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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(8): 813-816, 2019 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-31400135

RESUMO

OBJECTIVE: To carry out prenatal diagnosis for a fetus with ultrasonographic abnormality. METHODS: Chromosomal karyotyping and array comparative genomic hybridization (array-CGH) analysis were applied for the diagnosis. Peripheral blood samples were also taken from the parents for chromosome karyotyping analysis. RESULTS: The fetal karyotype showed additional material of unknown-origin attached to Yq. Array CGH analysis confirmed that the material was derived from 3q22.1q29. The father was found to carry a balanced translocation 46, X, t(Y;3)(q12;q23) (which was diagnosed as 46,XY,Y≥18 elsewhere), whilst the mother was found to be normal. CONCLUSION: 3q partial trisomy may present as malformation of multiple systems. Combination of chromosome karyotyping and array-CGH can provide reliable diagnosis for fetuses with abnormalities by ultrasonography.


Assuntos
Cromossomos Humanos Par 3/genética , Diagnóstico Pré-Natal , Trissomia , Hibridização Genômica Comparativa , Feminino , Feto , Humanos , Cariotipagem , Masculino , Gravidez
2.
BMC Cancer ; 18(1): 1262, 2018 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-30558566

RESUMO

BACKGROUND: Ocular melanoma is a rare but often deadly malignancy that arises in the uvea (commonest primary site), conjunctiva or the orbit. Primary orbital melanoma (POM) is exceedingly rare, with approximately 60 cases reported to date. Despite recent advances in our understanding of the genetics of primary uveal and conjunctival melanomas, this information is lacking for POM. METHODS: DNA was extracted from 12 POM tissues, with matched germline DNA (where available). MLPA was conducted to detect chromosomal alterations and Sanger sequencing used to identify point mutations in candidate melanoma driver genes (BRAF, NRAS, KRAS, GNA11, GNAQ), and other genes implicated in melanoma prognosis (EIF1AX, SF3B1). Immunohistochemistry was performed to analyse BAP1 nuclear expression. RESULTS: MLPA detected copy number alterations in chromosomes 1p, 3, 6 and 8. Sequencing of melanoma driver genes revealed GNAQ (p.Q209L) mutations in two samples; although it is possible that these samples represent extraocular spread of an occult uveal melanoma. A recurrent mutation in SF3B1 (p.R625H) was observed in indolent, but not aggressive, tumours; a mutation in EIF1AX (p.N4S) was detected in one patient with non-aggressive disease. CONCLUSIONS: EIF1AX and SF3B1 mutations appear have a role in determining the clinical course of POM and detection of these changes could have clinical significance. Further in depth analysis of this rare group using differing 'omic technologies will provide novel insights into tumour pathogenesis.


Assuntos
Fator de Iniciação 1 em Eucariotos/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Melanoma/genética , Mutação , Neoplasias Orbitárias/genética , Fosfoproteínas/genética , Fatores de Processamento de RNA/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 6/genética , Cromossomos Humanos Par 8/genética , Variações do Número de Cópias de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex , Análise de Sequência de DNA
3.
Genes Chromosomes Cancer ; 57(8): 387-400, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29689622

RESUMO

Uveal melanoma (UM) exhibits recurring chromosomal abnormalities and gene driver mutations, which are related to tumor evolution/progression. Almost half of the patients with UM develop distant metastases, predominantly to the liver, and so far there are no effective adjuvant therapies. An accurate UM genetic profile could assess the individual patient's metastatic risk, and provide the basis to determine an individualized targeted therapeutic strategy for each UM patient. To investigate the presence of specific chromosomal and gene alterations, BAP1 protein expression, and their relationship with distant progression free survival (DPFS), we analyzed tumor samples from 63 UM patients (40 men and 23 women, with a median age of 64 years), who underwent eye enucleation by a single cancer ophthalmologist from December 2005 to June 2016. UM samples were screened for the presence of losses/gains in chromosomes 1p, 3, 6p, and 8q, and for mutations in GNAQ, GNA11, BAP1, SF3B1, and EIF1AX. BAP1 protein expression was detected by immunohistochemistry (IHC). Multivariate analysis showed that the presence of monosomy 3, 8q gain, and loss of BAP1 protein were significantly associated to DPFS, while BAP1 gene mutation was not, mainly due to the presence of metastatic UM cases with negative BAP1 IHC and no BAP1 mutation detected by Sanger sequencing. Loss of BAP1 protein expression and monosomy 3 represent the strongest predictors of metastases, and may have important implications for implementation of patient surveillance, properly designed clinical trials enrollment, and adjuvant therapy.


