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1.
Nat Neurosci ; 22(10): 1624-1634, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31551593

RESUMO

Hundreds of genes are implicated in autism spectrum disorder (ASD), but the mechanisms through which they contribute to ASD pathophysiology remain elusive. Here we analyzed leukocyte transcriptomics from 1- to 4-year-old male toddlers with ASD or typical development from the general population. We discovered a perturbed gene network that includes highly expressed genes during fetal brain development. This network is dysregulated in human induced pluripotent stem cell-derived neuron models of ASD. High-confidence ASD risk genes emerge as upstream regulators of the network, and many risk genes may impact the network by modulating RAS-ERK, PI3K-AKT and WNT-ß-catenin signaling pathways. We found that the degree of dysregulation in this network correlated with the severity of ASD symptoms in the toddlers. These results demonstrate how the heterogeneous genetics of ASD may dysregulate a core network to influence brain development at prenatal and very early postnatal ages and, thereby, the severity of later ASD symptoms.


Assuntos
Transtorno do Espectro Autista/genética , Redes Reguladoras de Genes/genética , Transtorno do Espectro Autista/patologia , Encéfalo/embriologia , Encéfalo/patologia , Pré-Escolar , Desenvolvimento Fetal/genética , Humanos , Lactente , Leucócitos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Mutação/genética , Células-Tronco Neurais , Proteína Oncogênica v-akt/genética , Fosfatidilinositol 3-Quinases/genética , Transdução de Sinais/genética , Via de Sinalização Wnt/genética , beta Catenina/genética
2.
Anticancer Res ; 39(8): 4495-4502, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366551

RESUMO

BACKGROUND/AIM: In mice, fetal liver is the first tissue of definitive erythropoiesis for definitive erythroid expansion and maturation. ZFAT, originally identified as a candidate susceptibility gene for autoimmune thyroid disease, has been reported to be involved in primitive hematopoiesis and T cell development. The aim of this study was to examine whether or not Zfat is involved in definitive erythropoiesis in the fetal liver during mammalian development. MATERIALS AND METHODS: The role of Zfat during mouse fetal erythropoiesis in the fetal liver was examined using tamoxifen-inducible CreERT2 Zfat-deficient mice. RESULTS: Zfat-deficient mice exhibit moderate anemia with small and pale fetal liver through a decreased number of erythroblasts by E12.5. Apoptosis sensitivity in fetal liver erythroid progenitors was enhanced by Zfat-deficiency ex vivo. Moreover, Zfat knockdown partially inhibited CD71-/lowTer119- to CD71highTer119- transition of fetal liver erythroid progenitors with impairment in the elevation of CD71 expression. CONCLUSION: Zfat plays a critical role for erythropoiesis in the fetal liver.


Assuntos
Antígenos CD/genética , Eritropoese/genética , Fígado/crescimento & desenvolvimento , Receptores da Transferrina/genética , Fatores de Transcrição/genética , Animais , Apoptose/genética , Diferenciação Celular/genética , Células Eritroides/metabolismo , Células Eritroides/patologia , Desenvolvimento Fetal/genética , Feto , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Silenciamento de Genes , Humanos , Fígado/metabolismo , Camundongos , Linfócitos T/citologia , Linfócitos T/metabolismo , Tireoidite Autoimune/genética , Tireoidite Autoimune/patologia
3.
BMC Med Genet ; 20(1): 116, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253109

RESUMO

BACKGROUND: Preterm birth is a significant clinical problem and an enormous burden on society, affecting one in eight pregnant women and their newborns. Despite decades of research, the molecular mechanism underlying its pathogenesis remains unclear. Many studies have shown that preterm birth is associated with health risks across the later life course. The "fetal origins" hypothesis postulates that adverse intrauterine exposures are associated with later disease susceptibility. Our recent studies have focused on the placental epigenome at term. We extended these studies to genome-wide placental DNA methylation across a wide range of gestational ages. We applied methylation dependent immunoprecipitation/DNA sequencing (MeDIP-seq) to 9 placentas with gestational age from 25 weeks to term to identify differentially methylated regions (DMRs). RESULTS: Enrichment analysis revealed 427 DMRs with nominally significant differences in methylation between preterm and term placentas (p < 0.01) and 21 statistically significant DMRs after multiple comparison correction (FDR p < 0.05), of which 62% were hypo-methylated in preterm placentas vs term placentas. The majority of DMRs were in distal intergenic regions and introns. Significantly enriched pathways identified by Ingenuity Pathway Analysis (IPA) included Citrulline-Nitric Oxide Cycle and Fcy Receptor Mediated Phagocytosis in macrophages. The DMR gene set overlapped placental gene expression data, genes and pathways associated evolutionarily with preterm birth. CONCLUSION: These studies form the basis for future studies on the epigenetics of preterm birth, "fetal programming" and the impact of environment exposures on this important clinical challenge.


