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1.
PLoS Negl Trop Dis ; 14(6): e0008373, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32479541

RESUMO

BACKGROUND: Atypical enteropathogenic Escherichia coli (aEPEC) are one of the most frequent intestinal E. coli pathotypes isolated from diarrheal patients in Brazil. Isolates of aEPEC contain the locus of enterocyte effacement, but lack the genes of the bundle-forming pilus of typical EPEC, and the Shiga toxin of enterohemorrhagic E. coli (EHEC). The objective of this study was to evaluate the phylogeny and the gene content of Brazilian aEPEC genomes compared to a global aEPEC collection. METHODOLOGY: Single nucleotide polymorphism (SNP)-based phylogenomic analysis was used to compare 106 sequenced Brazilian aEPEC with 221 aEPEC obtained from other geographic origins. Additionally, Large-Scale BLAST Score Ratio was used to determine the shared versus unique gene content of the aEPEC studied. PRINCIPAL FINDINGS: Phylogenomic analysis demonstrated the 106 Brazilian aEPEC were present in phylogroups B1 (47.2%, 50/106), B2 (23.6%, 25/106), A (22.6%, 24/106), and E (6.6%, 7/106). Identification of EPEC and EHEC phylogenomic lineages demonstrated that 42.5% (45/106) of the Brazilian aEPEC were in four of the previously defined lineages: EPEC10 (17.9%, 19/106), EPEC9 (10.4%, 11/106), EHEC2 (7.5%, 8/106) and EPEC7 (6.6%, 7/106). Interestingly, an additional 28.3% (30/106) of the Brazilian aEPEC were identified in five novel lineages: EPEC11 (14.2%, 15/106), EPEC12 (4.7%, 5/106), EPEC13 (1.9%, 2/106), EPEC14 (5.7%, 6/106) and EPEC15 (1.9%, 2/106). We identified 246 genes that were more frequent among the aEPEC isolates from Brazil compared to the global aEPEC collection, including espG2, espT and espC (P<0.001). Moreover, the nleF gene was more frequently identified among Brazilian aEPEC isolates obtained from diarrheagenic patients when compared to healthy subjects (69.7% vs 41.2%, P<0.05). CONCLUSION: The current study demonstrates significant genomic diversity among aEPEC from Brazil, with the identification of Brazilian aEPEC isolates to five novel EPEC lineages. The greater prevalence of some virulence genes among Brazilian aEPEC genomes could be important to the specific virulence strategies used by aEPEC in Brazil to cause diarrheal disease.


Assuntos
Hibridização Genômica Comparativa/métodos , Escherichia coli Enteropatogênica/classificação , Escherichia coli Enteropatogênica/genética , Genoma Bacteriano , Filogenia , Fatores de Virulência/genética , Brasil , Infecções por Escherichia coli , Proteínas de Escherichia coli/genética , Humanos , Tipagem de Sequências Multilocus , Sorotipagem , Virulência
2.
PLoS One ; 15(5): e0231881, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32357186

RESUMO

The sequencing and bioinformatics analysis of bacteriophages infecting mycobacteria has yielded a large amount of information on their evolution, including that on their environmental propagation on other genera such as Gordonia, closely related to Mycobacterium. However, little is known on mycobacteriophages cell biology such as the nature of their receptor(s) or their replication cycle. As part of our on-going screening for novel mycobacteriophages, we herein report the isolation and genome bioinformatics analysis of Weirdo19ES, a singleton Siphoviridae temperate mycobacteriophage with a 70.19% GC content. Nucleotide and protein sequence comparison to actinobacteriophage databases revealed that Weirdo19ES shows low homology to Gordonia phage Ruthy and mycobacteriophages falling in clusters Q and G and to singleton DS6A.Weirdo19ES also displays uncommon features such as a very short Lysin A gene (with only one enzymatic domain) and two putative HNH endonucleases. Mycobacterium smegmatis mutants resistant to Weirdo19ES are cross- resistant to I3. In agreement with that phenotype, analysis of cell envelope of those mutants showed that Weirdo19ES shares receptors with the transducing mycobacteriophage I3.This singleton mycobacteriophage adds up to the uncommonness of local mycobacteriophages previously isolated by our group and helps understanding the nature of mycobacteriophage receptors.


