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1.
Nat Commun ; 10(1): 2985, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278258

RESUMO

Mosaic genetic variants can have major clinical impact. We systematically analyse trio exome sequence data from 4,293 probands from the DDD Study with severe developmental disorders for pathogenic postzygotic mosaicism (PZM) in the child or a clinically-unaffected parent, and use ultrahigh-depth sequencing to validate candidate mosaic variants. We observe that levels of mosaicism for small genetic variants are usually equivalent in both saliva and blood and ~3% of causative de novo mutations exhibit PZM; this is an important observation, as the sibling recurrence risk is extremely low. We identify parental PZM in 21 trios (0.5% of trios), resulting in a substantially increased sibling recurrence risk in future pregnancies. Together, these forms of mosaicism account for 40 (1%) diagnoses in our cohort. Likely child-PZM mutations occur equally on both parental haplotypes, and the penetrance of detectable mosaic pathogenic variants overall is likely to be less than half that of constitutive variants.


Assuntos
Deficiências do Desenvolvimento/genética , Exoma/genética , Mosaicismo , Sequenciamento Completo do Exoma/métodos , Criança , Estudos de Coortes , Deficiências do Desenvolvimento/diagnóstico , Feminino , Testes Genéticos/métodos , Variação Genética , Haplótipos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Herança Materna/genética , Pais , Herança Paterna/genética
2.
BMC Med Genet ; 20(1): 105, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31185933

RESUMO

BACKGROUND: Axenfeld-Rieger syndrome (ARS) is an autosomal dominant genetic disorder that is characterized by specific abnormalities of the anterior segment of the eye. Heterozygous mutations in two developmental transcription factor genes PITX2 and FOXC1 have been identified within ARS patients, accounting for 40 to 70% of cases. Our purpose is to describe clinical and genetic findings in a Chinese family with ARS. METHODS: An ARS family with three affected members was recruited. The patients underwent a series of complete ophthalmologic examinations, general physical examination and dental radiography. DNA samples of proband II-1 were used for targeted exome sequencing of the FOXC1 and PITX2 genes. Sanger sequencing was used to validate the variation in PITX2. Quantitative real-time PCR was carried out to detect the expression of PITX2 in patients and normal controls. RESULTS: All affected members showed iris atrophy, corectopia, shallow anterior chamber, complete or partial angle closure, and advanced glaucoma. In addition, they revealed systemic anomalies, including microdontia, hypodontia, and redundant periumbilical skin. A novel heterozygous frameshift variation, c.515delA, in PITX2 was found in the proband, which might lead to a truncated PITX2 protein (p.Gln172ArgfsX36). Sanger sequencing validated that the variation completely cosegregated with the ARS phenotype among this family, but was absent in 100 unrelated controls. Quantitative real-time PCR analysis revealed that the mRNA expression of PITX2 was significantly decreased in patients compared with that in unrelated normal controls. CONCLUSIONS: PITX2 c.515delA (p.Gln172ArgfsX36) was the genetic etiology of our pedigree. The mutation led to decreased PITX2 gene expression and a truncated mRNA transcript.


Assuntos
Segmento Anterior do Olho/anormalidades , Anormalidades do Olho/genética , Oftalmopatias Hereditárias/genética , Mutação da Fase de Leitura , Predisposição Genética para Doença/genética , Proteínas de Homeodomínio/genética , Fatores de Transcrição/genética , Sequenciamento Completo do Exoma/métodos , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático , China , Anormalidades do Olho/etnologia , Oftalmopatias Hereditárias/etnologia , Saúde da Família , Feminino , Predisposição Genética para Doença/etnologia , Humanos , Masculino , Linhagem , Adulto Jovem
3.
Cancer Sci ; 110(8): 2620-2628, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31152682

RESUMO

Tumor mutational burden (TMB) and mutational signatures reflect the process of mutation accumulation in cancer. However, the significance of these emerging characteristics remains unclear. In the present study, we used whole-exome sequencing to analyze the TMB and mutational signature in solid tumors of 4046 Japanese patients. Eight predominant signatures-microsatellite instability, smoking, POLE, APOBEC, UV, mismatch repair, double-strand break repair, and Signature 16-were observed in tumors with TMB higher than 1.0 mutation/Mb, whereas POLE and UV signatures only showed moderate correlation with TMB, suggesting the extensive accumulation of mutations due to defective POLE and UV exposure. The contribution ratio of Signature 16, which is associated with hepatocellular carcinoma in drinkers, was increased in hypopharynx cancer. Tumors with predominant microsatellite instability signature were potential candidates for treatment with immune checkpoint inhibitors such as pembrolizumab and were found in 2.8% of cases. Furthermore, based on microarray analysis, tumors with predominant signatures were classified into 2 subgroups depending on the expression of immune-related genes reflecting differences in the immune context of the tumor microenvironment. Tumor subpopulations differing in the content of infiltrating immune cells might respond differently to immunotherapeutics. An understanding of cancer characteristics based on TMB and mutational signatures could provide new insights into mutation-driven tumorigenesis.


