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1.
BMC Bioinformatics ; 20(1): 496, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615419

RESUMO

BACKGROUND: When applying genomic medicine to a rare disease patient, the primary goal is to identify one or more genomic variants that may explain the patient's phenotypes. Typically, this is done through annotation, filtering, and then prioritization of variants for manual curation. However, prioritization of variants in rare disease patients remains a challenging task due to the high degree of variability in phenotype presentation and molecular source of disease. Thus, methods that can identify and/or prioritize variants to be clinically reported in the presence of such variability are of critical importance. METHODS: We tested the application of classification algorithms that ingest variant annotations along with phenotype information for predicting whether a variant will ultimately be clinically reported and returned to a patient. To test the classifiers, we performed a retrospective study on variants that were clinically reported to 237 patients in the Undiagnosed Diseases Network. RESULTS: We treated the classifiers as variant prioritization systems and compared them to four variant prioritization algorithms and two single-measure controls. We showed that the trained classifiers outperformed all other tested methods with the best classifiers ranking 72% of all reported variants and 94% of reported pathogenic variants in the top 20. CONCLUSIONS: We demonstrated how freely available binary classification algorithms can be used to prioritize variants even in the presence of real-world variability. Furthermore, these classifiers outperformed all other tested methods, suggesting that they may be well suited for working with real rare disease patient datasets.


Assuntos
Algoritmos , Doenças Genéticas Inatas/diagnóstico , Genômica/métodos , Mutação , Doenças Raras/diagnóstico , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Genoma Humano , Humanos , Fenótipo , Polimorfismo Genético , Medicina de Precisão/métodos , Doenças Raras/genética , Estudos Retrospectivos , Análise de Sequência de DNA/métodos , Software
7.
Hum Genet ; 138(10): 1117-1122, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31243543

RESUMO

The Israeli population mainly includes Jews, Muslim and Christian Arabs, and Druze. Data on genetic diseases present in the population have been systematically collected and are available online in the Israeli national genetic database. Among the Israeli Arabs in December 31 2018, the database included molecular data on six diseases relatively frequent in the whole population: thalassemia, familial Mediterranean fever (FMF), cystic fibrosis, deafness, phenylketonuria or congenital adrenal hyperplasia as well as data on 632 autosomal recessive diseases among Muslim Israeli Arabs, 52 among the Christian Arabs and 79 among Druze. A single variant was characterized in 590 out of the 771 genes causing disorders in which the molecular basis was known. Many of the variants reported among Arabs in Israel are novels, most being found in one community only. Some variants are ancient and for instance, consistent with the migration history, several variants are found in the Bedouins from the Negev as well as from the Arab peninsula. In the 181 other disorders more than one variant was characterized either in the same gene or in more than one gene. While it is probable that most of these cases represent random events in some cases the reason may be a selective advantage to the heterozygotes.


Assuntos
Árabes/genética , Genes Recessivos , Doenças Genéticas Inatas/epidemiologia , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Doenças Genéticas Inatas/diagnóstico , Variação Genética , Heterozigoto , Humanos , Israel/epidemiologia , Programas de Rastreamento , Vigilância da População
8.
Nat Med ; 25(6): 890-897, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31160821

RESUMO

Monogenic disorders occur at a high frequency in human populations and are commonly inherited through the germline. Unfortunately, once the mutation has been transmitted to a child, only limited treatment options are available in most cases. However, means of correcting disease-causing nuclear and mitochondrial DNA mutations in gametes or preimplantation embryos have now been developed and are commonly referred to as germline gene therapy (GGT). We will discuss these novel strategies and provide a path forward for safe, high-efficiency GGT that may provide a promising new paradigm for preventing the passage of deleterious genes from parent to child.


Assuntos
Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/terapia , Terapia Genética/métodos , Mutação em Linhagem Germinativa , Criança , Reparo do DNA , DNA Mitocondrial/genética , Feminino , Fertilização In Vitro , Conversão Gênica , Terapia Genética/ética , Terapia Genética/legislação & jurisprudência , Humanos , Masculino , Terapia de Substituição Mitocondrial , Gravidez , Diagnóstico Pré-Implantação , Segurança
9.
Mol Cell ; 74(5): 866-876, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31173722

RESUMO

The replisome quickly and accurately copies billions of DNA bases each cell division cycle. However, it can make errors, especially when the template DNA is damaged. In these cases, replication-coupled repair mechanisms remove the mistake or repair the template lesions to ensure high fidelity and complete copying of the genome. Failures in these genome maintenance activities generate mutations, rearrangements, and chromosome segregation problems that cause many human diseases. In this review, I provide a broad overview of replication-coupled repair pathways, explaining how they fix polymerase mistakes, respond to template damage that acts as obstacles to the replisome, deal with broken forks, and impact human health and disease.