Assuntos
Genoma Viral , Glicolipídeos/genética , Micobacteriófagos/genética , Mycobacterium smegmatis/virologia , Composição de Bases , Parede Celular/metabolismo , Análise por Conglomerados , Uso do Códon , Hibridização Genômica Comparativa , Glicolipídeos/deficiência , Micobacteriófagos/classificação , Micobacteriófagos/isolamento & purificação , Mycobacterium smegmatis/genética , Mycobacterium smegmatis/isolamento & purificação , Fenótipo , Filogenia
3.
Gene ; 753: 144816, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32473250

RESUMO

Hemizygosity of the MIR17HG gene encoding the miR-17 ~ 92 cluster is associated with Feingold syndrome 2 characterized by intellectual disability, skeletal abnormalities, short stature, and microcephaly. Here, we report on a female with a de novo 13q31.3 microduplication encompassing MIR17HG but excluding GPC5. She presented developmental delay, skeletal and digital abnormalities, and features such as tall stature and macrocephaly mirroring those of Feingold syndrome 2 patients. The limited extent of the proband's rearrangement to the miR cluster and the corresponding normal expression level of the neighboring GPC5 in her cells, together with previously described data on affected individuals of two families carrying overlapping duplications of the miR-17 ~ 92 cluster that comprise part of GPC5, who likewise presented macrocephaly, developmental delay, as well as skeletal, digital and stature abnormalities, allow to define a new syndrome due to independent microduplication of the miR-17 ~ 92 cluster.


Assuntos
Transtornos Cromossômicos/genética , Pálpebras/anormalidades , Deficiência Intelectual/genética , Deformidades Congênitas dos Membros/genética , MicroRNAs/genética , Microcefalia/genética , Fístula Traqueoesofágica/genética , Adolescente , Deleção Cromossômica , Cromossomos Humanos Par 13/genética , Hibridização Genômica Comparativa/métodos , Deficiências do Desenvolvimento/genética , Nanismo/genética , Feminino , Duplicação Gênica/genética , Glipicanas/genética , Glipicanas/metabolismo , Humanos , Fenótipo
4.
Adv Exp Med Biol ; 1195: 163-166, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468472

RESUMO

INTRODUCTION: Chromosome 18q deletion syndrome (18q-) is a rare chromosomal disorder with phenotypic variability, including mental deficiency, short stature, hypotonia, cleft palate, and hearing impairment. We present a case with features of 18q- syndrome who had combined 18q partial monosomy and 18p partial trisomy. MATERIAL AND METHODS: A 50-year-old female patient was examined during the genetic counseling of her brother. She had a history of congenital cleft palate and developmental deficiency with hypotonia, hearing loss, and epilepsy until adulthood. Her family history was free of related cases. Karyotype analysis and comparative genomic hybridization array (aCGH) were performed in patient's blood samples. RESULTS: Clinical examination showed features of 18q- syndrome including hypotonia and tremor. Neuropsychological deficiency of moderate cognitive disorder was noticed. The patient's karyotype was normal. The aCGH analysis revealed 8 Mb deletion (del18q22.3q23) and 7.2 Mb duplication (dup18p11.32p11.23). CONCLUSION: Almost all patients' clinical features were associated with 18q- syndrome. There are very few reported cases with similar genotype possibly caused by a de novo unequal recombination mechanism.


Assuntos
Deleção Cromossômica , Transtornos Cromossômicos/genética , Duplicação Cromossômica/genética , Cromossomos Humanos Par 18/genética , Anormalidades Craniofaciais/genética , Hibridização Genômica Comparativa , Feminino , Humanos , Cariotipagem , Masculino , Pessoa de Meia-Idade , Fenótipo , Síndrome
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(5): 584-587, 2020 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-32335892

RESUMO

With the application of BACs-on-BeadsTM (BoBs) and array-comparative genome hybridization (aCGH) technologies in prenatal diagnosis, microdeletion/microduplications at Xp22.3 have been frequently detected. However, the relatively high prevalence and lack of knowledge of such disorders have brought difficulties for clinical genetic counseling. Here, recent progress of research on microdeletion/microduplications at Xp22.3, including epidemiology, pathogenesis, clinical manifestation, and prenatal diagnosis, is reviewed.


Assuntos
Cromossomos Humanos X , Diagnóstico Pré-Natal , Cromossomos Humanos X/genética , Hibridização Genômica Comparativa , Feminino , Aconselhamento Genético , Humanos , Cariotipagem , Gravidez , Pesquisa/tendências
6.
Mol Genet Genomics ; 295(4): 923-931, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32246227