Assuntos
Carcinogênese/genética , Mutação/genética , Neoplasias/genética , Carcinogênese/patologia , Reparo de Erro de Pareamento de DNA/genética , Reparo do DNA/genética , Genoma Humano/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Japão , Instabilidade de Microssatélites , Neoplasias/patologia , Carga Tumoral/genética , Microambiente Tumoral/genética , Sequenciamento Completo do Exoma/métodos
4.
BMC Cancer ; 19(1): 443, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088516

RESUMO

BACKGROUND: The progress of treatments of childhood acute lymphoblastic leukemia (ALL) has made it possible to reach a survival rate superior to 80%. However, the treatments lead to several long-term adverse effects, including cardiac toxicity. Although studies have reported associations between genetic variants and cardiorespiratory fitness, none has been performed on childhood ALL survivors. METHODS: We performed whole-exome sequencing in 239 childhood ALL survivors from the PETALE cohort. Germline variants (both common and rare) in selected set of genes (N = 238) were analyzed for an association with cardiorespiratory fitness. RESULTS: Our results showed that the common variant in the TTN gene was significantly associated with a low cardiorespiratory fitness level (p = 0.0005) and that the LEPR, IGFBPI and ENO3 genes were significantly associated with a low cardiorespiratory fitness level in female survivors (p ≤ 0.002). Also, we detected an association between the low cardiorespiratory fitness level in participants that were stratified to the "high risk" prognostic group and functionally predicted rare variants in the SLC22A16 gene (p = 0.001). Positive associations between cardiorespiratory fitness level and trainability genes were mainly observed in females. CONCLUSIONS: For the first time, we observed that low cardiorespiratory fitness in childhood ALL survivors can be associated with variants in genes related to subjects' trainability. These findings could allow better childhood ALL patient follow-up tailored to their genetic profile and cardiorespiratory fitness, which could help reduce at least some of the burden of long-term adverse effects of treatments.


Assuntos
Mutação em Linhagem Germinativa , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Sequenciamento Completo do Exoma/métodos , Aptidão Cardiorrespiratória , Criança , Pré-Escolar , Conectina/genética , Feminino , Estudos de Associação Genética , Humanos , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Masculino , Proteínas de Transporte de Cátions Orgânicos/genética , Receptores para Leptina/genética , Sobreviventes
5.
BMC Genomics ; 20(1): 377, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088374

RESUMO

BACKGROUND: Sulforaphane is a natural isothiocyanate available from cruciferous vegetables with multiple characteristics including antioxidant, antitumor and anti-inflammatory effect. Single-molecule real-time (SMRT) sequencing has been used for long-read de novo assembly of plant genome. Here, we investigated the molecular mechanism related to glucosinolates biosynthesis in Chinese kale using combined NGS and SMRT sequencing. RESULTS: SMRT sequencing produced 185,134 unigenes, higher than 129,325 in next-generation sequencing (NGS). NaCl (75 mM), methyl jasmonate (MeJA, 40 µM), selenate (Se, sodium selenite 100 µM), and brassinolide (BR, 1.5 µM) treatment induced 6893, 13,287, 13,659 and 11,041 differentially expressed genes (DEGs) in Chinese kale seedlings comparing with control. These genes were associated with pathways of glucosinolates biosynthesis, including phenylalanine, tyrosine and tryptophan biosynthesis, cysteine and methionine metabolism, and glucosinolate biosynthesis. We found NaCl decreased sulforaphane and glucosinolates (indolic and aliphatic) contents and downregulated expression of cytochrome P45083b1 (CYP83b1), S-alkyl-thiohydroximatelyase or carbon-sulfur lyase (SUR1) and UDP-glycosyltransferase 74B1 (UGT74b1). MeJA increased sulforaphane and glucosinolates contents and upregulated the expression of CYP83b1, SUR1 and UGT74b1; Se increased sulforaphane; BR increased expression of CYP83b1, SUR1 and UGT74b1, and increased glucosinolates contents. The desulfoglucosinolate sulfotransferases ST5a_b_c were decreased by all treatments. CONCLUSIONS: We confirmed that NaCl inhibited the biosynthesis of both indolic and aliphatic glucosinolates, while MeJA and BR increased them. MeJA and BR treatments, conferred the biosynthesis of glucosinolates, and Se and MeJA contributed to sulforaphane in Chinese kale via regulating the expression of CYP83b1, SUR1 and UGT74b1.


