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1.
Am J Med Genet A ; 194(7): e63604, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38511879

RESUMO

Orthodenticle homeobox 2 (OTX2) is a known oncogenic driver of medulloblastoma. Germline duplication of 14q22.3 including OTX2 is a rare condition reported in patients with combined pituitary hormone deficiency, oculo-auriculo-vertebral spectrum, and hemifacial microsomia. There has been one previously published case of a patient carrying a 14q22.3 duplication that included OTX2 with hemifacial microsomia who also developed medulloblastoma. Here, we present a case of a 6-year-old girl with a history of delayed development who was diagnosed with medulloblastoma. Genetic evaluations revealed that she inherited a germline duplication of 14q22.3, which included OTX2. This genetic alteration was passed down from her mother, who also had a history of delayed development. Results from other genetic testing, including exome sequencing, fragile X syndrome, and mtDNA testing, were negative/normal. This is the second report of a 14q22.3 duplication that included OTX2 in a patient with medulloblastoma. Further studies are necessary to establish a clear association.


Assuntos
Meduloblastoma , Fatores de Transcrição Otx , Humanos , Fatores de Transcrição Otx/genética , Feminino , Meduloblastoma/genética , Meduloblastoma/patologia , Criança , Cromossomos Humanos Par 14/genética , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/diagnóstico , Duplicação Cromossômica/genética
2.
Mol Genet Genomic Med ; 11(1): e2088, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36424846

RESUMO

BACKGROUND: Dystrophinopathies are X-linked recessive conditions caused by pathogenic variants in the dystrophin (DMD) gene. In a family that included two boys with Becker muscular dystrophy (BMD) due to a DMD deletion of exons 45-47, maternal carrier testing unexpectedly identified biallelic DMD deletions of exons 45-47 and 49-51. METHODS: The patient's mild phenotype in the setting of biallelic DMD variants prompted further investigation of the exon 49-51 deletion in particular, via literature review and retrospective chart review of patients who have been evaluated in our institution's comprehensive neuromuscular center and/or diagnosed in our clinical genetic testing laboratory. RESULTS: To our knowledge, this is only the fifth case of confirmed biallelic DMD variants in a female. In males, the DMD exon 49-51 deletion appears to result in a mild BMD phenotype with low or normal creatine kinase levels. This deletion comprised 19% (4/21) of dystrophinopathies diagnosed by chromosomal microarray (CMA) in males during the past ten years in our clinical laboratory. Most individuals identified by chart review were diagnosed through CMA, despite the fact that microarray was genome-wide and not DMD-specific. This case raised important genetic counseling issues. CONCLUSION: The DMD exon 49-51 deletion appears to cause a variable but generally mild BMD phenotype. Its relatively frequent detection by CMA suggests it may be underdiagnosed.


Assuntos
Distrofia Muscular de Duchenne , Masculino , Feminino , Humanos , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patologia , Distrofina/genética , Estudos Retrospectivos , Fenótipo , Éxons
3.
Am J Med Genet A ; 191(2): 526-539, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36433683

RESUMO

Deletion of 17p13.3 has varying degrees of severity on brain development based on precise location and size of the deletion. The most severe phenotype is Miller-Dieker syndrome (MDS) which is characterized by lissencephaly, dysmorphic facial features, growth failure, developmental disability, and often early death. Haploinsufficiency of PAFAH1B1 is responsible for the characteristic lissencephaly in MDS. The precise role of YWHAE haploinsufficiency in MDS is unclear. Case reports are beginning to elucidate the phenotypes of individuals with 17p13.3 deletions that have deletion of YWHAE but do not include deletion of PAFAH1B1. Through our clinical genetics practice, we identified four individuals with 17p13.3 deletion that include YWHAE but not PAFAH1B1. These patients have a similar phenotype of dysmorphic facial features, developmental delay, and leukoencephalopathy. In a review of the literature, we identified 19 patients with 17p13.3 microdeletion sparing PAFAH1B1 but deleting YWHAE. Haploinsufficiency of YWHAE is associated with brain abnormalities including cystic changes. These individuals have high frequency of epilepsy, intellectual disability, and dysmorphic facial features including prominent forehead, epicanthal folds, and broad nasal root. We conclude that deletion of 17p13.3 excluding PAFAH1B1 but including YWHAE is associated with a consistent phenotype and should be considered a distinct condition from MDS.