RESUMO

Amelogenesis imperfecta type IG (AI1G) is caused by mutations in FAM20A. Genotypic and phenotypic features of AI1G are diverse and their full spectra remain to be characterized. The aim of this study was to identify and summarize variants in FAM20A in a broad population of patients with AI1G. We identified a Thai female (Pt-1) and a Saudi male (Pt-2) affected with AI1G. Both had hypoplastic enamel, gingival hyperplasia, and intrapulpal calcification. Pt-1 also had rapidly progressive embedding of unerupted teeth, early eruption of permanent teeth, and spontaneous dental infection. Uniquely, Pt-2 had all permanent teeth erupted which was uncommon in AI1G patients. Whole exome sequencing (WES) identified that Pt-1 was heterozygous for FAM20A, c.758A > G (p.Tyr253Cys), inherited from her father. The mutation on maternal allele was not detected by WES. Pt-2 possessed compound heterozygous mutations, c.1248dupG (p.Phe417Valfs*7); c.1081C > T (p.Arg361Cys) in FAM20A. Array comparative genomic hybridization (aCGH), cDNA sequencing, and whole genome sequencing successfully identified 7531 bp deletion on Pt-1's maternal allele. This was the largest FAM20A deletion ever found. A review of all 70 patients from 50 independent families with AI1G (including two families in this study) showed that the penetrance of hypoplastic enamel and gingival hyperplasia was complete. Unerupted permanent teeth were found in all 70 patients except Pt-2. Exons 1 and 11 were mutation-prone. Most mutations were frameshift. Certain variants showed founder effect. To conclude, this study reviews and expands phenotypic and genotypic spectra of AI1G. A large deletion missed by WES can be detected by WGS. Hypoplastic enamel, gingival hyperplasia, and unerupted permanent teeth prompt genetic testing of FAM20A. Screening of nephrocalcinosis, early removal of embedded teeth, and monitoring of dental infection are recommended.


Assuntos
Amelogênese Imperfeita/genética , Proteínas do Esmalte Dentário/genética , Nefrocalcinose/genética , Deleção de Sequência/genética , Adolescente , Adulto , Amelogênese Imperfeita/patologia , Criança , Hibridização Genômica Comparativa , Éxons/genética , Feminino , Mutação da Fase de Leitura/genética , Genótipo , Heterozigoto , Homozigoto , Humanos , Masculino , Mutação/genética , Nefrocalcinose/patologia , Linhagem , Fenótipo
7.
Int J Syst Evol Microbiol ; 70(3): 1596-1604, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32228748

RESUMO

We performed high-quality genome sequencing of eight strains of the species of the genus Tepidimonas and examined the genomes of closely related strains from the databases to understand why Tepidimonas taiwanensis is the only strain of this genus that utilizes glucose and fructose for growth. We found that the assimilation of these hexoses by T. taiwanensis was due to the presence of two transporters that are absent in all other genomes of strains of members of the genus Tepidimonas examined. Some strains lack genes coding for glucokinase, but the Embden-Meyerhof-Parnas pathway appears to be otherwise complete. The pentose phosphate pathway has a complete set of genes, but genes of the Entner-Doudoroff pathway were not identified in the genomes of any of the strains examined. Genome analysis using average nucleotide identity (ANIb), digital DNA-DNA hybridization (dDDH), average amino acid identity (AAI) and phylogenetic analysis of 400 conserved genes was performed to assess the taxonomic classification of the organisms. Two isolates of the genus Tepidimonas from the hot spring at São Pedro do Sul, Portugal, designated SPSP-6T and SPSPC-18 were also examined in this study. These organisms are mixotrophic, have an optimum growth temperature of about 50 ºC, utilize several organic acids and amino acids for growth but do not grow on sugars. Distinctive phenotypic, 16S rRNA gene sequence and genomic characteristics of strains SPSP-6T and SPSPC-18 lead us to propose a novel species based on strain SPSP-6T for which we recommend the name Tepidimonas charontis sp. nov. (=CECT 9683T=LMG 30884T).


Assuntos
Burkholderiales/classificação , Fontes Termais/microbiologia , Filogenia , Técnicas de Tipagem Bacteriana , Composição de Bases , Burkholderiales/isolamento & purificação , Hibridização Genômica Comparativa , DNA Bacteriano/genética , Ácidos Graxos/química , Hibridização de Ácido Nucleico , Portugal , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Microbiologia da Água
8.
Gene ; 741: 144557, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32171824