Assuntos
Brassica/metabolismo , Perfilação da Expressão Gênica/métodos , Isotiocianatos/metabolismo , Proteínas de Plantas/genética , Acetatos/farmacologia , Brassica/genética , Brassinosteroides/farmacologia , Ciclopentanos/farmacologia , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Oxilipinas/farmacologia , Ácido Selênico/farmacologia , Análise de Sequência de RNA/métodos , Análise de Célula Única , Cloreto de Sódio/farmacologia , Esteroides Heterocíclicos/farmacologia , Sequenciamento Completo do Exoma/métodos
6.
BMC Med Genet ; 20(1): 90, 2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-31126250

RESUMO

BACKGROUND: Hereditary spherocytosis (HS) is a common type of hereditary hemolytic anemia. According to the current diagnostic criteria of HS, patients with a family history of HS, typical clinical features and laboratory investigations could be diagnosed without the requirement of any additional tests, including genetic analysis. However, the clinical heterogeneities incur difficulties in HS diagnosis. We therefore aimed to investigate the application of genetic diagnosis in a family-based cohort. CASE PRESENTATION: In the present Chinese family, two probands sharing similar clinical manifestations, including jaundice, cholelithiasis, splenomegaly and spherocytes, while the clinical features of other family members were inconclusive. Whole-exome sequencing (WES) unexpectedly unveiled two separate disease-causing mutations in the two probands. SPTB R1625X mutation detected in proband D was a de novo mutation; while proband W inherited the SLC4A1 c.G1469A mutation from her mother, which was also inherited by her brother. However, the clinical features of proband W and her mother and brother were discrepant: proband W suffered from significant splenomegaly, jaundice and cholelithiasis, which resulted in cholecystectomy and splenectomy; while her mother and brother's HS were not complicated by cholelithiasis, and their splenomegaly and elevated serum bilirubin were moderate. In addition, additional genomic defects involved with HS-related symptoms have not been detected in this family. CONCLUSIONS: Both genotypes and phenotypes could be heterogeneous in the same HS family. The analysis of pathogenic gene mutations may endeavor to play an indispensable role in the accurate diagnosis and genetic consultation of HS individuals and their family members.


Assuntos
Saúde da Família , Heterogeneidade Genética , Mutação , Esferocitose Hereditária/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , China , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Esferocitose Hereditária/etnologia , Esferocitose Hereditária/patologia , Sequenciamento Completo do Exoma/métodos
7.
Genet Test Mol Biomarkers ; 23(6): 428-432, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31081706

RESUMO

Background: Autosomal recessive congenital ichthyoses (ARCI) are a group of rare nonsyndromic genodermatoses characterized by generalized scaly appearance of the epidermis with markedly impaired cutaneous barriers owing to defects in keratinization related genes. In this study, we ascertained a consanguineous Pakistani family affected with ARCI. Aims: To investigate genetic defect underlying disease phenotype in the affected family. Methods: All available members of the family (affected and unaffected) were sampled. Whole exome sequencing (WES) was performed on DNA of the proband and the data were analyzed for probable pathogenic variants. Segregation of the identified variant was validated by Sanger sequencing. Results: Analysis of the WES data identified a novel nonsense mutation, c.762C>G, in the PNPLA1 (patatin-like phospholipase domain containing 1) gene. The protein product of of this gene is involved in lipid organization during cornified cell envelope formation. The variant is predicted to result in the generation of a premature truncation site at amino acid position 254 (p.Tyr254*). This would result in the loss of a large C-terminal portion of the protein suggesting it to be rendered nonfunctional. In silico protein structure modeling confirmed a detrimental effect of the variation on protein structure. Conclusions: The study supports the evidence for the prevalence of PNPLA1 mutations in distant ethnic groups. Despite the significant number of reported ARCI cases with PNPLA1 variants, a straightforward genotype-phenotype correlation cannot be established.