Assuntos
Lissencefalias Clássicas e Heterotopias Subcorticais em Banda , Deficiência Intelectual , Lisencefalia , Humanos , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/genética , Deleção Cromossômica , Lisencefalia/genética , Fenótipo , Deficiência Intelectual/genética , Cromossomos Humanos Par 17/genética , Encéfalo , Proteínas 14-3-3/genética
4.
Mol Cytogenet ; 15(1): 10, 2022 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-35248119

RESUMO

BACKGROUND: Unbalanced translocations may be de novo or inherited from one parent carrying the balanced form and are usually present in all cells. Mosaic unbalanced translocations are extremely rare with a highly variable phenotype depending on the tissue distribution and level of mosaicism. Mosaicism for structural chromosomal abnormalities is clinically challenging for diagnosis and counseling due to the limitation of technical platforms and complex mechanisms, respectively. Here we report a case with a tremendously rare maternally-derived mosaic unbalanced translocation of t(3;12), and we illustrate the unreported complicated mechanism using single nucleotide polymorphism (SNP) array, fluorescence in situ hybridization (FISH), and chromosome analyses. CASE PRESENTATION: An 18-year-old female with a history of microcephaly, pervasive developmental disorder, intellectual disability, sensory integration disorder, gastroparesis, and hypotonia presented to our genetics clinic. She had negative karyotype by parental report but no other genetic testing performed previously. SNP microarray analysis revealed a complex genotype including 8.4 Mb terminal mosaic duplication on chromosome 3 (3p26.3->3p26.1) with the distal 5.7 Mb involving two parental haplotypes and the proximal 2.7 Mb involving three parental haplotypes, and a 6.1 Mb terminal mosaic deletion on chromosome 12 (12p13.33->12p13.31) with no evidence for a second haplotype. Adjacent to the mosaic deletion is an interstitial mosaic copy-neutral region of homozygosity (1.9 Mb, 12p13.31). The mother of this individual was confirmed by chromosome analysis and FISH that she carries a balanced translocation, t(3;12)(p26.1;p13.31). CONCLUSION: Taken together, the proband, when at the stage of a zygote, likely carried the derivative chromosome 12 from this translocation, and a postzygotic mitotic recombination event occurred between the normal paternal chromosome 12 and maternal derivative chromosome 12 to "correct" the partial 3p trisomy and partial deletion of 12p. To the best of our knowledge, it is the first time to report the mechanism utilizing a combined cytogenetic and cytogenomic approach, and we believe it expands our knowledge of mosaic structural chromosomal disorders and provides new insight into clinical management and genetic counseling.

5.
J Autism Dev Disord ; 52(11): 4828-4842, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34773222

RESUMO

Our institution developed and continuously improved a Neurodevelopmental Reflex (NDR) algorithm to help physicians with genetic test ordering for neurodevelopmental disorders (NDDs). To assess its performance, we performed a retrospective study of 511 patients tested through NDR from 2018 to 2019. SNP Microarray identified pathogenic/likely pathogenic copy number variations in 27/511 cases (5.28%). Among the 484 patients tested for Fragile X FMR1 CGG repeats, a diagnosis (0.20%) was established for one male mosaic for a full mutation, a premutation, and a one-CGG allele. Within the 101 normocephalic female patients tested for MECP2, two patients were found to carry pathogenic variants (1.98%). This retrospective study suggested the NDR algorithm effectively established diagnoses for patients with NDDs with a yield of 5.87%.