RESUMO

The MDM2 oncogene is a negative regulator of the p53 tumour suppressor. This relationship appears to have originated over a billion years ago. The human MDM2 gene encodes a variety of mRNAs with exceptionally long 3'UTRs (up to 5.7 kb); however, it was unclear whether MDM2 3'UTRs from other species are similarly long or conserved at the sequence level. Here, we report that all but one of the primate species most closely related to humans (greater and lesser apes) have similarly long 3'UTRs with high sequence similarity across their entire length. More distantly related species (Old world monkeys and new world monkeys) tend to have shorter MDM2 3'UTRs homologous to the corresponding position of the human MDM2 3'UTR while non-primate species exhibit little similarity at all. Remarkably, DNA sequences downstream of the shorter primate 3'UTRs are syntenic with distal regions in the human and other ape MDM2 3'UTRs. These homologous non-transcribed intergenic and transcribed 3'UTR-encoding regions are comprised of a variety of transposable elements, an RLP24 pseudogene and a cluster of novel repeat sequences suggestive of another unknown transposable element. Our analysis suggests that the primary difference between long and short MDM2 3'UTRs is a switch in polyA site usage to include conserved transposable elements that remain intergenic in more distantly related primates. It will be important to determine the relative contribution of these elements to post-transcriptional and translational regulation of MDM2 and hence p53-mediated tumour suppression.


Assuntos
Evolução Molecular , Genômica , Primatas/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Regiões 3' não Traduzidas/genética , Animais , Hibridização Genômica Comparativa , Elementos de DNA Transponíveis/genética , Regulação da Expressão Gênica/genética , Genoma/genética , Humanos , Poliadenilação/genética , Pseudogenes/genética , Proteína Supressora de Tumor p53/genética
9.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(4): 475-478, 2020 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-32219841

RESUMO

OBJECTIVE: To explore the genetic basis for a child with supravalvular aortic stenosis. METHODS: The child and his parents were subjected to conventional G-banding karyotyping, array comparative genomic hybridization (aCGH) and multiplex ligation-dependent probe amplification (MLPA) analysis. RESULTS: No karyotypic abnormality was detected in the child and his parents. aCGH has identified a de novo 278 kb deletion encompassing the ELN gene in 7q11.23, which overlapped with the critical region of Williams-Beuren syndrome (WBS). MLPA has confirmed above findings. CONCLUSION: The proband was diagnosed with atypical WBS. Deletion of the ELN gene may predispose to supravalvular aortic stenosis in the proband.


Assuntos
Estenose Aórtica Supravalvular/genética , Deleção de Genes , Síndrome de Williams/genética , Criança , Bandeamento Cromossômico , Cromossomos Humanos Par 7/genética , Hibridização Genômica Comparativa , Testes Genéticos , Humanos , Síndrome de Williams/complicações
10.
Cytogenet Genome Res ; 160(2): 72-79, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32187601

RESUMO

In this report, we present a new case of mosaic trisomy 13 with prolonged survival, firstly detected by array-CGH analysis which was carried out because of moderate intellectual disability with postaxial hexadactyly, dermatologic features, ventricular septal defect, bicuspid aortic valve, and aortic dystrophy in a 19-year-old male patient. In a subset of 15% of the cells, the patient carried a derivative chromosome 10 generated by a nonreciprocal (10;13) translocation inherited from his healthy mother who carried the translocation in a balanced and homogeneous state. FISH analyses showed interstitial telomeric sequences at the breakpoints. To our knowledge, this is the second report of a patient with trisomy 13 mosaicism displaying a severe aortic root dilatation. We also discuss the mechanisms which could explain the mosaic state, the most likely one being related to the instability of the interstitial telomere.


Assuntos
Aorta/anormalidades , Síndrome de Marfan/etiologia , Mosaicismo , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Cromossomos Humanos Par 10/genética , Cromossomos Humanos Par 13/genética , Hibridização Genômica Comparativa , Humanos , Hibridização in Situ Fluorescente , Masculino , Translocação Genética , Síndrome da Trissomia do Cromossomo 13/genética , Adulto Jovem
11.
Medicina (B Aires) ; 80 Suppl 2: 26-30, 2020.
Artigo em Espanhol | MEDLINE | ID: mdl-32150709

RESUMO

Advances in genetics have been able to support the clinical suspicion on the large hereditary component of most of these neurodevelopmental disorders (NDD). Initial studies on heritability, linkage or association showed from the beginning the great contribution of genotypic variation to the clinic in general, and to NDD in particular. The effectiveness of genetic studies in clinical practice, targeted to aetiological diagnosis, should not be ignored. Most of these are protocolized in the study of disorders such as intellectual disability and autism; within these, the array comparative genomic hybridization have supported a greater diagnostic effectiveness with respect to historical cytogenetic techniques (3 vs. 10% respectively). However, the irruption and success of molecular genetic sequencing techniques, particularly the exome and genome in trio, analyzing the parents (diagnostic rates of 30-50%), are conditioning the modification of the genetic algorithms in the diagnosis of different NDD. The greater knowledge of causal variants in intellectual disability and autism is also modifying the polygenic theoretical models established to date.


