METHODS: Clinical data of the two children were collected, and the peripheral blood was extracted for whole exome sequencing. Literature of the disease were reviewed. RESULTS: The two patients were 11 years and 9.5 years old when examined for short stature. They presented with intrauterine growth retardation, intellectual disability, microcephaly, birdhead-like face and coffee au lait spots. The bone age was more than 2 years behind the chronical age and the growth hormone levels were normal. Whole exome sequencing revealed novel compound heterozygous variants c.1A>G (p.M1?) and c.4853-18A>G of ART gene in both children. CONCLUSION: Children with prenatal onset short stature, developmental delay, microcephaly and special facial featuresshould be considered for the possibility of Seckel's syndrome, whole exome sequencing could help to confirm the clinical diagnosis.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Nanismo , Deficiência Intelectual , Microcefalia , Criança , Nanismo/genética , Humanos , Deficiência Intelectual/genética , Masculino , Microcefalia/genética , Irmãos , Sequenciamento Completo do Exoma
3.
BMC Genomics ; 22(1): 730, 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34625021

RESUMO

BACKGROUND: Differential expression (DE) analysis of RNA-seq data typically depends on gene annotations. Different sets of gene annotations are available for the human genome and are continually updated-a process complicated with the development and application of high-throughput sequencing technologies. However, the impact of the complexity of gene annotations on DE analysis remains unclear. RESULTS: Using "mappability", a metric of the complexity of gene annotation, we compared three distinct human gene annotations, GENCODE, RefSeq, and NONCODE, and evaluated how mappability affected DE analysis. We found that mappability was significantly different among the human gene annotations. We also found that increasing mappability improved the performance of DE analysis, and the impact of mappability mainly evident in the quantification step and propagated downstream of DE analysis systematically. CONCLUSIONS: We assessed how the complexity of gene annotations affects DE analysis using mappability. Our findings indicate that the growth and complexity of gene annotations negatively impact the performance of DE analysis, suggesting that an approach that excludes unnecessary gene models from gene annotations improves the performance of DE analysis.


Assuntos
Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Anotação de Sequência Molecular , RNA-Seq , Sequenciamento Completo do Exoma
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(10): 937-941, 2021 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-34625927

RESUMO

OBJECTIVE: To explore the genetic basis of three families with recurrence of non-immune hydrops fetalis (NIHF) but negative result by copy number variation sequencing (CNV-seq). METHODS: Amniotic fluid sample and/or abortive tissues of the fetuses were collected and subjected to CNV-seq analysis. Peripheral blood samples of the parents were also taken for trio whole exome sequencing (trio WES). RESULTS: Fetus 1 was found to harbor heterozygous c.976G>T(p.Glu326*) variant of the SOX18 gene in addition with compound heterozygous variants c.844C>T(p.Arg282Trp) and c.9472+1G>A of the RYR1 gene. The three variants were all inherited from its parents and have been associated with the etiology of NIHF. Based on the American College of Medical Genetics and Genomics (ACMG) standards and guidelines, the c.976G>T variant of SOX18 gene and c.9472+1G>A of RYR1 gene were predicted to be pathogenic (PVS1+PM2+PP3+PP4, PVS1+PM2+PP3), and c.844C>T variant of RYR1 gene to be likely pathogenic (PM1+PM2+PP3). Fetus 2 was found to harbor compound heterozygous variants c.6682C>T(p.Gln2228*) and c.4373_4383del(p.Val1458Alafs*63) of the PIEZO1 gene. Both variants were also inherited from its parents and are associated with the etiology of NIHF. Based on ACMG standards and guidelines, both c.6682C>T and c.4373_4383del variants of PIEZO1 gene were predicted to be pathogenic (PVS1+PM2+PP4, PVS1+PM2). Fetus 3 was found to harbor compound heterozygous variants of the TTN gene c.29860G>C(p.Asp9954His) and c.21107A>T(p.Asp7036Val), which were respectively inherited from its parents. Both variants have been strongly associated with the phenotype, though the connection between the etiology of NIHF and variants of the TTN gene remains elusive. Based on ACMG standards and guidelines, the c.29860G>C and c.21107A>T variants of TTN gene were predicted to be likely pathogenic (PM1+PM2+PP3). CONCLUSION: Trio WES can improve the diagnosis rate of NIHF with a negative result by CNV-seq. Considering the urgency of prenatal diagnosis, CNV-seq and trio WES should be carried out at the same time for fetuses with NIHF.