Assuntos
Transtorno do Espectro Autista , Síndrome do Cromossomo X Frágil , Transtornos do Neurodesenvolvimento , Transtorno do Espectro Autista/diagnóstico , Criança , Variações do Número de Cópias de DNA , Feminino , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/diagnóstico , Síndrome do Cromossomo X Frágil/genética , Testes Genéticos , Hospitais , Humanos , Masculino , Mutação , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/genética , Estudos Retrospectivos , Expansão das Repetições de Trinucleotídeos
6.
Fertil Steril ; 114(1): 110-117, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32622405

RESUMO

OBJECTIVE: To describe institutional clinical policies and individual provider opinions regarding aneuploid embryo transfer (aET). DESIGN: A survey about clinical policies was electronically sent to Society for Assisted Reproductive Technology (SART) member laboratory directors, and a separate survey about personal opinions was electronically sent to all SART members. SETTING: Not applicable. PATIENTS: Patients pursuing preimplantation genetic testing for aneuploidy (PGT-A). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Current clinical policies about aET were described. Individual provider opinions about aET in the context of specific aneuploidies and mosaicism were also described. RESULTS: A total of 48 laboratory directors and 212 individual providers responded to their respective surveys. Twelve (25%) clinics report that they do not have a policy regarding aET, but clinics performing PGT-A in >100 cycles per year were more likely to have a policy. Half of the individual providers agree that an embryo with trisomy 21 should be available for aET, but most disagreed with aET of embryos with other aneuploidies and most were either unsure about or unwilling to transfer embryos with mosaicism. Those who worked in primarily patient-facing roles held more agreeable opinions regarding aET. CONCLUSION: There is no consensus regarding ideal clinical policies for aET. The wide range of current clinical practices and individual provider opinions regarding under what circumstances, if any, aET should be available to patients indicates that this is a divisive issue among ART providers, and there is a clear need for specific professional guidelines to address this issue.


Assuntos
Aneuploidia , Transferência Embrionária/normas , Clínicas de Fertilização/normas , Política de Saúde , Padrões de Prática Médica/normas , Adulto , Idoso , Idoso de 80 Anos ou mais , Transferência Embrionária/métodos , Prova Pericial , Feminino , Clínicas de Fertilização/estatística & dados numéricos , Testes Genéticos/métodos , Testes Genéticos/normas , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mosaicismo/embriologia , Padrões de Prática Médica/estatística & dados numéricos , Gravidez , Diagnóstico Pré-Implantação/métodos , Diagnóstico Pré-Implantação/normas , Inquéritos e Questionários , Estados Unidos
7.
Am J Med Genet C Semin Med Genet ; 184(2): 294-301, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32476283

RESUMO

More and more women rely on non-invasive prenatal screening (NIPS) to detect fetal sex and risk for aneuploidy. The testing applies massively parallel sequencing or single nucleotide polymorphism (SNP) microarray to circulating cell-free DNA to determine relative copy number. In addition to trisomies 13, 18, and 21, some labs offer screening for sex chromosome abnormalities as part of their test. In this study, an index neonate screened positive for monosomy X and had discordant postnatal chromosomes indicating an X;autosome translocation. This patient prompted a retrospective chart review for similar cases at a large NIPS testing center. The review found 28 patients with an abnormal NIPS for monosomy X who were eventually diagnosed with additional discrepant structural sex chromosome abnormalities including translocations, isochromosomes, deletions, rings, markers, and uniparental disomy. The majority of these were mosaic with monosomy X, but in seven cases, there was no evidence of mosaicism on confirmatory testing. The identification of multiple sex chromosome aneuploidies in these cases supports the need for additional genetic counseling prior to NIPS testing and following abnormal NIPS results that are positive for monosomy X. This finding broadens our knowledge about the variable outcomes of positive monosomy X NIPS results and emphasizes the importance of confirmatory testing and clinical follow up for these patients.