Assuntos
Ictiose Lamelar/genética , Lipase/genética , Adulto , Idoso , Códon sem Sentido/genética , Grupos Étnicos/genética , Família , Feminino , Genes Recessivos/genética , Humanos , Ictiose Lamelar/metabolismo , Lipase/fisiologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Paquistão , Linhagem , Fenótipo , Sequenciamento Completo do Exoma/métodos
8.
Medicine (Baltimore) ; 98(20): e15692, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31096510

RESUMO

RATIONALE: Hereditary multiple exostoses (HMEs) is an autosomal dominant skeletal disorder. PATIENT CONCERNS: Six probands of the 6 unrelated Han Chinese families were identified as having HME. These patients had exostoses at multiple sites and significantly affected joints malformation and movement. DIAGNOSES: Hereditary multiple exostoses. INTERVENTIONS: To detect the genetic mechanism of HME in 6 unrelated Chinese families, whole-exome sequencing (WES) and multiplex ligation-dependent probe amplification (MLPA) were used after genomic DNA was isolated from peripheral blood leucocytes. Point mutations identified by these methods were verified by Sanger sequencing after PCR amplification. OUTCOMES: Six mutations in the EXT1 and EXT2 genes were identified, including a heterozygous deletion mutation from exon 2 to exon 8 (Family 1), a c.448C>T, p.(Gln150X) heterozygous nonsense mutation (Family 4), a c.1057-2A>T heterozygous splicing substitution (Family 5), and a c.1468dupC, p.(Leu490fs519X) (Family 6) heterozygous duplication mutation in the EXT1 gene in addition to a heterozygous deletion mutation from exon 2 to exon 3 (Family 2) and a c.1197C>G, p.(Tyr399X) heterozygous nonsense mutation (Family 3) in the EXT2 gene. LESSONS: Overall, we identified 5 novel mutations and 1 recurrent mutation in the EXT1 and EXT2 genes in 6 Chinese families with HME. Our findings expand the mutational spectrum of the EXT1 and EXT2 genes and are useful for genetic counseling and prenatal diagnosis.


Assuntos
Exostose Múltipla Hereditária/diagnóstico , Exostose Múltipla Hereditária/genética , Reação em Cadeia da Polimerase Multiplex/métodos , Mutação/genética , Sequenciamento Completo do Exoma/métodos , Adulto , Grupo com Ancestrais do Continente Asiático/etnologia , Criança , Exostose Múltipla Hereditária/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , N-Acetilglucosaminiltransferases , Linhagem , Diagnóstico Pré-Natal/métodos
9.
Cancer Sci ; 110(8): 2431-2441, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31144406

RESUMO

The landscape of genetic alterations in disease models such as transgenic mice or mice with carcinogen-induced tumors has provided a huge amount of information that has shed light on the process of tumorigenesis in human non-small-cell lung cancer (NSCLC). We have previously identified stratifin (SFN) as a potent oncogene, and generated SFN-transgenic (Tg-SPC-SFN+/- ) mice, which express human SFN (hSFN) only in the lung. Here, we have found that carcinogen nicotine-derived nitrosaminoketone (NNK)-induced tumors developing in Tg-SPC-SFN+/- mice show a similar histology to human lung adenocarcinoma and exhibit high hSFN expression. In order to compare the genetic characteristics of Tg-SPC-SFN+/- tumors and human lung adenocarcinoma, the former were subjected to whole-exome sequencing. Interestingly, Tg-SPC-SFN+/- tumors showed the distinct distribution of exonic mutations and high number of mutated genes and transversion. Moreover, Tg-SPC-SFN+/- tumors showed 73 genes that were commonly detected in more than 2 tumors, mutations of which were also found in human lung adenocarcinoma. The expression levels of some of these genes were significantly associated with the clinical outcome of lung adenocarcinoma patients. Additionally, mutated genes in Tg-SPC-SFN+/- tumors were closely associated with key canonical pathways such as PI3K/AKT signaling and apoptosis signaling. These results suggest that SFN overexpression is a universal abnormality in human lung adenocarcinogenesis and Tg-SPC-SFN+/- tumors recapitulate key features of major human lung adenocarcinoma. Therefore, Tg-SPC-SFN+/- mice provide a useful model for clarifying the molecular mechanism underlying lung adenocarcinogenesis.