Assuntos
Aberrações Cromossômicas , Melanoma/genética , Mutação , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Neoplasias Uveais/genética , Idoso , Deleção Cromossômica , Cromossomos Humanos Par 3/genética , Análise Mutacional de DNA , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Melanoma/metabolismo , Melanoma/mortalidade , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Transcriptoma , Proteínas Supressoras de Tumor/biossíntese , Ubiquitina Tiolesterase/biossíntese , Neoplasias Uveais/metabolismo , Neoplasias Uveais/mortalidade
4.
Biochem Cell Biol ; 96(2): 161-166, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29533680

RESUMO

Fetal alcohol spectrum disorder (FASD) is characterized by a combination of neurological, developmental, and congenital defects that may occur as a consequence of prenatal alcohol exposure. Earlier reports showed that large chromosomal anomalies may link to FASD. Here, we examined the prevalence and types of copy number variations (CNVs) in FASD cases previously diagnosed by a multidisciplinary FASD team in sites across Canada. We genotyped 95 children with FASD and 87 age-matched, typically developing controls on the Illumina Human Omni2.5 SNP (single nucleotide polymorphisms) array platform. We compared their CNVs with those of 10 851 population controls to identify rare CNVs (<0.1% frequency), which may include large unbalanced chromosomal abnormalities, that might be relevant to FASD. In 12/95 (13%) of the FASD cases, rare CNVs were found that impact potentially clinically relevant developmental genes, including the CACNA1H involved in epilepsy and autism, the 3q29 deletion disorder, and others. Our results show that a subset of children diagnosed with FASD have chromosomal deletions and duplications that may co-occur or explain the neurodevelopmental impairments in a diagnosed cohort of FASD individuals. Children suspected to have FASD with or without sentinel facial features of fetal alcohol syndrome and neurodevelopmental delays should potentially be evaluated by a clinical geneticist and possibly have genetic investigations as appropriate to exclude other etiologies.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 3/genética , Transtornos do Espectro Alcoólico Fetal/genética , Dosagem de Genes , Polimorfismo de Nucleotídeo Único , Criança , Pré-Escolar , Feminino , Humanos , Masculino
5.
PLoS One ; 13(3): e0194044, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29558500

RESUMO

Chronic kidney disease (CKD) is an important social health problem characterized by a decrease in the kidney glomerular filtration rate (GFR). In this study, we analyzed genome-wide association studies for kidney disease-related traits using data from a Korean adult health screening cohort comprising 7,064 participants. Kidney disease-related traits analyzed include blood urea nitrogen (BUN), serum creatinine, estimated GFR, and uric acid levels. We detected two genetic loci (SLC14A2 and an intergenic region) and 8 single nucleotide polymorphisms (SNPs) associated with BUN, 3 genetic loci (BCAS3, C17orf82, ALDH2) and 6 SNPs associated with serum creatinine, 3 genetic loci (BCAS3, C17orf82/TBX2, LRP2) and 7 SNPs associated with GFR, and 14 genetic loci (3 in ABCG2/PKD2, 2 in SLC2A9, 3 in intergenic regions on chromosome 4; OTUB1, NRXN2/SLC22A12, CDC42BPG, RPS6KA4, SLC22A9, and MAP4K2 on chromosome 11) and 84 SNPs associated with uric acid levels. By comparing significant genetic loci associated with serum creatinine levels and GFR, rs9895661 in BCAS3 and rs757608 in C17orf82 were simultaneously associated with both traits. The SNPs rs11710227 in intergenic regions on chromosome 3 showing significant association with BUN is newly discovered. Genetic variations of multiple gene loci are associated with kidney disease-related traits, and differences in associations between kidney disease-related traits and genetic variation are dependent on the population. The meanings of the mutations identified in this study will need to be reaffirmed in other population groups in the future.