Assuntos
Variações do Número de Cópias de DNA , Hidropisia Fetal , Feminino , Genômica , Heterozigoto , Humanos , Hidropisia Fetal/genética , Canais Iônicos , Gravidez , Fatores de Transcrição SOXF , Estados Unidos , Sequenciamento Completo do Exoma
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(10): 981-984, 2021 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-34625937

RESUMO

OBJECTIVE: To explore the genetic basis for a girl with febrile convulsion as the main manifestation. METHODS: The child was subjected to whole exome sequencing (WES) and copy number variation sequencing(CNV-seq). Fluorescence quantitative PCR was carried out to validate the microdeletion in her family. RESULTS: The 7-year-old girl was diagnosed with febrile convulsion (complex type) for having fever for 3 days, mild cough and low thermal convulsion once. Her father, mother and aunt also had a history of febrile convulsion. A heterozygous deletion with a size of approximately 1.5 Mb was detected in the 16p13.11 region by WES and CNV-seq. The deletion has derived from her father and was confirmed by fluorescence quantitative PCR. CONCLUSION: 16p13.11 microdeletion syndrome has significant clinical heterogeneity. Different from those with epilepsy, mental retardation, autism, multiple malformations, carriers of 16p13.11 deletion may only manifest with febrile convulsion. Deletion of certain gene(s) from the region may be related to febrile convulsion and underlay the symptom of this child.


Assuntos
Epilepsia , Convulsões Febris , Criança , Variações do Número de Cópias de DNA , Feminino , Humanos , Convulsões/genética , Convulsões Febris/genética , Sequenciamento Completo do Exoma
6.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(10): 989-992, 2021 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-34625939

RESUMO

OBJECTIVE: To investigate the clinical features and SLC35A2 variant of a case of congenital disorder of glycosylation type IIm (CDG-IIm), and to identify the possible causes of the disease. METHODS: Trio-whole exome sequencing (WES) was used to analyze the gene variant of the children and their parents. The suspicious gene variants were screened for Sanger verification and the bioinformatics prediction was used to analyze the hazard of variant. RESULTS: The clinical manifestations of the child were epilepsy, global growth retardation, nystagmus, myocarditis and other symptoms. MRI showed brain dysplasia such as wide frontal temporal sulcus and subarachnoid space on both sides. Echocardiography showed left ventricular wall thickening and patent foramen ovale. According to the results of gene detection, there was a heterozygous missense variant c.335C>A (p.Thr112Lys) in SLC35A2 gene. The parents were wild-type at this locus, which was a de novo variant. At the same time, there was no report of this variant in the relevant literature, which was a novel variant in SLC35A2 gene. According to the genetic variant guidelines of American College of Medical Genetics and Genomics, SLC35A2 gene c.335C>A (p.Thr112Lys) variant was predicted to be likely pathogenic (PS2+PM2+PP3). CONCLUSION: The variant of SLC35A2 gene c.335C>A(p.Thr112Lys) may be the cause of the disease in the child.