Assuntos
Modelos Genéticos , Transtornos do Neurodesenvolvimento/genética , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/genética , Hibridização Genômica Comparativa/métodos , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/diagnóstico , Sequenciamento Completo do Exoma/métodos
12.
Am J Surg Pathol ; 44(5): 607-616, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32187044

RESUMO

Rhabdomyosarcoma (RMS) encompasses a heterogenous collection of tumors in which new groups have recently been identified that improved the World Health Organization (WHO) classification. While performing RNA-sequencing in our routine practice, we identified 3 cases of well-differentiated RMS harboring new fusion genes. We also analyzed these tumors through array-comparative genomic hybridization. Clinically, these tumors were deep paraspinal tumors, occurring in neo-nat and young children. The patients underwent resection and adjuvant therapy. At the time of last follow-up (ranging from 12 to 108 mo), they were alive without disease. Histologically, these tumors consisted of well-differentiated rhabdomyoblastic proliferations with nuclear atypia, infiltrative borders, and a specific growth pattern. These tumors harbored new fusion genes involving SRF and either FOXO1 or NCOA1. We compared the expression profiles of these 3 tumors to the expression data of a series of 33 skeletal muscle tumors including embryonal RMSs, alveolar rhandomyosarcomas, RMSs with VGLL2 fusions, RMSs with the myoD1 mutation, EWSR1/FUS-TFCP2 epithelioid and spindle cell RMSs of the bone, and rhabdomyomas with PTCH1 loss. According to clustering analyses, the 3 SRF-fused tumors formed a distinct group with a specific expression profile different from that of the other types of skeletal muscle tumors. Array-comparative genomic hybridization showed a recurrent gain of chromosome 11. These 3 tumors define a new group of RMS associated with a fusion of the SRF gene. FOXO1 rearrangements, usually used to confirm the diagnosis of alveolar RMS and identify poor-outcome RMSs, were identified in a nonalveolar RMS for the first time.


Assuntos
Biomarcadores Tumorais/genética , Proteína Forkhead Box O1/genética , Fusão Gênica , Neoplasias de Cabeça e Pescoço/genética , Coativador 1 de Receptor Nuclear/genética , Rabdomiossarcoma/genética , Fator de Resposta Sérica/genética , Diferenciação Celular , Pré-Escolar , Hibridização Genômica Comparativa , Feminino , Predisposição Genética para Doença , Neoplasias de Cabeça e Pescoço/classificação , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Músculos do Pescoço/patologia , Músculos Paraespinais/patologia , Fenótipo , Rabdomiossarcoma/classificação , Rabdomiossarcoma/patologia , Rabdomiossarcoma/terapia , Análise de Sequência de RNA , Resultado do Tratamento
13.
Am J Hum Genet ; 106(4): 525-534, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32220293

RESUMO

Despite next-generation sequencing, which now allows for the accurate detection of segmental aneuploidies from in vitro fertilization embryo biopsies, the origin and characteristics of these aneuploidies are still relatively unknown. Using a multifocal biopsy approach (four trophectoderms [TEs] and one inner cell mass [ICM] analyzed per blastocyst; n = 390), we determine the origin of the aneuploidy and the diagnostic predictive value of segmental aneuploidy detection in TE biopsies toward the ICM's chromosomal constitution. Contrary to the prevalent meiotic origin of whole-chromosome aneuploidies, we show that sub-chromosomal abnormalities in human blastocysts arise from mitotic errors in around 70% of cases. As a consequence, the positive-predictive value toward ICM configuration was significantly lower for segmental as compared to whole-chromosome aneuploidies (70.8% versus 97.18%, respectively). In order to enhance the clinical utility of reporting segmental findings in clinical TE biopsies, we have developed and clinically verified a risk stratification model based on a second TE biopsy confirmation and segmental length; this model can significantly improve the prediction of aneuploidy risk in the ICM in over 86% of clinical cases enrolled. In conclusion, we provide evidence of the predominant mitotic origin of segmental aneuploidies in preimplantation embryos and develop a risk stratification model that can help post-test genetic counseling and that facilitates the decision-making process on clinical utilization of these embryos.