Assuntos
Loci Gênicos/genética , Predisposição Genética para Doença/genética , Insuficiência Renal Crônica/genética , Adulto , Nitrogênio da Ureia Sanguínea , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 4/genética , Creatinina/sangue , Feminino , Estudo de Associação Genômica Ampla/métodos , Taxa de Filtração Glomerular/genética , Humanos , Rim/patologia , Testes de Função Renal/métodos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Insuficiência Renal Crônica/sangue , Seul , Ácido Úrico/sangue
6.
Pathol Res Pract ; 214(6): 919-923, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29496305

RESUMO

Juvenile myelomonocytic leukemia (JMML) is a rare aggressive childhood leukemia characterized by an excess proliferation of cells of granulocytic and monocytic lineages. The WHO classifies JMML with the myelodysplastic/myeloproliferative neoplasms. Myelodysplasia in JMML is usually minimal to mild. Auer rods have never been reported in JMML. We present a 2-year-old boy with splenomegaly, leukocytosis, thrombocytopenia, anemia, and excess myeloblasts with easily seen Auer rods, and marked dysgranulopoiesis and dyserythropoiesis. Conventional cytogenetic analysis showed a sole abnormality of t(3;5)(q25;q35). Microarray analysis showed a terminal 21 Mb region of copy-neutral loss of heterozygosity on 19q. Disease-related somatic NRAS mutation was detected. This case represents an unusual JMML with Auer rods and marked myelodysplasia. These unusual histopathologic features may be related to the t(3;5)(q25;q35). A t(3;5) with variable breakpoints has been reported in a small proportion of acute myeloid leukemias and myelodysplastic syndromes. To our knowledge, this is the first JMML case reported with this translocation.


Assuntos
Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 5/genética , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/patologia , Translocação Genética/genética , Pré-Escolar , Humanos , Masculino
7.
Gene ; 656: 86-94, 2018 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-29496554

RESUMO

Congenital hypoplastic bone marrow failure is a rare condition in neonates. The genetics and mechanisms behind are largely obscure. Here we characterize a neonate presenting with congenital thrombocytopenia and anemia. During the first 2-4 weeks after birth the neonate developed severe neutropenia while the lymphoid lineages were unaffected. The neonate was without dysmorphic signs. A de novo mono-allelic constitutional microdeletion of 175.1 kb at 3q26.2 affecting exon 2 of MECOM, involving MDS1 but not EVI1, was identified as the only copy number alteration by oligo-based array-CGH analysis. Expression analysis showed profoundly reduced expression of multiple MECOM transcripts in the bone marrow cells. Whole exome sequencing detected no pathogenic mutations in genes known to be associated with inherited bone marrow failure syndromes. The patient was successfully treated with hematopoietic stem cell transplantation at 5 months of age. Interstitial deletions encompassing the 3q26.2 region are very rare. A literature search revealed two previous cases with microdeletions involving this region, and the cases were associated with congenital thrombocytopenia and anemia, but unaffected lymphopoiesis. Together these data indicate that MECOM may be important for normal myeloid hematopoiesis in humans but dispensable for lymphoid differentiation. We suggest that partial deletion in MECOM may be a primary event associated with congenital pancytopenia.