Assuntos
Metilação de DNA , Desenvolvimento Fetal/genética , Genoma , Recém-Nascido Prematuro/metabolismo , Placenta/metabolismo , Nascimento Prematuro/genética , DNA/metabolismo , Epigênese Genética , Feminino , Feto , Estudos de Associação Genética , Predisposição Genética para Doença , Idade Gestacional , Humanos , Recém-Nascido , Doenças do Recém-Nascido/genética , Masculino , Gravidez , Análise de Sequência de DNA
4.
PLoS Genet ; 15(6): e1008107, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31194736

RESUMO

Spontaneous preterm birth (SPTB) is the leading cause of neonatal death and morbidity worldwide. Both maternal and fetal genetic factors likely contribute to SPTB. We performed a genome-wide association study (GWAS) on a population of Finnish origin that included 247 infants with SPTB (gestational age [GA] < 36 weeks) and 419 term controls (GA 38-41 weeks). The strongest signal came within the gene encoding slit guidance ligand 2 (SLIT2; rs116461311, minor allele frequency 0.05, p = 1.6×10-6). Pathway analysis revealed the top-ranking pathway was axon guidance, which includes SLIT2. In 172 very preterm-born infants (GA <32 weeks), rs116461311 was clearly overrepresented (odds ratio 4.06, p = 1.55×10-7). SLIT2 variants were associated with SPTB in another European population that comprised 260 very preterm infants and 9,630 controls. To gain functional insight, we used immunohistochemistry to visualize SLIT2 and its receptor ROBO1 in placentas from spontaneous preterm and term births. Both SLIT2 and ROBO1 were located in villous and decidual trophoblasts of embryonic origin. Based on qRT-PCR, the mRNA levels of SLIT2 and ROBO1 were higher in the basal plate of SPTB placentas compared to those from term or elective preterm deliveries. In addition, in spontaneous term and preterm births, placental SLIT2 expression was correlated with variations in fetal growth. Knockdown of ROBO1 in trophoblast-derived HTR8/SVneo cells by siRNA indicated that it regulate expression of several pregnancy-specific beta-1-glycoprotein (PSG) genes and genes involved in inflammation. Our results show that the fetal SLIT2 variant and both SLIT2 and ROBO1 expression in placenta and trophoblast cells may be correlated with susceptibility to SPTB. SLIT2-ROBO1 signaling was linked with regulation of genes involved in inflammation, PSG genes, decidualization and fetal growth. We propose that this receptor-ligand couple is a component of the signaling network that promotes SPTB.


Assuntos
Desenvolvimento Fetal/genética , Predisposição Genética para Doença , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas do Tecido Nervoso/genética , Nascimento Prematuro/genética , Receptores Imunológicos/genética , Feminino , Feto , Finlândia , Regulação da Expressão Gênica/genética , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Placenta/patologia , Polimorfismo de Nucleotídeo Único , Gravidez , Glicoproteínas beta 1 Específicas da Gravidez/genética , Nascimento Prematuro/patologia , Transdução de Sinais , Trofoblastos/patologia
5.
Eur J Med Genet ; 62(7): 103671, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31100449

RESUMO

The growth factor binding protein 10 (GRB10) has been suggested as a candidate gene for Silver-Russell syndrome because of its localization in 7p12, its imprinting status, data from mice models and its putative role in growth. Based on a new patient with normal growth carrying a GRB10 deletion affecting the paternal allele and data from the literature, we conclude that the heterogeneous clinical findings in patients with copy number variations (CNVs) of GRB10 gene depend on the size and the gene content of the CNV. However, evidence from mouse and human cases indicate a growth suppressing role of GRB10 in prenatal development. As a result, an increase of active maternal GRB10 copies, e.g. by maternal uniparental disomy of chromosome 7 or duplications of the region results in intrauterine growth retardation. In contrast, a defective GRB10 copy might result in prenatal overgrowth, whereas the paternal GRB10 allele is not required for proper prenatal growth.