Assuntos
Proteínas 14-3-3/genética , Adenocarcinoma de Pulmão/induzido quimicamente , Adenocarcinoma de Pulmão/genética , Biomarcadores Tumorais/genética , Carcinógenos/farmacologia , Exorribonucleases/genética , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/genética , Mutação/genética , Células A549 , Animais , Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/induzido quimicamente , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Transgênicos , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/genética , Sequenciamento Completo do Exoma/métodos
10.
Pediatr Cardiol ; 40(5): 950-957, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30993396

RESUMO

Dilated cardiomyopathy (DCM) is characterized by left or bilateral ventricular dilation and systolic dysfunction without rational conditions, which can lead to progressive heart failure and sudden cardiac death. Most of the pathogenic genes have been reported in adult population by locus mapping in familial cases and animal model studies. However, it still remains challenging to decipher the role of genetics in the etiology of pediatric DCM. We applied whole-exome sequencing (WES) for 30 sporadic pediatric DCM subjects and 100 non-DCM local controls. We identified the pathogenic mutations using bioinformatics tools based on genomic strategies synergistically and confirmed mutations by Sanger sequencing. We identified compound heterozygous nonsense mutations in DSP (c.3799C > T, p.R1267X; c.4444G > T, p.E1482X). In sporadic cases, the two heterozygous mutations in XIRP2 were identified. Then we performed an exome-wide association study with 30 case and 100 control subjects. Interestingly, we could not identify TTN truncating variants in all cases. Collectively, we observed a significant risk signal between carriers of TTN deleterious missense variants and DCM risk (odds ratio 4.0, 95% confidence interval 1.1-22.2, p = 3.12 × 10-2). Our observations expanded the spectrum of mutations and were valuable in the pre- and postnatal screening and genetic diagnosis for DCM.


Assuntos
Cardiomiopatia Dilatada/genética , Heterogeneidade Genética , Sequenciamento Completo do Exoma/métodos , Cardiomiopatia Dilatada/diagnóstico , Estudos de Casos e Controles , Criança , Pré-Escolar , China , Códon sem Sentido , Feminino , Humanos , Masculino , Linhagem , Mutação Puntual
11.
Hum Genet ; 138(6): 593-600, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30982135

RESUMO

Postaxial polydactyly (PAP) is a common limb malformation that often leads to cosmetic and functional complications. Molecular evaluation of polydactyly can serve as a tool to elucidate genetic and signaling pathways that regulate limb development, specifically, the anterior-posterior specification of the limb. To date, only five genes have been identified for nonsyndromic PAP: FAM92A, GLI1, GLI3, IQCE and ZNF141. In this study, two Pakistani multiplex consanguineous families with autosomal recessive nonsyndromic PAP were clinically and molecularly evaluated. From both pedigrees, a DNA sample from an affected member underwent exome sequencing. In each family, we identified a segregating frameshift (c.591dupA [p.(Q198Tfs*21)]) and nonsense variant (c.2173A > T [p.(K725*)]) in KIAA0825 (also known as C5orf36). Although KIAA0825 encodes a protein of unknown function, it has been demonstrated that its murine ortholog is expressed during limb development. Our data contribute to the establishment of a catalog of genes important in limb patterning, which can aid in diagnosis and obtaining a better understanding of the biology of polydactyly.


Assuntos
Dedos/anormalidades , Genes Recessivos/genética , Predisposição Genética para Doença/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Polidactilia/genética , Dedos do Pé/anormalidades , Animais , Consanguinidade , Saúde da Família , Feminino , Dedos/patologia , Genótipo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Linhagem , Fenótipo , Polidactilia/patologia , Dedos do Pé/patologia , Sequenciamento Completo do Exoma/métodos
12.
Zhonghua Fu Chan Ke Za Zhi ; 54(4): 221-225, 2019 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-31006186

RESUMO

Objective: To investigate pathogenic genes related to the phenotype of fetus with severely short limbs in the first and second trimester by whole exome sequencing (WES). Methods: Thirteen fetuses with severely short limbs detected by ultrasonography in the first and second trimester admitted in Chinese PLA General Hospital from September 2016 to June 2018 were collected. All cases were performed induced abortion, 6 of which were carried out karyotype analysis of amniotic fluid at the same time. WES and copy number variations (CNV) were performed on specimens from fetal tissues after labor induction. The suspected pathogenic mutations were validated by Sanger sequencing reactions. Results: No abnormal karyotypes or pathological CNV were found. In 10 fetuses, pathogenic or possibly pathogenic mutations were detected in the following genes: COL2A1, FGFR3, COL1A1, COL1A2, DYNC2LI1 and TRIP11, all of which were essential to skeletal development. The diagnostic yield of WES in the fetuses with severe short limbs was 10/13. Conclusions: In the first and second trimester, most of the fetuses with extremely short limbs suffer from monogenic diseases. WES is likely to be a valuable diagnostic testing option for the fetuses with severe short limbs.