Assuntos
Transtornos Cromossômicos/diagnóstico , Diagnóstico Pré-Natal , Aberrações dos Cromossomos Sexuais , Síndrome de Turner/diagnóstico , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/patologia , Feminino , Feto/diagnóstico por imagem , Feto/patologia , Humanos , Mosaicismo/embriologia , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Síndrome de Turner/genética , Síndrome de Turner/patologia
8.
Cancer Genet ; 243: 52-72, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32302940

RESUMO

Clinical management and risk stratification of B-lymphoblastic leukemia/ lymphoma (B-ALL/LBL) depend largely on identification of chromosomal abnormalities obtained using conventional cytogenetics and Fluorescence In Situ Hybridization (FISH) testing. In the last few decades, testing algorithms have been implemented to support an optimal risk-oriented therapy, leading to a large improvement in overall survival. In addition, large scale genomic studies have identified multiple aberrations of prognostic significance that are not routinely tested by existing modalities. However, as chromosomal microarray analysis (CMA) and next-generation sequencing (NGS) technologies are increasingly used in clinical management of hematologic malignancies, these abnormalities may be more readily detected. In this article, we have compiled a comprehensive, evidence-based review of the current B-ALL literature, focusing on known and published subtypes described to date. More specifically, we describe the role of various testing modalities in the diagnosis, prognosis, and therapeutic relevance. In addition, we propose a testing algorithm aimed at assisting laboratories in the most effective detection of the underlying genomic abnormalities.


Assuntos
Aberrações Cromossômicas , Genômica/normas , Oncologia/normas , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Adulto , Fatores Etários , Criança , Tomada de Decisão Clínica , Análise Citogenética , Intervalo Livre de Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Análise de Sequência com Séries de Oligonucleotídeos , Seleção de Pacientes , Guias de Prática Clínica como Assunto , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , Medição de Risco/métodos , Medição de Risco/normas
9.
J Pediatr ; 216: 227-231, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31635814

RESUMO

Early diagnosis of Turner syndrome enhances care, but in routine practice, even within larger referral centers, diagnosis is delayed. Our study examines the utility of an electronic health record algorithm in identifying patients at high risk for Turner syndrome. Six percent of those identified had missed diagnoses of Turner syndrome.


Assuntos
Algoritmos , Registros Eletrônicos de Saúde , Síndrome de Turner/diagnóstico , Adolescente , Criança , Pré-Escolar , Diagnóstico Precoce , Feminino , Humanos
11.
J Pediatr ; 206: 286-292.e1, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30413314

RESUMO

Variable lung disease was documented in 2 infants with heterozygous TBX4 mutations; their clinical presentations, pathology, and outcomes were distinct. These findings demonstrate that TBX4 gene mutations are associated with neonatal respiratory failure and highlight the wide spectrum of clinicopathological outcomes that have implications for patient diagnosis and management.


Assuntos
Mutação/genética , Insuficiência Respiratória/genética , Insuficiência Respiratória/patologia , Proteínas com Domínio T/genética , Feminino , Humanos , Recém-Nascido , Masculino
12.
Am J Med Genet A ; 173(3): 647-653, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27862945

RESUMO

Phenotypic variability among individuals with neurofibromatosis type 1 (NF1) has long been a challenge for clinicians and an enigma for researchers. Members of the same family and even identical twins with NF1 often demonstrate variable disease expression. Many mechanisms for this variability have been proposed. We have performed an exploratory study of copy number variants (CNVs) as a possible source of phenotypic variability in NF1. We enrolled 11 pairs of monozygotic (MZ) twins with NF1 and their parents, catalogued their clinical characteristics, and utilized a single nucleotide polymorphism (SNP) microarray to identify CNVs in blood and saliva. The 11 twin pairs showed high concordance for presence and number of café-au-lait spots, cutaneous neurofibromas, IQ, and ADHD. They were more likely to be discordant for optic pathway glioma, plexiform neurofibromas, skeletal manifestations, and malignancy. Microarray analysis identified a total of 81 CNVs meeting our conservative criteria, 37 of which overlap known genes. Of interest, three CNVs were previously unreported. Microarray analysis failed to ascertain any CNV differences within twin pairs, between twins and parents, or between tissues in any one individual. Results of this small pilot study did not demonstrate any de novo CNV events in our MZ twin pairs, nor were de novo CNVs overrepresented in these individuals with NF1. A much larger sample size would be needed to form any conclusions about the role of CNVs in NF1 variable expressivity. Alternative explanations for discordant phenotypes include epigenetic changes, smaller genetic alterations, or environmental factors. © 2016 Wiley Periodicals, Inc.