Assuntos
Defeitos Congênitos da Glicosilação , Proteínas de Transporte de Monossacarídeos , Criança , Defeitos Congênitos da Glicosilação/genética , Glicosilação , Humanos , Imageamento por Ressonância Magnética , Proteínas de Transporte de Monossacarídeos/genética , Sequenciamento Completo do Exoma
7.
BMC Bioinformatics ; 22(Suppl 10): 419, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34479487

RESUMO

BACKGROUND: RNA velocity is a novel and powerful concept which enables the inference of dynamical cell state changes from seemingly static single-cell RNA sequencing (scRNA-seq) data. However, accurate estimation of RNA velocity is still a challenging problem, and the underlying kinetic mechanisms of transcriptional and splicing regulations are not fully clear. Moreover, scRNA-seq data tend to be sparse compared with possible cell states, and a given dataset of estimated RNA velocities needs imputation for some cell states not yet covered. RESULTS: We formulate RNA velocity prediction as a supervised learning problem of classification for the first time, where a cell state space is divided into equal-sized segments by directions as classes, and the estimated RNA velocity vectors are considered as ground truth. We propose Velo-Predictor, an ensemble learning pipeline for predicting RNA velocities from scRNA-seq data. We test different models on two real datasets, Velo-Predictor exhibits good performance, especially when XGBoost was used as the base predictor. Parameter analysis and visualization also show that the method is robust and able to make biologically meaningful predictions. CONCLUSION: The accurate result shows that Velo-Predictor can effectively simplify the procedure by learning a predictive model from gene expression data, which could help to construct a continous landscape and give biologists an intuitive picture about the trend of cellular dynamics.


Assuntos
RNA , Análise de Célula Única , Perfilação da Expressão Gênica , Aprendizado de Máquina , RNA/genética , Análise de Sequência de RNA , Sequenciamento Completo do Exoma
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 849-852, 2021 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-34487528

RESUMO

OBJECTIVE: To explore the clinical feature and gene variant for two cases of primary male infertility caused by severe asthenospermia and to analyze the etiology of the disease. METHODS: Genomic DNA of peripheral blood samples of patients and their parents was extracted and gene variant analysis of the patients was conducted by using whole exome sequencing. Suspected pathogenic variant was verified by Sanger sequencing and pathogenic analysis. RESULTS: Whole exome sequencing showed that the DNAH1 gene of patient 1 had two heterozygous variants of c.2016T>G(p.Y672X) and c.6017T>G (p.V2006G). The DNAH1 gene of patient 2 had a homozygous variant of c.2610G>A(p.W870X), which were inherited from his father and mother, respectively. According to American College of Medical Genetics and Genomics standards and guidelines, the c.2016T>G (p.Y672X) and c.2610G>A (p.W870X) varaints of DNAH1 gene were predicted to be pathogenic (PVS1+PM2+PM3+PP3). CONCLUSION: The two patients of multiple morphological abnormalities of the sperm flagella may be caused by DNAH1 gene variant, which has resulted in primary male infertility.


Assuntos
Dineínas , Infertilidade Masculina , Cauda do Espermatozoide , Dineínas/genética , Genômica , Humanos , Infertilidade Masculina/genética , Masculino , Mutação , Cauda do Espermatozoide/patologia , Sequenciamento Completo do Exoma
9.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 857-860, 2021 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-34487530

RESUMO

OBJECTIVE: To report on a patient with congenital muscular dystrophy (CMD) due to a missense variant of LMNA gene and explore its pathogenicity. METHODS: The 1-year-and-1-month-old boy has presented with motor development delay and elevation of muscle enzymes for more than half a year. Congenital myopathy was suspected. Following muscle biopsy, HE staining, immunostaining and electron microscopy were conducted to clarify the clinical diagnosis. Meanwhile, DNA was extracted from the child and his parents' peripheral venous blood samples. Trio-whole exome sequencing (trio-WES) was carried out to detect pathogenic variant in the child. Candidate variant was verified by Sanger sequencing and bioinformatic analysis. RESULTS: Both light and electron microscopy showed a large area of necrotic muscle tissues with infiltration of inflammatory cells. Immunohistochemistry revealed a large amount of muscle cells to be diffusely positive for Dysferlin. The patient's motor delays, elevations of muscle enzymes and histopathological results suggested a clinical diagnosis of CMD. A de novo missense c.1072G>A (p.E358K) variant was detected in the LMNA gene by trio-WES. The variant was unreported previously (PS2) and was absent from major allele frequency databases (PM2). It was a loss of function variant and was considered as hotspot variant in the LMNA gene (PM1) as the amino acid (E), located in position 358, was highly conserved, and change of this amino acid was found to cause destruction of the filament domain (AA: 30-386), which may result in serious damage to the intermediate filament protein. Furthermore, c.1072G>A (p. E358K) in LMNA gene was also predicted to be pathogenic based on MutationTaster, PROVEAN and PolyPhen-2 (PP3) analysis. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), the variant was classified to be likely pathogenic (PS2+PM1+PM2+PP3). CONCLUSION: The child's condition may be attributed to the de novo missense c.1072 G>A (p.E358K) variant of the LMNA gene. Above discovery has expanded the variant spectrum of the LMNA gene.