Assuntos
Anormalidades Congênitas/genética , Dineínas do Citoplasma , Variações do Número de Cópias de DNA , Desenvolvimento Fetal/genética , Feto/anormalidades , Sequenciamento Completo do Exoma/métodos , Anormalidades Congênitas/diagnóstico , Variações do Número de Cópias de DNA/genética , Feminino , Feto/diagnóstico por imagem , Humanos , Cariotipagem , Gravidez , Primeiro Trimestre da Gravidez , Segundo Trimestre da Gravidez , Ultrassonografia Pré-Natal
13.
PLoS Comput Biol ; 15(4): e1006953, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30986244

RESUMO

Determining the cancer type and molecular subtype has important clinical implications. The primary site is however unknown for some malignancies discovered in the metastatic stage. Moreover liquid biopsies may be used to screen for tumoral DNA, which upon detection needs to be assigned to a site-of-origin. Classifiers based on genomic features are a promising approach to prioritize the tumor anatomical site, type and subtype. We examined the predictive ability of causal (driver) somatic mutations in this task, comparing it against global patterns of non-selected (passenger) mutations, including features based on regional mutation density (RMD). In the task of distinguishing 18 cancer types, the driver mutations-mutated oncogenes or tumor suppressors, pathways and hotspots-classified 36% of the patients to the correct cancer type. In contrast, the features based on passenger mutations did so at 92% accuracy, with similar contribution from the RMD and the trinucleotide mutation spectra. The RMD and the spectra covered distinct sets of patients with predictions. In particular, introducing the RMD features into a combined classification model increased the fraction of diagnosed patients by 50 percentage points (at 20% FDR). Furthermore, RMD was able to discriminate molecular subtypes and/or anatomical site of six major cancers. The advantage of passenger mutations was upheld under high rates of false negative mutation calls and with exome sequencing, even though overall accuracy decreased. We suggest whole genome sequencing is valuable for classifying tumors because it captures global patterns emanating from mutational processes, which are informative of the underlying tumor biology.


Assuntos
Biologia Computacional/métodos , Neoplasias/classificação , Neoplasias/genética , Algoritmos , DNA de Neoplasias/classificação , DNA de Neoplasias/genética , Exoma/genética , Genômica , Humanos , Aprendizado de Máquina , Mutação/genética , Software , Sequenciamento Completo do Exoma/métodos , Sequenciamento Completo do Genoma/métodos
14.
Hum Genet ; 138(6): 625-634, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30963242

RESUMO

Rare heterozygous variants in SMAD6 have been identified as a significant genetic contributor to bicuspid aortic valve-associated thoracic aortic aneurysm on one hand and non-syndromic midline craniosynostosis on the other. In this study, we report two individuals with biallelic missense variants in SMAD6 and a complex cardiac phenotype. Trio exome sequencing in Proband 1, a male who had aortic isthmus stenosis, revealed the homozygous SMAD6 variant p.(Ile466Thr). He also had mild intellectual disability and radio-ulnar synostosis. Proband 2 is a female who presented with a more severe cardiac phenotype with a dysplastic and stenotic pulmonary valve and dilated cardiomyopathy. In addition, she had vascular anomalies, including a stenotic left main coronary artery requiring a bypass procedure, narrowing of the proximal left pulmonary artery and a venous anomaly in the brain. Proband 2 has compound heterozygous SMAD6 missense variants, p.(Phe357Ile) and p.(Ser483Pro). Absence of these SMAD6 variants in the general population and high pathogenicity prediction scores suggest that these variants caused the probands' phenotypes. This is further corroborated by cardiovascular anomalies and appendicular skeletal defects in Smad6-deficient mice. SMAD6 acts as an inhibitory SMAD and preferentially inhibits bone morphogenetic protein (BMP)-induced signaling. Our data suggest that biallelic variants in SMAD6 may affect the inhibitory activity of SMAD6 and cause enhanced BMP signaling underlying the cardiovascular anomalies and possibly other clinical features in the two probands.