Assuntos
Blastocisto/fisiologia , Embrião de Mamíferos/fisiologia , Desenvolvimento Embrionário/genética , Aneuploidia , Aberrações Cromossômicas , Cromossomos/genética , Hibridização Genômica Comparativa/métodos , Feminino , Fertilização In Vitro/métodos , Humanos , Incidência , Gravidez , Diagnóstico Pré-Implantação/métodos
14.
Ann Hematol ; 99(4): 809-818, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32078009

RESUMO

Risk-adapted therapy has significantly contributed to improved survival rates in pediatric acute lymphoblastic leukemia (ALL) and reliable detection of chromosomal aberrations is mandatory for risk group stratification. This study evaluated the applicability of panel-based RNA sequencing and array CGH within the diagnostic workflow of the German study group of the international AIEOP-BFM ALL 2017 trial. In a consecutive cohort of 117 children with B cell precursor (BCP) ALL, array analysis identified twelve cases with an IKZF1plus profile of gene deletions and one case of masked hypodiploidy. Genetic markers BCR-ABL1 (n = 1), ETV6-RUNX1 (n = 25), and rearrangements involving KMT2A (n = 3) or TCF3 (n = 3) were assessed by established conventional techniques such as karyotyping, FISH, and RT-PCR. Comparison of these results with RNA sequencing analysis revealed overall consistency in n=115/117 cases, albeit with one undetected AFF1-KMT2A fusion in RNA sequencing and one undetected ETV6-RUNX1 fusion in conventional analyses. The combined application of RNA sequencing, FISH, and CGH+SNP array reliably detected all genetic markers necessary for risk stratification and will be used as the diagnostic standard workflow for BCP-ALL patients enrolled in the AIEOP-BFM ALL 2017 study. Prospectively, consistent collection of genome-wide CGH+SNP array as well as RNA sequencing data will be a valuable source to elucidate new prognostic lesions beyond established markers of pediatric ALL. In this respect, RNA sequencing identified various gene fusions in up to half of the IKZF1plus (n = 6/12) and B-other (n = 19/36) cases but not in cases with hyperdiploid karyotypes (n = 35). Among these fusions, this study reports several previously undescribed in frame PAX5 fusions, including PAX5-MYO1G and PAX5-NCOA6.


Assuntos
Hibridização Genômica Comparativa , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , RNA Mensageiro/análise , RNA Neoplásico/análise , Análise de Sequência de RNA , Cariótipo Anormal , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Asparaginase/administração & dosagem , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Genes Neoplásicos , Humanos , Fator de Transcrição Ikaros/genética , Hibridização in Situ Fluorescente , Mercaptopurina/administração & dosagem , Metotrexato/administração & dosagem , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prednisona/administração & dosagem , Estudos Prospectivos , Fatores de Risco , Transcriptoma , Vincristina/administração & dosagem , Fluxo de Trabalho
15.
Cancer Sci ; 111(4): 1180-1192, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32080953

RESUMO

The onset of malignant mesothelioma (MM) is linked to exposure to asbestos fibers. Asbestos fibers are classified as serpentine (chrysotile) or amphibole, which includes the crocidolite, amosite, anthophyllite, tremolite, and actinolite types. Although few studies have been undertaken, anthophyllite has been shown to be associated with mesothelioma, and tremolite, a contaminant in talc and chrysotile, is a risk factor for carcinogenicity. Here, after characterizing the length and width of these fibers by scanning electron microscopy, we explored the cytotoxicity induced by tremolite and anthophyllite in cells from an immortalized human mesothelial cell line (MeT5A), murine macrophages (RAW264.7), and in a rat model. Tremolite and short anthophyllite fibers were phagocytosed and localized to vacuoles, whereas the long anthophyllite fibers were caught on the pseudopod of the MeT5A and Raw 264.7 cells, according to transmission electron microscopy. The results from a 2-day time-lapse study revealed that tremolite was engulfed and damaged the MeT5A and RAW264.7 cells, but anthophyllite was not cytotoxic to these cells. Intraperitoneal injection of tremolite in rats induced diffuse serosal thickening, whereas anthophyllite formed focal fibrosis and granulomas on peritoneal serosal surfaces. Furthermore, the loss of Cdkn2a/2b, which are the most frequently lost foci in human MM, were observed in 8 cases of rat MM (homozygous deletion [5/8] and loss of heterozygosity [3/8]) by array-based comparative genomic hybridization techniques. These results indicate that tremolite initiates mesothelial injury and persistently frustrates phagocytes, causing subsequent peritoneal fibrosis and MM. The possible mechanisms of carcinogenicity based on fiber diameter/length are discussed.