Assuntos
Lamina Tipo A , Distrofias Musculares , Frequência do Gene , Genômica , Humanos , Lactente , Lamina Tipo A/genética , Masculino , Distrofias Musculares/genética , Mutação , Sequenciamento Completo do Exoma
10.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 865-868, 2021 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-34487532

RESUMO

OBJECTIVE: To analyze the clinical characteristics and genetic variants in a two-month-and-one-day male infant with aldosterone synthase deficiency. METHODS: Clinical data of the child was collected. Whole exome sequencing was carried out by next generation sequencing(NGS). Candidate variants were verified by Sanger sequencing. RESULTS: The infant had measured 54 cm (-2.1 SD) in length and 3.9 kg (-2.8 SD) in weight, and featured recurrent vomiting, poor feeding, apathetic appearance and failure to thrive. Blood electrolyte testing showed low sodium and increased potassium. Serum cortisol, adrenocorticotrophic hormone, 17-alpha-hydroxyl progesterone, androstenedione, and testosterone were all within the normal ranges. The plasma renin activity activity was increased, and plasma aldosterone level was low. NGS revealed that the infant has harbored compound heterozygous variants of the CYP11B2 gene, namely c.1334T>G(p.Phe445Cys) inherited from his father and c.1121G>A(p.Arg374Gln) inherited from his mother. Neither variant was reported previously, and both were predicted to be deleterious for the function of the protein product. CONCLUSION: The compound heterozygous variants of c.1334T>G (p.Phe445Cys) and c.1121G>A (p.Arg374Gln) of the CYP11B2 gene probably underlay the disease in this patient.


Assuntos
Citocromo P-450 CYP11B2 , Testes Genéticos , Criança , Citocromo P-450 CYP11B2/deficiência , Citocromo P-450 CYP11B2/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Mutação , Sequenciamento Completo do Exoma
11.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 873-876, 2021 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-34487534

RESUMO

OBJECTIVE: To report the clinical manifestation and genetic characteristics of a child with Thiamine metabolism dysfunction syndrome 5. METHODS: Clinical data and genetic results were collected and analyzed. Peripheral blood samples of the child and their parents were collected for whole exome sequencing, and the functional effect of the variants on the TPK1 enzyme activity was verified by an in vitro assay. RESULTS: A four-year-old boy presented with preschool onset of ataxia were characterized. High-throughput sequencing identified a novel homozygous variant of TPK1 gene c.382G>A (p.Leu128Phe). His father and mother were both found carrying the variant. The variant protein showed a 30.9% reduction in TPK1 enzyme activity compared with the wildtype. CONCLUSION: A novel pathogenic variant has been identified in a boy with thiamine metabolic dysfunction syndrome type 5.


Assuntos
Testes Genéticos , Tiamina , Pré-Escolar , Homozigoto , Humanos , Masculino , Mutação , Sequenciamento Completo do Exoma
12.
BMC Pediatr ; 21(1): 384, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34479510