Assuntos
Anemia Aplástica/genética , Anemia Hipoplástica Congênita/genética , Doenças da Medula Óssea/genética , Deleção Cromossômica , Cromossomos Humanos Par 3/genética , Hemoglobinúria Paroxística/genética , Proteína do Locus do Complexo MDS1 e EVI1/genética , Anemia Aplástica/patologia , Doenças da Medula Óssea/patologia , Variações do Número de Cópias de DNA , Deleção de Genes , Hemoglobinúria Paroxística/patologia , Humanos , Recém-Nascido , Masculino , Linhagem , Trombocitopenia/congênito , Trombocitopenia/genética
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 35(1): 96-99, 2018 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-29419871

RESUMO

OBJECTIVE To assess the value of whole genome sequencing for the identification of de novo structural chromosomal abnormalities. METHODS Whole genome sequencing was utilized to analyze a boy with a peripheral blood karyotype of 46,XY,ins(3)(q21p13p21). The patient manifested with ocular abnormalities including blepharophimosis and ptosis. RESULTS Whole genome sequencing suggested a fragmentation of chromosome 3 (from position 55 473 257 to 78 341 929) has been inserted into between 136 876 730 to 138 643 831, and the breakpoints have occurred in the intergenic region. Meanwhile, there was a deletion between 138 643 831 and 138 694 476. This region contains FOXL2, a pathogenic gene associated with blepharophimosis-ptosis-epicanthus inversus syndrome. CONCLUSION De novo structural chromosomal abnormalities may be caused by novel breakpoints or microdeletion flanking the deletion region. To confirm its pathogenic nature, a mutation needs to be assessed at both genetic and genomic levels, for which whole genome sequencing is a good option.


Assuntos
Blefarofimose/genética , Deleção Cromossômica , Cromossomos Humanos Par 3/genética , Anormalidades da Pele/genética , Anormalidades Urogenitais/genética , Sequenciamento Completo do Genoma/métodos , Proteína Forkhead Box L2/genética , Deleção de Genes , Humanos , Lactente , Cariotipagem , Masculino
10.
Acta Ophthalmol ; 96(1): 31-38, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28444874

RESUMO

PURPOSE: To evaluate clinico-pathological and molecular prognostic factors in a well-defined series of posterior uveal melanoma (UM) with focus on chromosomal aberrations and mutations in the GNAQ, GNA11 and BRCA1-associated protein 1 (BAP1) genes. METHODS: Formalin-fixed paraffin-embedded (FFPE) tissue samples were obtained from 50 consecutive eyes enucleated for UM between 1993 and 2005. The material was tested for loss of chromosome 3 and gain of chromosome 8q gene signatures by selective molecular gene markers using multiplex ligation-dependent probe amplification (MLPA), and for DNA mutations in the GNAQ, GNA11 and BAP1 genes. RESULTS: After a mean follow-up of 83 months (range, 8-205 months), 21 patients had died of metastatic UM and 16 patients of other causes. Tumour diameter, ciliary body involvement, mixed/epithelioid cell types, mitotic index, Ki-67 proliferation index, loss of chromosome 3 and gain of chromosome 8q showed statistically significant associations with metastatic disease. There were no significant differences in the prevalence of GNAQ and GNA11 mutations between patients with or without metastatic disease. Mutational analysis of the BAP1 gene was performed in 32 primary UM and in five UM liver metastases. Nine different BAP1 missense mutations were identified. BAP1 mutations were not more common in metastasizing than in nonmetastasizing UM. CONCLUSION: The molecular gene markers showing loss of chromosome 3 and gain of 8q gene signatures were associated with an increased risk of metastatic disease. BRCA1-associated protein 1 (BAP1) gene mutation status had no prognostic significance. The frequency and spectrum of BAP1 mutations in UM may be more dependent on ethnicity and demographic variables than hitherto considered.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 3/genética , DNA de Neoplasias/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Melanoma/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Neoplasias Uveais/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Análise Mutacional de DNA , Feminino , Seguimentos , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Humanos , Masculino , Melanoma/metabolismo , Melanoma/secundário , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex , Mutação , Metástase Neoplásica , Prognóstico , Estudos Retrospectivos , Fatores de Tempo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/metabolismo , Úvea/metabolismo , Úvea/patologia , Neoplasias Uveais/metabolismo , Neoplasias Uveais/secundário , Adulto Jovem
11.
Acta Ophthalmol ; 96(3): 251-256, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29091347