Assuntos
Reparo do DNA/genética , Replicação do DNA/genética , Doenças Genéticas Inatas/genética , Genoma Humano/genética , Ciclo Celular/genética , Segregação de Cromossomos/genética , Dano ao DNA/genética , Instabilidade Genômica/genética , Humanos , Mutação/genética
10.
Int J Mol Sci ; 20(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052252

RESUMO

Ectopic mineralization disorders comprise a broad spectrum of inherited or acquired diseases characterized by aberrant deposition of calcium crystals in multiple organs, such as the skin, eyes, kidneys, and blood vessels. Although the precise mechanisms leading to ectopic calcification are still incompletely known to date, various molecular targets leading to a disturbed balance between pro- and anti-mineralizing pathways have been identified in recent years. Vitamin K and its related compounds, mainly those post-translationally activated by vitamin K-dependent carboxylation, may play an important role in the pathogenesis of ectopic mineralization as has been demonstrated in studies on rare Mendelian diseases, but also on highly prevalent disorders, like vascular calcification. This narrative review compiles and summarizes the current knowledge regarding the role of vitamin K, its metabolism, and associated compounds in the pathophysiology of both monogenic ectopic mineralization disorders, like pseudoxanthoma elasticum or Keutel syndrome, as well as acquired multifactorial diseases, like chronic kidney disease. Clinical and molecular aspects of the various disorders are discussed according to the state-of-the-art, followed by a comprehensive literature review regarding the role of vitamin K in molecular pathophysiology and as a therapeutic target in both human and animal models of ectopic mineralization disorders.


Assuntos
Calcinose/metabolismo , Doenças Genéticas Inatas/metabolismo , Vitamina K/metabolismo , Anormalidades Múltiplas , Animais , Calcinose/genética , Doenças das Cartilagens , Doenças Genéticas Inatas/genética , Deformidades Congênitas da Mão , Humanos , Estenose da Valva Pulmonar , Vitamina K/genética
11.
Hum Genet ; 138(6): 673-679, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31069506

RESUMO

The study of Mendelian diseases and the identification of their causative genes are of great significance in the field of genetics. The evaluation of the pathogenicity of genes and the total number of Mendelian disease genes are both important questions worth studying. However, very few studies have addressed these issues to date, so we attempt to answer them in this study. We calculated the gene pathogenicity prediction (GPP) score by a machine learning approach (random forest algorithm) to evaluate the pathogenicity of genes. When we applied the GPP score to the testing gene set, we obtained an accuracy of 80%, recall of 93% and area under the curve of 0.87. Our results estimated that a total of 10,384 protein-coding genes were Mendelian disease genes. Furthermore, we found the GPP score was positively correlated with the severity of disease. Our results indicate that GPP score may provide a robust and reliable guideline to predict the pathogenicity of protein-coding genes. To our knowledge, this is the first trial to estimate the total number of Mendelian disease genes.


Assuntos
Algoritmos , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença/genética , Aprendizado de Máquina , Genes Dominantes/genética , Genes Recessivos/genética , Doenças Genéticas Inatas/diagnóstico , Humanos , Curva ROC
12.
Int J Lab Hematol ; 41 Suppl 1: 131-141, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31069978