RESUMO

BACKGROUND: The Raynaud-Claes type of X-linked syndromic mental retardation (MRXSRC) is a very rare condition, by intellectual disability ranged from borderline to profound, impaired language development, brain abnormalities, facial dysmorphisms and seizures. MRXSRC is caused by variants in CLCN4 which encodes the 2Cl-/H+ exchanger ClC-4 prominently expressed in brain. CASE PRESENTATION: We present a 3-year-old Chinese girl with intellectual disability, dysmorphic features, brain abnormalities, significant language impairment and autistic features. Brain magnetic resonance imaging (MRI) showed a thin corpus callosum, a mega cisterna magna and ventriculomegaly. Whole exome sequencing (WES) was performed to detect the molecular basis of the disease. It was confirmed that this girl carried a novel heterozygous missense variant (c.1343C > T, p.Ala448Val) of CLCN4 gene, inherited from her mother. This variant has not been registered in public databases and was predicted to be pathogenic by multiple in silico prediction tools. CONCLUSION: Our investigation expands the phenotype spectrum for CLCN4 variants with syndromic X-linked intellectual disability, which help to improve the understanding of CLCN4-related intellectual disability and will help in genetic counselling for this family.


Assuntos
Deficiência Intelectual , Retardo Mental Ligado ao Cromossomo X , Pré-Escolar , China , Canais de Cloreto/genética , Feminino , Genes Ligados ao Cromossomo X , Humanos , Deficiência Intelectual/genética , Retardo Mental Ligado ao Cromossomo X/genética , Mutação , Linhagem , Fenótipo , Sequenciamento Completo do Exoma
13.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 900-906, 2021 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-34487541

RESUMO

OBJECTIVE: To investigate the application value of whole exome sequencing technology in fetuses with congenital structural abnormalities. METHODS: The chromosomal abnormalities of 1147 families were analyzed. According to the follow-up results, the data of fetuses with new phenotypes in late pregnancy or after birth were reanalyzed. Subgroups were divided according to the organs involved and whether single malformation or not. The gene regulatory network map was drawn by using string database and Cytoscape software. Fisher exact probability method was used to compare the difference of the diagnostic rate of pathogenic genes among the groups. RESULTS: A total of 160 fetal cases received positive molecular diagnosed, involving 178 variant sites of 125 pathogenic genes, including 8 cases (4.9%, 8/163) by data reanalysis, and the overall positive diagnosis rate was 13.9%. Diagnostic rate was highest in the group of skeletal malformation (31.5%, 39/124) and lowest in that with thoracic malformation (0, 0/32). The gene clusters of fetal edema and intrauterine growth restriction were independent, and were not associated with the major structural malformations. The probability of each parent carrying the same recessive gene variant was 0.03 (39/1146) and 0.08 (4/53) with positive family history. CONCLUSION: For fetuses with congenital structural abnormalities that are negative for conventional genetic tests, 13.9% of phenotypic associated pathogenic/likely pathogenic genetic variants can be detected by whole exome sequencing technology. Its application value for prenatal diagnosis varies in fetus with different organs involved. Reanalysis of sequencing data for cases with new phenotypes in late pregnancy or after birth can further improve the molecular diagnosis rate. Further investigations are needed to explore the related genetic mechanisms.


Assuntos
Doenças Fetais , Feto , Feminino , Feto/diagnóstico por imagem , Humanos , Gravidez , Diagnóstico Pré-Natal , Tecnologia , Ultrassonografia Pré-Natal , Sequenciamento Completo do Exoma
14.
Nat Biotechnol ; 39(9): 1141-1150, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504346

RESUMO

Clinical applications of precision oncology require accurate tests that can distinguish true cancer-specific mutations from errors introduced at each step of next-generation sequencing (NGS). To date, no bulk sequencing study has addressed the effects of cross-site reproducibility, nor the biological, technical and computational factors that influence variant identification. Here we report a systematic interrogation of somatic mutations in paired tumor-normal cell lines to identify factors affecting detection reproducibility and accuracy at six different centers. Using whole-genome sequencing (WGS) and whole-exome sequencing (WES), we evaluated the reproducibility of different sample types with varying input amount and tumor purity, and multiple library construction protocols, followed by processing with nine bioinformatics pipelines. We found that read coverage and callers affected both WGS and WES reproducibility, but WES performance was influenced by insert fragment size, genomic copy content and the global imbalance score (GIV; G > T/C > A). Finally, taking into account library preparation protocol, tumor content, read coverage and bioinformatics processes concomitantly, we recommend actionable practices to improve the reproducibility and accuracy of NGS experiments for cancer mutation detection.