Assuntos
Variações do Número de Cópias de DNA , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/genética , Gêmeos Monozigóticos/genética , Adolescente , Adulto , Criança , Pré-Escolar , Mapeamento Cromossômico , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Mutação , Fenótipo , Polimorfismo de Nucleotídeo Único , Adulto Jovem
13.
Artigo em Inglês | MEDLINE | ID: mdl-27821535

RESUMO

Genomic disorders and rare copy number abnormalities are identified in 15-25% of patients with syndromic conditions, but their prevalence in individuals with isolated birth defects is less clear. A spectrum of congenital heart defects (CHDs) is seen in heterotaxy, a highly heritable and genetically heterogeneous multiple congenital anomaly syndrome resulting from failure to properly establish left-right (L-R) organ asymmetry during early embryonic development. To identify novel genetic causes of heterotaxy, we analysed copy number variants (CNVs) in 225 patients with heterotaxy and heterotaxy-spectrum CHDs using array-based genotyping methods. Clinically relevant CNVs were identified in approximately 20% of patients and encompassed both known and putative heterotaxy genes. Patients were carefully phenotyped, revealing a significant association of abdominal situs inversus with pathogenic or likely pathogenic CNVs, while d-transposition of the great arteries was more frequently associated with common CNVs. Identified cytogenetic abnormalities ranged from large unbalanced translocations to smaller, kilobase-scale CNVs, including a rare, single exon deletion in ZIC3, a gene known to cause X-linked heterotaxy. Morpholino loss-of-function experiments in Xenopus support a role for one of these novel candidates, the platelet isoform of phosphofructokinase-1 (PFKP) in heterotaxy. Collectively, our results confirm a high CNV yield for array-based testing in patients with heterotaxy, and support use of CNV analysis for identification of novel biological processes relevant to human laterality.This article is part of the themed issue 'Provocative questions in left-right asymmetry'.


Assuntos
Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Síndrome de Heterotaxia/genética , Análise de Sequência com Séries de Oligonucleotídeos , Fosfofrutoquinase-1/genética , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Fosfofrutoquinase-1/metabolismo
14.
Adv Ther ; 33(11): 1964-1982, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27585978

RESUMO

INTRODUCTION: PF-06438179, a potential biosimilar to Remicade® (infliximab, Janssen Biotech, Inc.), is a chimeric mouse-human monoclonal antibody targeting human tumor necrosis factor alpha (TNF). METHODS: Analytical (small subset reported here) and nonclinical studies compared the structural, functional, and in vivo nonclinical similarity of PF-06438179 with Remicade sourced from the United States (infliximab-US) and/or European Union (infliximab-EU). RESULTS: The peptide map profiles were superimposable, and peptide masses were the same, indicating identical amino acid sequences. Data on post-translational modifications, biochemical properties, and biological function provided strong support for analytical similarity. Administration of a single intravenous (IV) dose (10 or 50 mg/kg) of PF-06438179 or infliximab-EU to male rats was well tolerated. There were no test article-related clinical signs or effects on body weight or food consumption. Systemic exposures [maximum drug concentration (C max) and area under the concentration-time curve (AUC)] in rats administered PF-06438179 or infliximab-EU were similar, with mean exposure ratio of PF-06438179 relative to infliximab-EU ranging from 0.88 to 1.16. No rats developed anti-drug antibodies. A 2-week IV toxicity study was conducted with once-weekly administration of 10 or 50 mg/kg of PF-06438179 to male and female rats. PF-06438179-related hyperplasia of sinusoidal cells occurred in the liver in rats administered 50 mg/kg, but was not adverse based on its minimal to mild severity. The no-observed adverse-effect level for PF-06438179 was 50 mg/kg. At this dose, C max was 1360 µg/mL and AUC at 168 h was 115,000 µg h/mL on day 8. CONCLUSIONS: The analytical and nonclinical studies have supported advancement of PF-06438179 into global comparative clinical trials. FUNDING: Pfizer Inc.