RESUMO

Advances in molecular genetic sequencing techniques have contributed to the elucidation of previously unknown germline mutations responsible for inherited thrombocytopenia (IT). Regardless of age of presentation and severity of symptoms related to thrombocytopenia and/or platelet dysfunction, a subset of patients with IT are at increased risk of developing myeloid neoplasms during their life time, particularly those with germline autosomal dominant mutations in RUNX1, ANKRD26, and ETV6. Patients may present with isolated thrombocytopenia and megakaryocytic dysmorphia or atypia on baseline bone marrow evaluation, without constituting myelodysplasia (MDS). Bone marrow features may overlap with idiopathic thrombocytopenic purpura (ITP) or sporadic MDS leading to misdiagnosis. Progression to myelodysplastic syndrome/ acute myeloid leukemia (MDS/AML) may be accompanied by progressive bi- or pancytopenia, multilineage dysplasia, increased blasts, cytogenetic abnormalities, acquisition of bi-allelic mutations in the underlying gene with germline mutation, or additional somatic mutations in genes associated with myeloid malignancy. A subset of patients may present with MDS/AML at a young age, underscoring the growing concern for evaluating young patients with MDS/AML for germline mutations predisposing to myeloid neoplasm. Early recognition of germline mutation and predisposition to myeloid malignancy permits appropriate treatment, adequate monitoring for disease progression, proper donor selection for hematopoietic stem cell transplantation, as well as genetic counseling of the affected patients and their family members. Herein, we describe the clinical and diagnostic features of IT with germline mutations predisposing to myeloid neoplasms focusing on mutations involving RUNX1, ANKRD26, and ETV6.


Assuntos
Doenças Genéticas Inatas , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Proteínas de Neoplasias , Trombocitopenia , Aloenxertos , Genes Dominantes , Aconselhamento Genético , Doenças Genéticas Inatas/sangue , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/terapia , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutação , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Trombocitopenia/sangue , Trombocitopenia/diagnóstico , Trombocitopenia/genética , Trombocitopenia/terapia
13.
Math Biosci Eng ; 16(3): 1376-1391, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30947425

RESUMO

For discovery of new usage of drugs, the function type of their target genes plays an important role, and the hypothesis of "Antagonist-GOF" and "Agonist-LOF" has laid a solid foundation for supporting drug repurposing. In this research, an active gene annotation corpus was used as training data to predict the gain-of-function or loss-of-function or unknown character of each human gene after variation events. Unlike the design of(entity, predicate, entity) triples in a traditional three way tensor, a four way and a five way tensor, GMFD-/GMAFD-tensor, were designed to represent higher order links among or among part of these entities: genes(G), mutations(M), functions(F), diseases( D) and annotation labels(A). A tensor decomposition algorithm, CP decomposition, was applied to the higher order tensor and to unveil the correlation among entities. Meanwhile, a state-of-the-art baseline tensor decomposition algorithm, RESCAL, was carried on the three way tensor as a comparing method. The result showed that CP decomposition on higher order tensor performed better than RESCAL on traditional three way tensor in recovering masked data and making predictions. In addition, The four way tensor was proved to be the best format for our issue. At the end, a case study reproducing two disease-gene-drug links(Myelodysplatic Syndromes-IL2RA-Aldesleukin, Lymphoma- IL2RA-Aldesleukin) presented the feasibility of our prediction model for drug repurposing.


Assuntos
Reposicionamento de Medicamentos/economia , Reposicionamento de Medicamentos/métodos , Variação Genética , Aprendizado de Máquina , Mutação , Algoritmos , Análise Custo-Benefício , Doenças Genéticas Inatas/genética , Humanos , Interleucina-2/análogos & derivados , Interleucina-2/uso terapêutico , Subunidade alfa de Receptor de Interleucina-2/genética , Linfoma/genética , Modelos Genéticos , Anotação de Sequência Molecular , Síndromes Mielodisplásicas/genética , Proteínas Recombinantes/uso terapêutico , Software
14.
Curr Genet ; 65(4): 905-912, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30953124

RESUMO

The spliceosome has been implicated in genome maintenance for decades. Recently, a surge in discoveries in cancer has suggested that the oncogenic mechanism of spliceosomal defects may involve defective genome stability. The action of the core spliceosome prevents R-loop accumulation, and regulates the expression of genome stability factors. At the same time, specific spliceosomal components have non-canonical functions in genome maintenance. Here we review these different models, highlighting their discovery in different model systems, and describing their potential impact on human disease states.