Assuntos
Benchmarking , Neoplasias/genética , Análise de Sequência de DNA/normas , Sequenciamento Completo do Exoma/normas , Sequenciamento Completo do Genoma/normas , Linhagem Celular , Linhagem Celular Tumoral , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Mutação , Neoplasias/patologia , Reprodutibilidade dos Testes
16.
Nat Commun ; 12(1): 5183, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34465776

RESUMO

Plasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor a MYC translocation. Here, we provide a comprehensive integrated genomic analysis using whole exome sequencing (WES) and genome-wide copy number determination in a large cohort of 96 primary PBL samples. We identify alterations activating the RAS-RAF, JAK-STAT, and NOTCH pathways as well as frequent high-level amplifications in MCL1 and IRF4. The functional impact of these alterations is assessed using an unbiased shRNA screen in a PBL model. These analyses identify the IRF4 and JAK-STAT pathways as promising molecular targets to improve outcome of PBL patients.


Assuntos
Linfoma Plasmablástico/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Amplificação de Genes , Dosagem de Genes , Perfilação da Expressão Gênica , Humanos , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Janus Quinases/genética , Janus Quinases/metabolismo , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Linfoma Plasmablástico/metabolismo , Linfoma Plasmablástico/mortalidade , Linfoma Plasmablástico/terapia , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismo , Translocação Genética , Sequenciamento Completo do Exoma , Adulto Jovem
17.
Nat Commun ; 12(1): 5262, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489456

RESUMO

TFE3-translocation renal cell carcinoma (TFE3-tRCC) is a rare and heterogeneous subtype of kidney cancer with no standard treatment for advanced disease. We describe comprehensive molecular characteristics of 63 untreated primary TFE3-tRCCs based on whole-exome and RNA sequencing. TFE3-tRCC is highly heterogeneous, both clinicopathologically and genotypically. ASPSCR1-TFE3 fusion and several somatic copy number alterations, including the loss of 22q, are associated with aggressive features and poor outcomes. Apart from tumors with MED15-TFE3 fusion, most TFE3-tRCCs exhibit low PD-L1 expression and low T-cell infiltration. Unsupervised transcriptomic analysis reveals five molecular clusters with distinct angiogenesis, stroma, proliferation and KRAS down signatures, which show association with fusion patterns and prognosis. In line with the aggressive nature, the high angiogenesis/stroma/proliferation cluster exclusively consists of tumors with ASPSCR1-TFE3 fusion. Here, we describe the genomic and transcriptomic features of TFE3-tRCC and provide insights into precision medicine for this disease.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Neoplasias Renais/genética , Neoplasias Renais/mortalidade , Adolescente , Adulto , Idoso , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Criança , Pré-Escolar , Feminino , Regulação Neoplásica da Expressão Gênica , Fusão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Análise de Sequência de RNA , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Sequenciamento Completo do Exoma , Adulto Jovem
18.
Front Immunol ; 12: 718744, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34531865

RESUMO

COVID-19 associated multisystem inflammatory syndrome (MIS) is a rare condition mostly affecting children but also adults (MIS-A). Although severe systemic inflammation and multiorgan dysfunction are hallmarks of the syndrome, the underlying pathogenesis is unclear. We aimed to provide novel immunological and genetic descriptions of MIS-A patients. Cytokine responses (IL-6, IL-1ß, TNFα, CXCL10, type I, II and III interferons) following SARS-CoV-2 infection of peripheral blood mononuclear cells in vitro were analyzed as well as antibodies against IFNα and IFNω (by ELISA) in patients and healthy controls. We also performed whole exome sequencing (WES) of patient DNA. A total of five patients (ages 19, 23, 33, 38, 50 years) were included. The patients shared characteristic features, although organ involvement and the time course of disease varied slightly. SARS-CoV-2 in vitro infection of patient PBMCs revealed impaired type I and III interferon responses and reduced CXCL10 expression, whereas production of proinflammatory cytokines were less affected, compared to healthy controls. Presence of interferon autoantibodies was not detected. Whole exome sequencing analysis of patient DNA revealed 12 rare potentially disease-causing variants in genes related to autophagy, classical Kawasaki disease, restriction factors and immune responses. In conclusion, we observed an impaired production of type I and III interferons in response to SARS-CoV-2 infection and detected several rare potentially disease-causing gene variants potentially contributing to MIS-A.