Assuntos
Asbestos/toxicidade , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Neoplasias Pulmonares/genética , Mesotelioma/genética , Animais , Amiantos Anfibólicos/toxicidade , Asbesto Crocidolita/toxicidade , Asbestos Serpentinas/toxicidade , Hibridização Genômica Comparativa , Homozigoto , Humanos , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/patologia , Mesotelioma/induzido quimicamente , Mesotelioma/patologia , Ratos , Fatores de Risco , Deleção de Sequência/genética
16.
Cytogenet Genome Res ; 160(1): 22-28, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32018267

RESUMO

We report on a novel variant of the dicentric chromosome 17;20 (dic (17;20)(p11.2;q11.2) in a patient with de novo myelodysplastic syndrome (MDS). Based on FISH and array-CGH, the variant turns out to be an insertion of chromosome 17 (17p11.2-telomere 17) into chromosome 20 with breakpoints at 20q11.22 and 20q13.33. Based on conventional chromosome analysis and G-banding patterns, the region 17p11.2-17q25 was directly inserted between 20q11.22 and 20q13.33. The breakpoint junctions occurred within KCNJ12 (17p11.2), UQCC1 (20q11.2), and CDH4 (20q13.3), leading to 5' deletions of all the genes and positioning the 3' of UQCC1 next to KCNJ12 at 17p11.2 and CDH4 next to an unknown gene at 17q25-20q13.3. In addition, the centromere of chromosome 17 was not active, transforming the primary constriction to a flat band. Therefore, the novel insertion variant is a pseudo dicentric derivative chromosome with one functional centromere: 45,XX,der(17;20)del(20)(q11.22q13.33)ins(20;17)(q11.2;p11.2q25). A review of the literature of all dic(17;20) cases is presented. For the first time, we report an array-CGH characterization of such rare variant that revealed to be an insertion.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 20/genética , Hibridização Genômica Comparativa , Síndromes Mielodisplásicas/genética , Linhagem da Célula , Centrômero/ultraestrutura , Bandeamento Cromossômico , Deleção Cromossômica , Feminino , Rearranjo Gênico , Humanos , Cariotipagem , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Canais de Potássio Corretores do Fluxo de Internalização/genética , Translocação Genética
17.
PLoS One ; 15(2): e0228622, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32040484

RESUMO

Optic nerve hypoplasia (ONH) is a congenital malformation with a reduced number of retinal ganglion cell axons in a thin optic nerve. It is a common cause of visual impairment in children and ONH is associated with neurodevelopmental disorders, pituitary hormone deficiencies, and brain malformations. In most cases, the aetiology is unknown, but both environmental factors and genetic causes have been described. This study aimed to identify genetic variants underlying ONH in a well-characterised cohort of individuals with ONH. We performed array comparative genomic hybridization and whole genome sequencing in 29 individuals with ONH. Rare variants were verified by Sanger sequencing and inheritance was assessed in parental samples. We identified 11 rare single nucleotide variants (SNVs) in ten individuals, including a homozygous variant in KIF7 (previously associated with Joubert syndrome), a heterozygous de novo variant in COL4A1 (previously described in an individual with porencephaly), and a homozygous variant in COL4A2. In addition, one individual harboured a heterozygous variant in OPA1 and a heterozygous variant in COL4A1, both were inherited and assessed as variants of unknown clinical significance. Finally, a heterozygous deletion of 341 kb involving exons 7-18 of SOX5 (associated with Lamb-Schaffer syndrome) was identified in one individual. The overall diagnostic yield of pathogenic or likely pathogenic variants in individuals with ONH using whole genome sequencing was 4/29 (14%). Our results show that there is a genetic heterogeneity in ONH and indicate that genetic causes of ONH are not rare. We conclude that genetic testing is valuable in a substantial proportion of the individuals with ONH, especially in cases with non-isolated ONH.


Assuntos
Heterogeneidade Genética , Hipoplasia do Nervo Óptico/genética , Nervo Óptico/patologia , Adolescente , Adulto , Criança , Hibridização Genômica Comparativa , Estudos Transversais , Éxons , Feminino , Testes Genéticos , Genoma Humano , Heterozigoto , Humanos , Masculino , Nervo Óptico/diagnóstico por imagem , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Células Ganglionares da Retina/patologia , Fatores de Transcrição SOXD/genética , Suécia/epidemiologia , Sequenciamento Completo do Genoma , Adulto Jovem
18.
BMC Med Genet ; 21(1): 26, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32028920

RESUMO

BACKGROUND: While Miller-Dieker syndrome critical region deletions are well known delineated anomalies, submicroscopic duplications in this region have recently emerged as a new distinctive syndrome. So far, only few cases have been described overlapping 17p13.3 duplications. METHODS: In this study, we report on clinical and cytogenetic characterization of two new cases involving 17p13.3 and 3p26 chromosomal regions in two sisters with familial history of lissencephaly. Fluorescent In Situ Hybridization and array Comparative Genomic Hybridization were performed. RESULTS: A deletion including the critical region of the Miller-Dieker syndrome of at least 2,9 Mb and a duplication of at least 3,6 Mb on the short arm of chromosome 3 were highlighted in one case. The opposite rearrangements, 17p13.3 duplication and 3p deletion, were observed in the second case. This double chromosomal aberration is the result of an adjacent 1:1 meiotic segregation of a maternal reciprocal translocation t(3,17)(p26.2;p13.3). CONCLUSIONS: 17p13.3 and 3p26 deletions have a clear range of phenotypic features while duplications still have an uncertain clinical significance. However, we could suggest that regardless of the type of the rearrangement, the gene dosage and interactions of CNTN4, CNTN6 and CHL1 in the 3p26 and PAFAH1B1, YWHAE in 17p13.3 could result in different clinical spectrums.