Assuntos
Processamento Alternativo/genética , Doenças Genéticas Inatas/genética , Genoma Humano/genética , Instabilidade Genômica/genética , Dano ao DNA/genética , Humanos , Mutação , Processamento de RNA/genética , Spliceossomos/genética
15.
Fertil Steril ; 111(6): 1151-1158, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31005312

RESUMO

OBJECTIVE: To evaluate the growth, health, and motor development of children born after preimplantation genetic diagnosis (PGD). DESIGN: Observational cohort study and comparison of 5-year-old children born after PGD to similar aged children born after IVF/intracytoplasmic sperm injection (ICSI) and children from families with a genetic disorder born after natural conception (NC). SETTING: University hospital. PATIENT(S): One hundred three children were included in the PGD group. The two control groups consisted of 90 children born after IVF/ICSI and 58 children born after NC. INTERVENTION(S): PGD. MAIN OUTCOME MEASURE(S): We measured height, weight, body circumferences, body mass index, and blood pressure and performed a dysmorphological and neurological examination. We also collected data about the children's medical history, health care consultations, and motor milestones. RESULT(S): The mean height, weight, and body mass index were comparable for all groups. Six (5.8%) PGD, four (4.4%) IVF/ICSI, and five (8.6%) NC children had a major congenital abnormality. The incidence of acute and chronic illnesses was similar in all groups. Motor milestones were achieved on time, but the IVF/ICSI group had a slightly younger mean sitting age. None of the children had severe neurological problems. CONCLUSION(S): Five-year-old children born after PGD show normal growth, health, and motor development when compared with children born after IVF/ICSI and NC children from families with a genetic disorder. TRIAL REGISTRATION NUMBER: NCT02149485.


Assuntos
Desenvolvimento Infantil , Saúde da Criança , Fertilização In Vitro/efeitos adversos , Doenças Genéticas Inatas/genética , Testes Genéticos , Infertilidade/terapia , Destreza Motora , Diagnóstico Pré-Implantação/métodos , Fatores Etários , Pressão Sanguínea , Estatura , Índice de Massa Corporal , Pré-Escolar , Feminino , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/fisiopatologia , Nível de Saúde , Humanos , Infertilidade/diagnóstico , Infertilidade/fisiopatologia , Masculino , Medição de Risco , Fatores de Risco , Injeções de Esperma Intracitoplásmicas/efeitos adversos , Resultado do Tratamento , Ganho de Peso
16.
Clin Appl Thromb Hemost ; 25: 1076029619834352, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31025572

RESUMO

Little is known about the pathogenesis of cerebral sinovenous thrombosis (CSVT) in the neonate. Although thrombophilia has been described as increasing the risk of CSVT in adults, it remains controversial in pediatric patients, and prospective case-control studies regarding neonatal CSVT are lacking. From 2008 to 2017, all 26 consecutive newborn infants ≥35 weeks of gestation diagnosed with neonatal CSVT, and their mothers, were tested for factor V Leiden (FV) G1691A, FII G20210A, and methylenetetrahydrofolate reductase C677T (MTHFR C677T) mutations. Eighty-five mother-infant pairs were recruited as controls. All infants except 1 with CSVT were suspected due to clinical symptoms, mainly seizures (22/25). Magnetic resonance imaging was performed in 24/26 infants. Heterozygous FV G1691A, FII G20210A, and homozygous MTHFR C677T mutations were present in 1/26, 3/26, and 3/20 infants with CSVT, respectively. FII (odds ratio: 10.96; 95% confidence interval [CI]: 1.09-110.35) and male sex (3.93; 95% CI: 1.43-10.76) were associated with CSVT. When FII G20210A analysis was adjusted for sex, the OR for FII G20210A was 6.70 (95% CI: 0.65-69.22). No differences were found for FV G1691A or homozygous MTHFR mutations between neonates with CSVT and their mothers, compared to controls.


Assuntos
Fator V/genética , Doenças Genéticas Inatas/genética , Trombose Intracraniana/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Mutação de Sentido Incorreto , Protrombina/genética , Adulto , Feminino , Heterozigoto , Humanos , Recém-Nascido , Masculino , Estudos Prospectivos
17.
Nutr. hosp ; 36(2): 309-314, mar.-abr. 2019. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-184323