Assuntos
COVID-19/patologia , Citocinas/sangue , Interferon-alfa/biossíntese , Interferons/biossíntese , Síndrome de Resposta Inflamatória Sistêmica/patologia , Adulto , Autoanticorpos/sangue , Quimiocina CXCL10/biossíntese , Comorbidade , Exoma/genética , Feminino , Humanos , Interferon-alfa/imunologia , Interferons/imunologia , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , Sequenciamento Completo do Exoma , Adulto Jovem
19.
Nat Commun ; 12(1): 5307, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489465

RESUMO

Prostate cancer is heterogeneous and patients would benefit from methods that stratify those who are likely to respond to systemic therapy. Here, we employ single-cell assays for transposase-accessible chromatin (ATAC) and RNA sequencing in models of early treatment response and resistance to enzalutamide. In doing so, we identify pre-existing and treatment-persistent cell subpopulations that possess regenerative potential when subjected to treatment. We find distinct chromatin landscapes associated with enzalutamide treatment and resistance that are linked to alternative transcriptional programs. Transcriptional profiles characteristic of persistent cells are able to stratify the treatment response of patients. Ultimately, we show that defining changes in chromatin and gene expression in single-cell populations from pre-clinical models can reveal as yet unrecognized molecular predictors of treatment response. This suggests that the application of single-cell methods with high analytical resolution in pre-clinical models may powerfully inform clinical decision-making.


Assuntos
Cromatina/química , DNA de Neoplasias/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Neoplasias/genética , Neoplasias da Próstata/genética , Transcriptoma , Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Linhagem Celular Tumoral , Cromatina/metabolismo , DNA de Neoplasias/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Proteínas de Neoplasias/metabolismo , Nitrilas/uso terapêutico , Feniltioidantoína/uso terapêutico , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Análise de Sobrevida , Sequenciamento Completo do Exoma
20.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(8): 749-752, 2021 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-34365616

RESUMO

OBJECTIVE: To explore the genetic basis for a Chinese patient featuring cleidocranial dysplasia(CCD). METHODS: Genomic DNA was extracted from peripheral blood samples of the patient and his parents. Whole exome sequencing (WES) was carried out for the patient, and suspected variant was verified by Sanger sequencing. RESULTS: WES has identified a missense c.460G>T (p.Val154Phe) (GRCh37/hg19) variant of the RUNX2 gene. The variant was located in the Runt domain, a highly conserved region (PM1); it was not present in either the Genome Aggregation Database or the 1000 Genomes Project (PM2), and was predicted to have a deleterious effect on the gene product by multiple in silico prediction tools (PP3); the clinical phenotype of the patient was highly consistent with that of cleidocranial dysplasia (PP4). Furthermore, the variant was unreported in medical literature and was absent in both parents (PS2). Based on the American College of Medical Genetics and Genomics guidelines, the c.460 G>T variant of RUNX2 gene was predicted to be pathogenic (PS2+PM1+PM2+PP3+PP4). CONCLUSION: The c.460G>T (p.Val154Phe) variant of the RUNX2 gene probably underlay the clinical phenotype in the patient. Above finding has enabled accurate diagnosis and expanded the spectrum of RUNX2 variants.


Assuntos
Displasia Cleidocraniana , China , Displasia Cleidocraniana/genética , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Humanos , Mutação , Sequenciamento Completo do Exoma
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