Assuntos
Doenças Cardiovasculares/genética , Predisposição Genética para Doença/genética , Mutação de Sentido Incorreto , Proteína Smad6/genética , Alelos , Animais , Doenças Cardiovasculares/patologia , Pré-Escolar , Feminino , Genótipo , Humanos , Masculino , Camundongos , Fenótipo , Sequenciamento Completo do Exoma/métodos
15.
Nat Commun ; 10(1): 1670, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975989

RESUMO

Esophageal squamous cell carcinoma (ESCC) ranks fourth among cancer-related deaths in China due to the lack of actionable molecules. We performed whole-exome and T-cell receptor (TCR) repertoire sequencing on multi-regional tumors, normal tissues and blood samples from 39 ESCC patients. The data revealed 12.8% of ERBB4 mutations at patient level and functional study supported its oncogenic role. 18% of patients with early BRCA1/2 variants were associated with high-level contribution of signature 3, which was validated in an independent large cohort (n = 508). Furthermore, knockdown of BRCA1/2 dramatically increased sensitivity to cisplatin in ESCC cells. 5% of patients harbored focal high-level amplification of CD274 that led to massive expression of PD-L1, and might be more sensitive to immune checkpoint blockade. Finally, we found a tight correlation between genomic and TCR repertoire intra-tumor heterogeneity (ITH). Collectively, we reveal high-level ITH in ESCC, identify several potential actionable targets and may provide novel insight into ESCC treatment.


Assuntos
Antineoplásicos/farmacologia , Carcinogênese/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Regulação Neoplásica da Expressão Gênica , Adulto , Idoso , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , China , Estudos de Coortes , Variações do Número de Cópias de DNA , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas do Esôfago/sangue , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/terapia , Esôfago/patologia , Esôfago/cirurgia , Feminino , Amplificação de Genes , Perfilação da Expressão Gênica , Genômica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Medicina de Precisão/métodos , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/genética , Transcriptoma/genética , Sequenciamento Completo do Exoma/métodos
16.
Gene ; 705: 177-180, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30986449

RESUMO

Congenital nystagmus (CN) is a heterogeneous disease that shows variable clinical features. There are a few mutations that are known to cause CN. Among them, a PAX6 mutation is known to cause CN with an extremely high frequency of aniridia. Here, we report on a family with an autosomal dominant PAX6 mutation, c.214G > A (p.Gly72Ser.), who presented with CN in the absence of aniridia. This study describes detailed clinical findings, including videonystagmography and fundus photography findings and emphasizes the importance of screening for the PAX6 gene in patients who present with CN in the absence of aniridia, as this will further elucidate the known phenotypes of PAX6-related diseases.


Assuntos
Coloboma/patologia , Nistagmo Congênito/patologia , Nervo Óptico/anormalidades , Fator de Transcrição PAX6/genética , Mutação Puntual , Sequenciamento Completo do Exoma/métodos , Pré-Escolar , Coloboma/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Nistagmo Congênito/genética , Disco Óptico/patologia , Nervo Óptico/patologia , Linhagem , Fenótipo , Gravação em Vídeo
17.
Gene ; 705: 109-112, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31028865

RESUMO

Variants of KCNQ4 are one of the most common causes of dominantly inherited nonsyndromic hearing loss. We investigated a consanguineous family in which two individuals had prelignual hearing loss, apparently inherited in a recessive mode. Whole-exome sequencing analyses demonstrated genetic heterogeneity as variants in two different genes segregated with the phenotype in two branches of the family. Members in one branch were homozygous for a pathogenic variant of TMC1. The other two affected individuals were homozygous for a missense pathogenic variant in KCNQ4 c.872C>T; p.(Pro291Leu). These two individuals had prelingual, progressive moderate to severe hearing loss, while a heterozygous carrier had late onset mild hearing loss. Our work demonstrates that p.Pro291L variant is semi-dominantly inherited. This is the first report of semi-dominance of a KCNQ4 variant.


Assuntos
Surdez/genética , Canais de Potássio KCNQ/genética , Mutação de Sentido Incorreto , Sequenciamento Completo do Exoma/métodos , Idade de Início , Consanguinidade , Feminino , Heterogeneidade Genética , Predisposição Genética para Doença , Humanos , Leucina/genética , Masculino , Linhagem , Prolina/genética
18.
Hum Genet ; 138(6): 601-611, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30968251