Assuntos
Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/genética , Lisencefalia/genética , Neurônios/patologia , Translocação Genética/genética , 1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Proteínas 14-3-3/genética , Moléculas de Adesão Celular/genética , Movimento Celular/genética , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 3/genética , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/diagnóstico , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/fisiopatologia , Hibridização Genômica Comparativa , Contactinas/genética , Feminino , Dosagem de Genes/genética , Estudos de Associação Genética , Humanos , Hibridização in Situ Fluorescente , Lisencefalia/diagnóstico , Lisencefalia/fisiopatologia , Meiose/genética , Proteínas Associadas aos Microtúbulos/genética , Neurônios/metabolismo , Fenótipo , Trissomia/genética
19.
Cancer Sci ; 111(3): 840-848, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31925975

RESUMO

Ionizing radiation can damage DNA and, therefore, is a risk factor for cancer. Eker rats, which carry a heterozygous germline mutation in the tumor-suppressor gene tuberous sclerosis complex 2 (Tsc2), are susceptible to radiation-induced renal carcinogenesis. However, the molecular mechanisms involved in Tsc2 inactivation are unclear. We subjected Fischer 344 × Eker (Long Evans Tsc2+/- ) F1 hybrid rats to gamma-irradiation (2 Gy) at gestational day 19 (GD19) or postnatal day 5 (PND5) and investigated the patterns of genomic alterations in the Tsc2 allele of renal tumors that developed at 1 year after irradiation (N = 24 tumors for GD19, N = 10 for PND5), in comparison with spontaneously developed tumors (N = 8 tumors). Gamma-irradiation significantly increased the multiplicity of renal tumors. The frequency of LOH at the chromosome 10q12 region, including the Tsc2 locus, was 38%, 29% and 60% in renal carcinomas developed from the nonirradiated, GD19 and PND5 groups, respectively. Array comparative genomic hybridization analysis revealed that the LOH patterns on chromosome 10 in renal carcinomas were classified into chromosomal missegregation, mitotic recombination and chromosomal deletion types. LOH of the interstitial chromosomal deletion type was observed only in radiation-associated carcinomas. Sequence analysis for the wild-type Tsc2 allele in the LOH-negative carcinomas identified deletions (nonirradiated: 26%; GD19: 21%) and base-substitution mutations (GD19: 4%). Reduced expression of Tsc2 was also observed in the majority of the LOH-negative carcinomas. Our results suggest that interstitial chromosomal deletion is a characteristic mutagenic event caused by ionizing radiation, and it may contribute to the assessment of radiation-induced cancer risk.


Assuntos
Neoplasias Renais/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Esclerose Tuberosa/genética , Alelos , Animais , Deleção Cromossômica , Cromossomos Humanos Par 10/genética , Hibridização Genômica Comparativa/métodos , Raios gama/efeitos adversos , Heterozigoto , Humanos , Masculino , Mutação/genética , Ratos , Ratos Endogâmicos F344 , Ratos Long-Evans , Risco , Proteínas Supressoras de Tumor/genética
20.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(1): 57-59, 2020 Jan 10.
Artigo em Chinês | MEDLINE | ID: mdl-31922598

RESUMO

OBJECTIVE: To explore the genetic basis of a child with idiopathic mental retardation. METHODS: Clinical data and peripheral blood sample of the child were collected. Genomic DNA was extracted and subjected to copy number analysis using single nucleotide polymrophism array comparative genome hybridization (SNP-aCGH) and targeted capture and next generation sequencing (NGS). RESULTS: No microdeletion/microduplication were detected by SNP-aCGH. NGS has detected homozygous c.722delA (p.Asp241fs) variant of the LISN1 gene, which is known to underlie autosomal recessive mental retardation-27 (MRT 27). Both parents are carriers of the variant, conforming to the autosomal recessive inheritance. CONCLUSION: A novel pathogenic variant of the LINS1 gene has been identified, which probably underlies the MRT 27 in the patient.


Assuntos
Deficiência Intelectual , Proteínas , Criança , Hibridização Genômica Comparativa , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Deficiência Intelectual/genética , Proteínas/genética
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