RESUMO

Introducción: la obesidad es un problema mundial que predispone a otras complicaciones de salud. Se ha demostrado que existe una relación directa entre obesidad y daño genético, lo que se considera en algunos casos como un marcador temprano de cáncer. Objetivo: evaluar el daño genético y los hábitos alimentarios de niños con obesidad y con normopeso. Métodos: estudio transversal realizado en niños en edad escolar. Partiendo de células de la mucosa del epitelio bucal, se evaluó el daño genético a través de la cuantificación de anormalidades nucleares tales como micronúcleos, cariorrexis, cariolisis, picnosis y presencia de dos núcleos. La evaluación nutricional se realizó mediante el análisis de peso, talla y la valoración de su alimentación por medio de historias clínicas nutricionales. Resultados: no se encontraron diferencias significativas en el número de anormalidades nucleares entre los grupos, aunque algunos niños con obesidad mostraron mayor número de anormalidades nucleares en comparación con niños con normopeso. En cuanto a sus hábitos alimentarios, se encontró una correlación positiva entre peso y el consumo de azúcares libres y proteínas en la dieta. Conclusiones: la falta de evidencia que correlacione los micronúcleos con el estado nutricional sugiere que la presencia de estas anormalidades se puede atribuir a factores ambientales o epigenéticos. Especial atención requiere el estudio de dietas similares a las consumidas habitualmente por esta población, con la finalidad de evitar sus potenciales consecuencias. Este estudio representa una contribución importante en la evaluación de los posibles riesgos para la salud asociados con la obesidad infantil


Introduction: obesity is a worldwide problem that predisposes to other health conditions. A direct relationship has been shown between obesity and genetic damage; the late is considered as an early marker of cancer in some cases. Objective: to evaluate the genetic damage and eating habits of children with obesity and normal weight. Methods: cross-sectional study conducted in school-age children. Genetic damage was assessed from buccal epithelial mucosal cells, through the quantification of nuclear abnormalities such as micronuclei, karyorrhexis, caryolysis, pyknosis and the presence of two nuclei. The nutritional evaluation was carried out through the analysis of weight, height and the evaluation of their diet through nutritional clinical records. Results: no significant differences were found in the number of nuclear abnormalities between the groups studied. However, some children with obesity showed higher number of nuclear abnormalities compared with children with normal weight. Regarding their eating habits, a positive correlation was found between weight and the consumption of free sugars and proteins in the diet. Conclusions: the lack of evidence that correlates micronuclei with nutritional status suggests that the presence of these abnormalities can be attributed to environmental or epigenetic factors. Special attention requires the study of diets similar to those habitually consumed by this population, in order to avoid their potential consequences. This study represents an important contribution in the evaluation of the possible health risks associated with childhood obesity


Assuntos
Humanos , Masculino , Feminino , Criança , Peso Corporal , Comportamento Alimentar , Doenças Genéticas Inatas/epidemiologia , Obesidade Pediátrica/epidemiologia , Obesidade Pediátrica/genética , Núcleo Celular/genética , Estudos Transversais , Carboidratos da Dieta , Proteínas na Dieta , Epigênese Genética , Células Epiteliais , Doenças Genéticas Inatas/genética , Testes para Micronúcleos , Estado Nutricional
18.
Nutr Hosp ; 36(2): 309-314, 2019 Apr 10.
Artigo em Espanhol | MEDLINE | ID: mdl-30868908

RESUMO

Introduction: Introduction: obesity is a worldwide problem that predisposes to other health conditions. A direct relationship has been shown between obesity and genetic damage; the late is considered as an early marker of cancer in some cases. Objective: to evaluate the genetic damage and eating habits of children with obesity and normal weight. Methods: cross-sectional study conducted in school-age children. Genetic damage was assessed from buccal epithelial mucosal cells, through the quantification of nuclear abnormalities such as micronuclei, karyorrhexis, caryolysis, pyknosis and the presence of two nuclei. The nutritional evaluation was carried out through the analysis of weight, height and the evaluation of their diet through nutritional clinical records. Results: no significant differences were found in the number of nuclear abnormalities between the groups studied. However, some children with obesity showed higher number of nuclear abnormalities compared with children with normal weight. Regarding their eating habits, a positive correlation was found between weight and the consumption of free sugars and proteins in the diet. Conclusions: the lack of evidence that correlates micronuclei with nutritional status suggests that the presence of these abnormalities can be attributed to environmental or epigenetic factors. Special attention requires the study of diets similar to those habitually consumed by this population, in order to avoid their potential consequences. This study represents an important contribution in the evaluation of the possible health risks associated with childhood obesity.