RESUMO

PURPOSE: To assess layer- and location-specific retinal thickness deficits in autosomal dominant optic atrophy (ADOA) using Spectralis SD-OCT. METHODS: This cross-sectional study included 41 ADOA patients with OPA1 exon 28 (2826delT) mutation [age, 8.6-83.5 years; best-corrected visual acuity (BCVA), 8-89 Early Treatment Diabetic Retinopathy Study (ETDRS) letters] and 55 mutation-free first-degree relatives as healthy controls (age, 8.9-68.7; BCVA, 80-99). Participants underwent routine examination and optical coherence tomography (OCT) with segmentation of the whole retina, inner retinal layers (IRL) and outer retinal layers (ORL). Individual segmentation was performed of the perifoveal retinal nerve fibre layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), retinal pigment epithelium (RPE) and the peripapillary RNFL. Combinations of layers and sectors were tested for their diagnostic significance. Only right eye data are presented. Statistical analysis was adjusted for age, gender, spherical equivalent, axial length and family clustering in a mixed model analysis. RESULTS: The perifoveal RNFL, GCL, IPL and the peripapillary RNFL were all significantly thinner in ADOA patients than in healthy controls (p < 0.0001). No statistical difference was found for other layers. The most prominent and diagnostically most valuable deficit was found in the GCL (-49.9%) in the 'nasal inner macula' (NIM) sector (-63%). Attenuation of the peripapillary RNFL was most significant in the temporal sector (-58.4%). CONCLUSION: In ADOA, retinal ganglion cells are most prominently reduced in the nasal perifoveal area of the GCL, which together with the temporal peripapillary RNFL area serves as the strongest diagnostic OCT marker.


Assuntos
Macula Lutea/patologia , Fibras Nervosas/patologia , Atrofia Óptica Autossômica Dominante/diagnóstico , Células Ganglionares da Retina/patologia , Tomografia de Coerência Óptica/métodos , Acuidade Visual , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Cromossomos Humanos Par 3/genética , Estudos Transversais , Análise Mutacional de DNA , Éxons , Feminino , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Atrofia Óptica Autossômica Dominante/genética , Atrofia Óptica Autossômica Dominante/fisiopatologia , Adulto Jovem
12.
J Comp Neurol ; 526(1): 59-79, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-28856687

RESUMO

Familial clustering of schizophrenia (SCZ), bipolar disorder (BPD), and major depressive disorder (MDD) was systematically reported (Aukes et al, Genet Med 2012, 14, 338-341) and convergent evidence from genetics, symptomatology, and psychopharmacology imply that there are intrinsic connections between these three major psychiatric disorders, for example, any two or even three of these disorders could co-exist in some families. A total of 60, 838 single-nucleotide polymorphisms (SNPs) on chromosome 3 were genotyped by Affymetrix Genome-Wide Human SNP array 6.0 on 119 SCZ, 253 BPD (type-I), 177 MDD patients and 1,000 controls. The population of Shandong province was formed in 14 century and believed that it belongs to homogenous population. Associated SNPs were systematically revealed and outstanding susceptibility genes (CADPS, GRM7,KALRN, LSAMP, NLGN1, PRICKLE2, ROBO2) were identified. Unexpectedly, flanking genes for the associated SNPs distinctive for BPD and/or MDD were replicated in an enlarged cohort of 986 SCZ patients. The evidence from this chromosome 3 analysis supports the notion that both of bipolar and MDD might be subtypes of schizophrenia rather than independent disease entity. Also, a similar finding was detected on chromosome 5, 6, 7, and 8 (Chen et al. Am J Transl Res 2017;9 (5):2473-2491; Curr Mol Med 2016;16(9):840-854; Behav Brain Res 2015;293:241-251; Mol Neurobiol 2016. doi: 10.1007/s12035-016-0102-1). Furthermore, PRICKLE2 play an important role in the pathogenesis of three major psychoses in this population.