RESUMO

Facial shape differences are one of the most significant phenotypes in humans. It is affected largely by skull shape. However, research into the genetic basis of the craniofacial morphology has rarely been reported. The present study aimed to identify genetic variants influencing craniofacial morphology in northern Han Chinese through whole-exome sequencing (WES). Phenotypic data of the volunteers' faces and skulls were obtained through three-dimensional CT scan of the skull. A total of 48 phenotypes (35 facial and 13 cranial phenotypes) were used for the bioinformatics analysis. Four genetic loci were identified affecting the craniofacial shapes. The four candidate genes are RGPD3, IGSF3, SLC28A3, and USP40. Four single-nucleotide polymorphism (SNP) site mutations in RGPD3, IGSF3, and USP40 were significantly associated with the skull shape (p < 1×10-6), and three SNP site mutations in RGPD3, IGSF3, and SLC28A3 were significantly associated with the facial shape (p < 1×10-6). The rs62152530 site mutation in the RGPD3 gene may be closely associated with the nasal length, ear length, and alar width. The rs647711 site mutation in the IGSF3 gene may be closely associated with the nasal length, mandibular width, and width between the mental foramina. The rs10868138 site mutation in the SLC28A3 gene may be associated with the nasal length, alar width, width between tragus, and width between the mental foramina. The rs1048603 and rs838543 site mutations in the USP40 gene may be closely associated with the pyriform aperture width. Our findings provide useful genetic information for the determination of face morphology.


Assuntos
Ossos Faciais/metabolismo , Loci Gênicos/genética , Polimorfismo de Nucleotídeo Único , Crânio/metabolismo , Sequenciamento Completo do Exoma/métodos , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , China , Anormalidades Craniofaciais/etnologia , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , Ossos Faciais/anatomia & histologia , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Crânio/anatomia & histologia
19.
Medicine (Baltimore) ; 98(8): e14524, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30813157

RESUMO

RATIONALE: Trio family-based whole exome sequencing (WES) is a powerful tool in the diagnosis of rare neurodevelopmental diseases, even in patients with the unclear diagnosis. There have been previous reports of variants in the phosphatidylinositol glycan anchor biosynthesis class T (PIGT) gene associated with multiple congenital anomalies, with a total of 14 affected individuals across 8 families. PATIENT CONCERNS: An 18-month-old boy of Greek ancestry presented with global developmental delay, generalized tonic-clonic seizures, hypotonia, renal cysts, esotropia, bilateral undescended testes, bilateral vesicoureteric reflux, marked cardiac dextroposition, bilateral talipes equinovarus, and dysmorphic features. DIAGNOSIS: WES revealed 2 compound heterozygous variants in the PIGT gene, c.[494-2A>G]; [547A>C]/p.[Asp122Glyfs*35]; [Thr183Pro]. The splicing mutation was demonstrated to lead to the skipping of exon 4. INTERVENTIONS: Seizures, infections, and other main symptoms were treated. OUTCOMES: The patient died at 2 years of age before the molecular diagnosis was achieved. Genetic counseling has been offered to the family. LESSONS: Most of the clinical features of the patient are in agreement with the previously described PIGT cases corroborating the usefulness of WES as a diagnostic tool.


Assuntos
Anormalidades Múltiplas/genética , Aciltransferases/genética , Técnicas de Cultura de Células , Deficiências do Desenvolvimento/genética , Diagnóstico Diferencial , Evolução Fatal , Humanos , Lactente , Masculino , Hipotonia Muscular/genética , Mutação , Reação em Cadeia da Polimerase em Tempo Real , Convulsões/genética , Síndrome , Sequenciamento Completo do Exoma/métodos
20.
Curr Protoc Hum Genet ; 101(1): e83, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30849219

RESUMO

With the advent of Next Generation Sequencing (NGS) technologies, whole genome and whole exome DNA sequencing has become affordable for routine genetic studies. Coupled with improved genotyping arrays and genotype imputation methodologies, it is increasingly feasible to obtain rare genetic variant information in large datasets. Such datasets allow researchers to gain a more complete understanding of the genetic architecture of complex traits caused by rare variants. State-of-the-art statistical methods for the statistical genetics analysis of sequence-based association, including efficient algorithms for association analysis in biobank-scale datasets, gene-association tests, meta-analysis, fine mapping methods that integrate functional genomic dataset, and phenome-wide association studies (PheWAS), are reviewed here. These methods are expected to be highly useful for next generation statistical genetics analysis in the era of precision medicine. © 2019 by John Wiley & Sons, Inc.


Assuntos
Predisposição Genética para Doença , Genoma Humano/genética , Herança Multifatorial/genética , Algoritmos , Estudo de Associação Genômica Ampla/métodos , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Sequenciamento Completo do Exoma/métodos , Sequenciamento Completo do Genoma/métodos
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