Assuntos
Peso Corporal , Comportamento Alimentar , Doenças Genéticas Inatas/epidemiologia , Obesidade Pediátrica/epidemiologia , Obesidade Pediátrica/genética , Núcleo Celular/genética , Criança , Estudos Transversais , Carboidratos da Dieta , Proteínas na Dieta , Epigênese Genética , Células Epiteliais , Feminino , Doenças Genéticas Inatas/genética , Humanos , Masculino , Testes para Micronúcleos , Estado Nutricional
19.
Hum Genet ; 138(4): 389-409, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30887117

RESUMO

Incidence rates of Mendelian diseases vary among ethnic groups, and frequencies of variant types of causative genes also vary among human populations. In this study, we examined to what extent we can predict population frequencies of recessive disorders from genomic data, and explored better strategies for variant interpretation and classification. We used a whole-genome reference panel from 3552 general Japanese individuals constructed by the Tohoku Medical Megabank Organization (ToMMo). Focusing on 32 genes for 17 congenital metabolic disorders included in newborn screening (NBS) in Japan, we identified reported and predicted pathogenic variants through variant annotation, interpretation, and multiple ways of classifications. The estimated carrier frequencies were compared with those from the Japanese NBS data based on 1,949,987 newborns from a previous study. The estimated carrier frequency based on genomic data with a recent guideline of variant interpretation for the PAH gene, in which defects cause hyperphenylalaninemia (HPA) and phenylketonuria (PKU), provided a closer estimate to that by the observed incidence than the other methods. In contrast, the estimated carrier frequencies for SLC25A13, which causes citrin deficiency, were much higher compared with the incidence rate. The results varied greatly among the 11 NBS diseases with single responsible genes; the possible reasons for departures from the carrier frequencies by reported incidence rates were discussed. Of note, (1) the number of pathogenic variants increases by including additional lines of evidence, (2) common variants with mild effects also contribute to the actual frequency of patients, and (3) penetrance of each variant remains unclear.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/genética , Triagem Neonatal/métodos , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Estudos de Coortes , Feminino , Frequência do Gene , Doenças Genéticas Inatas/epidemiologia , Estudo de Associação Genômica Ampla/normas , Heterozigoto , Humanos , Incidência , Recém-Nascido , Doenças do Recém-Nascido/epidemiologia , Japão/epidemiologia , Masculino , Padrões de Referência
20.
PLoS One ; 14(3): e0212811, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30897117

RESUMO

Adeno-associated virus (AAV) vectors represent promising candidates for gene therapy; however, pre-existing neutralizing antibodies (NAb) may reduce AAV vector delivery efficiency. In this study, the presence of AAV NAb was investigated in cats, which serve as a larger and outbred animal model for the prediction of gene therapy outcomes in humans but also in cats.Serum/plasma samples from 230 client-owned Swiss cats and 20 specified pathogen-free cats were investigated for NAb to AAV1, AAV2, AAV5, AAV6, AAV7, AAV8 and AAV9 using in vitro transduction inhibition and a beta-galactosidase assay. NAb to all tested AAV serotypes were found. Of the client-owned cats, 53% had NAb to one or more of the AAV serotypes. NAb (≥1:10) were found at frequencies of 5% (AAV6) to 28% (AAV7). The highest titers were found against AAV7 (≥1:160). The NAb prevalence to AAV2, AAV7 and AAV9 differed geographically. Regarding titers ≥1:10 against single AAV serotypes, age, breed and sex of the cats were not associated with the NAb prevalence. Cats with titers ≥1:20 against AAV2 and titers ≥1:40 against AAV7 were significantly younger than cats with low/no titers, and purebred cats were significantly more likely than non-purebred cats to have NAb to AAV2 (≥1:40). Additionally, regarding NAb to all AAV combined, female cats were significantly more likely than male cats to have NAb titers ≥1:40. Preliminary data using AAV-DJ indicated that less pre-existing NAb to the hybrid AAV-DJ can be expected compared to the wild-type AAV serotypes. AAV NAb will need to be taken into account for future in vivo gene therapy studies in cats.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Dependovirus/imunologia , Terapia Genética/efeitos adversos , Vetores Genéticos/imunologia , Fatores Etários , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/isolamento & purificação , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/isolamento & purificação , Doenças do Gato/genética , Doenças do Gato/terapia , Gatos , Linhagem Celular Tumoral , Dependovirus/genética , Feminino , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/terapia , Terapia Genética/métodos , Vetores Genéticos/genética , Células HEK293 , Humanos , Masculino , Modelos Animais , Sorogrupo , Fatores Sexuais
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