Assuntos
Transtorno Bipolar/genética , Cromossomos Humanos Par 3/genética , Transtorno Depressivo Maior/genética , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/genética , Adulto , Proteínas de Ligação ao Cálcio/genética , Moléculas de Adesão Celular Neuronais/genética , Estudos de Coortes , Feminino , Proteínas Ligadas por GPI/genética , Perfilação da Expressão Gênica , Predisposição Genética para Doença/genética , Genótipo , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Proteínas com Domínio LIM/genética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Serina-Treonina Quinases/genética , Receptores Imunológicos/genética , Receptores de Glutamato Metabotrópico/genética , Proteínas de Transporte Vesicular/genética , Adulto Jovem
13.
Exp Mol Pathol ; 103(3): 249-254, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29122566

RESUMO

The genetic status of candidate tumor suppressor genes (TSGs) at chromosome 3p has not yet been elucidated in intrahepatic cholangiocarcinoma (iCCA). Herein, we retrospectively investigated 32 fresh iCCA case samples from a single medical institution to clarify mutations of 11 TSGs by next-generation sequencing. Validation of the mutations was performed on the MassARRAY platform or by high-resolution melting curve analysis. We then integrated the gene mutations into copy number alterations at chromosome 3p that had been generated in a previous study using the same fresh iCCA samples, and correlated the integration results with the clinicopathologic features. Nine of the 32 (28.1%) iCCA patients had gene mutations at chromosome 3p, totaling 11 mutations across five genes. Those included five (15.6%) BAP1 mutations, two each (6.3%) of CACNA2D3 and RASSF1 mutations, and one each (3.1%) of ATG7 and PLCD1 mutations. Six (18.8%) cases had concurrent loss of chromosome 3p and gene mutations. Patients with TSG mutations had shorter disease-free and survival times than those without the mutations. Our data showed that iCCA patients with TSG mutations at chromosome 3p faced an adverse prognosis. BAP1 was the common target of mutational inactivation and may be a principal driver of 3p21 losses.


Assuntos
Proteína 7 Relacionada à Autofagia/genética , Canais de Cálcio/genética , Colangiocarcinoma/genética , Fosfolipase C delta/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Adulto , Idoso , Colangiocarcinoma/patologia , Cromossomos Humanos Par 3/genética , Feminino , Genes Supressores de Tumor , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação
14.
Nat Commun ; 8(1): 744, 2017 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-28963451

RESUMO

There are few examples of robust associations between rare copy number variants (CNVs) and complex continuous human traits. Here we present a large-scale CNV association meta-analysis on anthropometric traits in up to 191,161 adult samples from 26 cohorts. The study reveals five CNV associations at 1q21.1, 3q29, 7q11.23, 11p14.2, and 18q21.32 and confirms two known loci at 16p11.2 and 22q11.21, implicating at least one anthropometric trait. The discovered CNVs are recurrent and rare (0.01-0.2%), with large effects on height (>2.4 cm), weight (>5 kg), and body mass index (BMI) (>3.5 kg/m2). Burden analysis shows a 0.41 cm decrease in height, a 0.003 increase in waist-to-hip ratio and increase in BMI by 0.14 kg/m2 for each Mb of total deletion burden (P = 2.5 × 10-10, 6.0 × 10-5, and 2.9 × 10-3). Our study provides evidence that the same genes (e.g., MC4R, FIBIN, and FMO5) harbor both common and rare variants affecting body size and that anthropometric traits share genetic loci with developmental and psychiatric disorders.Individual SNPs have small effects on anthropometric traits, yet the impact of CNVs has remained largely unknown. Here, Kutalik and co-workers perform a large-scale genome-wide meta-analysis of structural variation and find rare CNVs associated with height, weight and BMI with large effect sizes.