Assuntos
Medicamentos Biossimilares/farmacologia , Infliximab/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Administração Intravenosa , Animais , Anticorpos Monoclonais/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Imunossupressores/farmacologia , Masculino , Ratos , Resultado do Tratamento
15.
Cancer Genet ; 209(1-2): 21-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26701195

RESUMO

Lipoblastoma is a benign myxoid neoplasm arising in young children that typically demonstrates adipose differentiation. It is often morphologically indistinguishable from primitive myxoid mesenchymal tumor of infancy (PMMTI), which is characterized by a well-circumscribed myxoid mass with a proliferation of primitive mesenchymal cells with mild cytologic atypia. PMMTI occurs in the first year of life and is known to have locally aggressive behavior. No specific genetic rearrangements have been reported to date. In contrast, the presence of PLAG1 (Pleomorphic Adenoma Gene 1) rearrangement is diagnostic for lipoblastoma. We hereby demonstrate the combined application of multiple approaches to tackle the diagnostic challenges of a rapidly growing neck tumor in a 3-month-old female. An incisional tumor biopsy had features of an undifferentiated, myxoid mesenchymal neoplasm mimicking PMMTI. However, tumor cells showed diffuse nuclear expression by immunohistochemical (IHC) stain. Conventional cytogenetic and fluorescence in situ hybridization (FISH) analyses as well as next generation sequencing (NGS) demonstrated evidence of PLAG1 rearrangement, confirming the diagnosis of lipoblastoma. This experience warrants that undifferentiated myxoid lipoblastoma can mimic PMMTI, and the combination of cytogenetic and molecular approaches is essential to distinguish these two myxoid neoplasms. Literature on lipoblastomas with relevant molecular and cytogenetic findings is summarized. Our case is the first lipoblastoma diagnosed with a PLAG1 fusion defined by NGS technology.


Assuntos
Proteínas de Ligação a DNA/genética , Glucuronosiltransferase/genética , Lipoblastoma/genética , Proteínas de Fusão Oncogênica/genética , Neoplasias de Tecidos Moles/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Hialuronan Sintases , Imuno-Histoquímica , Hibridização in Situ Fluorescente/métodos , Lactente , Lipoblastoma/patologia , Neoplasias de Tecidos Moles/patologia
16.
Cancer Genet ; 208(1-2): 1-18, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25678190

RESUMO

It is well documented that among subgroups of B-cell acute lymphoblastic leukemia (B-ALL), the genetic profile of the leukemic blasts has significant impact on prognosis and stratification for therapy. Recent studies have documented the power of microarrays to screen genome-wide for copy number aberrations (CNAs) and regions of copy number-neutral loss of heterozygosity (CNLOH) that are not detectable by G-banding or fluorescence in situ hybridization (FISH). These studies have involved application of a single array platform for the respective cases. The present investigation demonstrates the feasibility and usefulness of integrating array results from multiple laboratories (ARUP, The Children's Hospital of Philadelphia, Cincinnati Children's Hospital Medical Center, and University of Minnesota Medical Center) that utilize different array platforms (Affymetrix, Agilent, or Illumina) in their respective clinical settings. A total of 65 patients enrolled on the Children's Oncology Group (COG) study AALL08B1 were identified for study, as cytogenetic and FISH studies had also been performed on these patients, with a central review of those results available for comparison. Microarray data were first analyzed by the individual laboratories with their respective software systems; raw data files were then centrally validated using NEXUS software. The results demonstrated the added value of integrating multi-platform data with cytogenetic and FISH data and highlight novel findings identified by array including the co-occurrence of low and high risk abnormalities not previously reported to coexist within a clone, novel regions of chromosomal amplification, clones characterized by numerous whole chromosome LOH that do not meet criteria for doubling of a near-haploid, and characterization of array profiles associated with an IKZF1 deletion. Each of these findings raises questions that are clinically relevant to risk stratification.