Assuntos
Estatura/genética , Peso Corporal/genética , Grupo com Ancestrais do Continente Europeu/genética , Antropometria , Índice de Massa Corporal , Tamanho Corporal/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 18/genética , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 7/genética , Variações do Número de Cópias de DNA , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fenótipo , Relação Cintura-Quadril
15.
Am J Med Genet A ; 173(12): 3165-3171, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28905509

RESUMO

Although rare, 3p microdeletion cases have been well described in the clinical literature. The clinical phenotype includes; intellectual disability (ID), growth retardation, facial dysmorphism, and cardiac malformations. Advances in chromosome microarray (CMA) testing narrowed the 3p25 critical region to a 124 kb region, and recent Whole Exome Sequencing (WES) studies have suggested that the SETD5 gene contributes significantly to the 3p25 phenotype. Loss-of-Function (LoF) variants in SETD5 are now considered a likely cause of ID. We report here a patient with a frameshift LoF variant in exon 12 of SETD5. This patient has features overlapping with other patients described with LoF SETD5 variants to include; similar facial morphology, feeding difficulties, ID, behavioral abnormalities and leg length discrepancy. In addition, he presents with an aberrant blind ending bronchus. This report adds to publications describing intragenic mutations in SETD5 and supports the assertion that de novo LoF mutations in SETD5 present with an overlapping but distinct phenotype in comparison with 3p25 microdeletion syndromes.


Assuntos
Brônquios/anormalidades , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Mutação com Perda de Função , Metiltransferases/genética , Criança , Deleção Cromossômica , Cromossomos Humanos Par 3/genética , Estudos de Coortes , Deficiências do Desenvolvimento/diagnóstico , Éxons/genética , Mutação da Fase de Leitura , Heterozigoto , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Fenótipo
16.
Adv Exp Med Biol ; 1051: 139-168, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28815513

RESUMO

The distribution of nucleotide P2Y receptors across different tissues suggests that they fulfil key roles in a number of physiological and pathological conditions. P2Y13 is one of the latest P2Y receptors identified, a novel member of the Gi-coupled P2Y receptor subfamily that responds to ADP, together with P2Y12 and P2Y14. Pharmacological studies drew attention to this new ADP receptor, with a pharmacology that overlaps that of P2Y12 receptors but with unique features and roles. The P2RY12-14 genes all reside on human chromosome 3 at 3q25.1 and their strong sequence homology supports their evolutionary origin through gene duplication. Polymorphisms of P2Y13 receptors have been reported in different human populations, yet their consequences remain unknown. The P2Y13 receptor is versatile in its signalling, extending beyond the canonical signalling of a Gi-coupled receptor. Not only can it couple to different G proteins (Gs/Gq) but the P2Y13 receptor can also trigger several intracellular pathways related to the activation of MAPKs (mitogen-activated protein kinases) and the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3 axis. Moreover, the availability of P2Y13 receptor knockout mice has highlighted the specific functions in which it is involved, mainly in the regulation of cholesterol and glucose metabolism, bone homeostasis and aspects of central nervous system function like pain transmission and neuroprotection. This review summarizes our current understanding of this elusive receptor, not only at the pharmacological and molecular level but also, in terms of its signalling properties and specific functions, helping to clarify the involvement of P2Y13 receptors in pathological situations.


Assuntos
Sistema de Sinalização das MAP Quinases , Polimorfismo Genético , Receptores Purinérgicos P2 , Animais , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 3/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Camundongos , Camundongos Knockout , Receptores Purinérgicos P2/genética , Receptores Purinérgicos P2/metabolismo , Relação Estrutura-Atividade
19.
Mod Pathol ; 30(11): 1603-1612, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28731045

RESUMO

Clear cell renal cell carcinoma is by far the most common form of kidney cancer; however, a number of histologically similar tumors are now recognized and considered distinct entities. The Cancer Genome Atlas published data set was queried (http://cbioportal.org) for clear cell renal cell carcinoma tumors lacking VHL gene mutation and chromosome 3p loss, for which whole-slide images were reviewed. Of the 418 tumors in the published Cancer Genome Atlas clear cell renal cell carcinoma database, 387 had VHL mutation, copy number loss for chromosome 3p, or both (93%). Of the remaining, 27/31 had whole-slide images for review. One had 3p loss based on karyotype but not sequencing, and three demonstrated VHL promoter hypermethylation. Nine could be reclassified as distinct or emerging entities: translocation renal cell carcinoma (n=3), TCEB1 mutant renal cell carcinoma (n=3), papillary renal cell carcinoma (n=2), and clear cell papillary renal cell carcinoma (n=1). Of the remaining, 6 had other clear cell renal cell carcinoma-associated gene alterations (PBRM1, SMARCA4, BAP1, SETD2), leaving 11 specimens, including 2 high-grade or sarcomatoid renal cell carcinomas and 2 with prominent fibromuscular stroma (not TCEB1 mutant). One of the remaining tumors exhibited gain of chromosome 7 but lacked histological features of papillary renal cell carcinoma. Two tumors previously reported to harbor TFE3 gene fusions also exhibited VHL mutation, chromosome 3p loss, and morphology indistinguishable from clear cell renal cell carcinoma, the significance of which is uncertain. In summary, almost all clear cell renal cell carcinomas harbor VHL mutation, 3p copy number loss, or both. Of tumors with clear cell histology that lack these alterations, a subset can now be reclassified as other entities. Further study will determine whether additional entities exist, based on distinct genetic pathways that may have implications for treatment.


Assuntos
Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Cromossomos Humanos Par 3/genética , Dosagem de Genes , Humanos , Mutação , Proteína Supressora de Tumor Von Hippel-Lindau/genética
20.
Exp Mol Pathol ; 103(1): 14-25, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28625614

RESUMO

We studied an adult with de novo acute monocytic leukemia and a dismal outcome where her leukemic cells harbored an acquired rare jumping translocation (JT). We used oligo-based array CGH (oaCGH) analysis, fluorescence in situ hybridization (FISH), and 24-color karyotyping to enhance the characterization of the JT. G-banding detected a JT involving the 3q13.3-qter chromosomal segment and the recipient chromosomal regions 17p, 8q, and 15q. Each clone with JT was associated with trisomy 8. oaCGH analysis revealed an additional submicroscopic deletion in 3q13.31 as well as small subtelomeric duplications on several chromosomes. Locus-specific FISH with BAC-based probes from the 3q13.31-q13.32 region showed great heterogeneity. Telomere FISH revealed significantly reduced telomeric content in the aberrant cells with JT compared with cytogenetically normal cells at diagnosis and in normal cells at complete remission. A literature search revealed two previous de novo AML-M5 cases of JT involving the 3q13.3-qter chromosomal segment and concomitant trisomy 8. In addition, a case with an unbalanced der(Y)t(Y;3)(q12;q13.31) and additional trisomy 8 was previously reported in a patient with de novo AML-M5. All of these cases had a dismal outcome. In the present case, and in the der(Y)t(Y;3) case, a concurrent submicroscopic deletion at 3q13.31 was observed affecting the TUSC7 gene. Duplication of 3q13.31-qter might be a non-random chromosomal abnormality with concomitant submicroscopic deletion at 3q13.31 occurring in rare cases of acute monocytic leukemia, being associated with adverse prognosis. The impact of shortened telomeres in forming the JT is reviewed.


Assuntos
Cromossomos Humanos Par 3/genética , Leucemia Monocítica Aguda/genética , Translocação Genética , Idoso , Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos Par 8/genética , Clonagem Molecular , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Leucemia Monocítica Aguda/diagnóstico , Prognóstico , Trissomia/genética
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