Assuntos
Linfócitos B/metabolismo , Hibridização Genômica Comparativa/métodos , Análise Citogenética/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Linfócitos B/patologia , Criança , Aberrações Cromossômicas , Bandeamento Cromossômico , Variações do Número de Cópias de DNA , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Perda de Heterozigosidade , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Prognóstico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
17.
J Cardiovasc Dev Dis ; 2(2): 76-92, 2015 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-29371513

RESUMO

Cardiovascular malformations (CVMs) are the most common birth defect, occurring in 1%-5% of all live births. Although the genetic contribution to CVMs is well recognized, the genetic causes of human CVMs are identified infrequently. In addition, a failure of systematic deep phenotyping of CVMs, resulting from the complexity and heterogeneity of malformations, has obscured genotype-phenotype correlations and contributed to a lack of understanding of disease mechanisms. To address these knowledge gaps, we have developed the Cytogenomics of Cardiovascular Malformations (CCVM) Consortium, a multi-site alliance of geneticists and cardiologists, contributing to a database registry of submicroscopic genetic copy number variants (CNVs) based on clinical chromosome microarray testing in individuals with CVMs using detailed classification schemes. Cardiac classification is performed using a modification to the National Birth Defects Prevention Study approach, and non-cardiac diagnoses are captured through ICD-9 and ICD-10 codes. By combining a comprehensive approach to clinically relevant genetic analyses with precise phenotyping, the Consortium goal is to identify novel genomic regions that cause or increase susceptibility to CVMs and to correlate the findings with clinical phenotype. This registry will provide critical insights into genetic architecture, facilitate genotype-phenotype correlations, and provide a valuable resource for the medical community.

18.
BioDrugs ; 28(5): 451-9, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25001079

RESUMO

BACKGROUND AND OBJECTIVES: Trastuzumab (Herceptin(®)) is a humanized monoclonal antibody (mAb) that binds to the HER2 protein. PF-05280014 is being developed as a potential biosimilar to trastuzumab products marketed in the United States (trastuzumab-US) and European Union (trastuzumab-EU). Nonclinical studies were designed to evaluate the similarity of PF-05280014 to trastuzumab-US and trastuzumab-EU using in vitro structural and functional analyses, and in vivo pharmacokinetic and immunogenicity assessments. METHODS: Peptide mapping was utilized to determine structural similarity. Functional similarity was assessed via an in vitro tumor cell growth inhibition assay. CD-1 male mice were administered a single-dose (0, 1, 10, or 100 mg/kg) of PF-05280014, trastuzumab-US, or trastuzumab-EU. Mice were monitored for clinical signs and body weight changes over a 4-month period. At approximately 720, 1,080, 1,440, 2,160, and 2,880 h post-dose, terminal blood samples were collected and assayed for PF-05280014, trastuzumab-US, or trastuzumab-EU concentrations and anti-drug antibodies (ADA). Values for C max, area under the concentration time curve (AUC), clearance (CL), volume of distribution (V ss), half-life (t ½), and the presence of ADA were determined. RESULTS: In this report, peptide mapping of PF-05280014, trastuzumab-US, and trastuzumab-EU showed similar chromatographic profiles in a side-by-side analysis. The tumor cell growth inhibition of PF-05280014 was similar to trastuzumab-US and trastuzumab-EU. C max and AUC0-∞ values in mice were similar and dose-dependent across the mAbs at all doses, and CL and V ss values were similar and dose-independent. The CL values across doses ranged from 0.193 to 0.350 mL/h/kg (PF-05280014), from 0.200 to 0.346 mL/h/kg (trastuzumab-US), and from 0.193 to 0.335 mL/h/kg (trastuzumab-EU). V ss values across doses ranged from 84.9 to 120 mL/kg (PF-05280014), 86.7 to 130 mL/kg (trastuzumab-US), and 85.4 to 116 mL/kg (trastuzumab-EU). The incidence of ADA was low (~10%) and also similar across all dose levels and the three mAbs. The lower exposure generally observed in ADA-positive animals did not impact the overall PK interpretation. All animals survived to their scheduled terminal blood collection with no mAb-related differences in body weight gain or clinical signs. CONCLUSIONS: PF-05280014, trastuzumab-US, and trastuzumab-EU were well tolerated during the 4-month observation period following a single dose of up to 100 mg/kg. PF-05280014, trastuzumab-US, and trastuzumab-EU showed similar structural properties, tumor cell growth inhibition properties, and PK profiles. The incidence of ADA was low and similar across the three mAbs. The results of these studies support the development of PF-05280014 as a proposed biosimilar to Herceptin.


Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Área Sob a Curva , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , União Europeia , Inibidores do Crescimento/farmacologia , Meia-Vida , Masculino , Camundongos , Mapeamento de Peptídeos , Trastuzumab , Estados Unidos
19.
Genet Med ; 15(1): 70-8, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22858719

RESUMO

PURPOSE: The purpose of this study was to document the ability of single-nucleotide polymorphism microarray to identify copy-neutral regions of homozygosity, demonstrate clinical utility of regions of homozygosity, and discuss ethical/legal implications when regions of homozygosity are associated with a parental blood relationship. METHODS: Study data were compiled from consecutive samples sent to our clinical laboratory over a 3-year period. A cytogenetics database identified patients with at least two regions of homozygosity >10 Mb on two separate chromosomes. A chart review was conducted on patients who met the criteria. RESULTS: Of 3,217 single-nucleotide polymorphism microarrays, 59 (1.8%) patients met inclusion criteria. The percentage of homozygosity ranged from 0.9 to 30.1%, indicating parental relationships from distant to first-degree relatives. First-degree kinship was suspected in the parents of at least 11 patients with regions of homozygosity covering >21.3% of their autosome. In four patients from two families, homozygosity mapping discovered a candidate gene that was sequenced to identify a clinically significant mutation. CONCLUSION: This study demonstrates clinical utility in the identification of regions of homozygosity, as these regions may aid in diagnosis of the patient. This study establishes the need for careful reporting, thorough pretest counseling, and careful electronic documentation, as microarray has the capability of detecting previously unknown/unreported relationships.


Assuntos
Mapeamento Cromossômico , Genes Recessivos , Doenças Genéticas Inatas/diagnóstico , Homozigoto , Linhagem , Polimorfismo de Nucleotídeo Único , Cromossomos Humanos X , Consanguinidade , Feminino , Humanos , Masculino , Prontuários Médicos , Análise de Sequência com Séries de Oligonucleotídeos , Irmãos
20.
Sarcoma ; 2012: 780129, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22550426

RESUMO

Advances in molecular pathology now allow for identification of rare tumor cells in cancer patients. Identification of this minimal residual disease is particularly relevant for Ewing sarcoma, given the potential for recurrence even after complete remission is achieved. Using RT-PCR to detect specific tumor-associated fusion transcripts, otherwise occult tumor cells are found in blood or bone marrow in 20-30% of Ewing sarcoma patients, and their presence is associated with inferior outcomes. Although RT-PCR has excellent sensitivity and specificity for identifying tumor cells, technical challenges may limit its widespread applicability. The use of flow cytometry to identify tumor-specific antigens is a recently described method that may circumvent these difficulties. In this manuscript, we compare the advantages and drawbacks of these approaches, present data on a third method using fluorescent in situ hybridization, and discuss issues affecting the further development of these strategies.

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