Assuntos
Cromossomos Humanos Par 7/genética , Variações do Número de Cópias de DNA , Proteína Adaptadora GRB10/genética , Fenótipo , Síndrome de Silver-Russell/genética , Adolescente , Desenvolvimento Fetal/genética , Humanos , Masculino , Síndrome de Silver-Russell/patologia
6.
Nat Cell Biol ; 21(5): 651-661, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31036937

RESUMO

A single genome gives rise to diverse tissues through complex epigenomic mechanisms, including N6-methyladenosine (m6A), a widespread RNA modification that is implicated in many biological processes. Here, to explore the global landscape of m6A in human tissues, we generated 21 whole-transcriptome m6A methylomes across major fetal tissues using m6A sequencing. These data reveal dynamic m6A methylation, identify large numbers of tissue differential m6A modifications and indicate that m6A is positively correlated with gene expression homeostasis. We also report m6A methylomes of long intergenic non-coding RNA (lincRNA), finding that enhancer lincRNAs are enriched for m6A. Tissue m6A regions are often enriched for single nucleotide polymorphisms that are associated with the expression of quantitative traits and complex traits including common diseases, which may potentially affect m6A modifications. Finally, we find that m6A modifications preferentially occupy genes with CpG-rich promoters, features of which regulate RNA transcript m6A. Our data indicate that m6A is widely regulated by human genetic variation and promoters, suggesting a broad involvement of m6A in human development and disease.


Assuntos
Adenosina/análogos & derivados , Elementos Facilitadores Genéticos , Desenvolvimento Fetal/genética , Feto , Adenosina/genética , Epigenômica , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/genética , Humanos , Metilação , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas , RNA Longo não Codificante/genética , Transcriptoma/genética
7.
Nat Genet ; 51(5): 804-814, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043758

RESUMO

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.


Assuntos
Peso ao Nascer/genética , Adulto , Pressão Sanguínea/genética , Estatura/genética , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Desenvolvimento Fetal/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cardiopatias/etiologia , Cardiopatias/genética , Humanos , Recém-Nascido , Masculino , Herança Materna/genética , Troca Materno-Fetal/genética , Doenças Metabólicas/etiologia , Doenças Metabólicas/genética , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Gravidez , Fatores de Risco
8.
Zhonghua Fu Chan Ke Za Zhi ; 54(4): 221-225, 2019 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-31006186

RESUMO

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


Assuntos
Anormalidades Congênitas/genética , Dineínas do Citoplasma , Variações do Número de Cópias de DNA , Desenvolvimento Fetal/genética , Feto/anormalidades , Sequenciamento Completo do Exoma/métodos , Anormalidades Congênitas/diagnóstico , Variações do Número de Cópias de DNA/genética , Feminino , Feto/diagnóstico por imagem , Humanos , Cariotipagem , Gravidez , Primeiro Trimestre da Gravidez , Segundo Trimestre da Gravidez , Ultrassonografia Pré-Natal
9.
Nat Commun ; 10(1): 1893, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015461

RESUMO

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10-7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10-74) and BMI in pregnancy (3/914, p = 1.13x10-3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.


Assuntos
Peso ao Nascer/genética , DNA/metabolismo , Epigênese Genética , Genoma Humano , Adolescente , Adulto , Índice de Massa Corporal , Criança , Ilhas de CpG , DNA/genética , Metilação de DNA , Feminino , Desenvolvimento Fetal/genética , Feto , Ácido Fólico/sangue , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Fumar/efeitos adversos , Fumar/sangue , Fumar/genética
10.
Biosci Biotechnol Biochem ; 83(6): 1045-1061, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30935300

RESUMO

MicroRNAs (miRNAs) regulate the development and growth cycle of hair follicles (HFs). The molecular mechanism by which miRNAs determine the development of HFs in the sheep foetus remains elusive. In this study, the expression profiles of miRNAs at 11 development periods (45, 55, 65, 75, 85, 95, 105, 115, 125, 135 and 145 d) in sheep foetus skin were analysed by high-throughput sequencing and bioinformatics analysis. A total of 72 conserved miRNAs, 44 novel miRNAs and 32 known miRNAs were significantly differentially expressed. qRT-PCR results for 18 miRNAs were consistent with the sequencing data. 85 d of foetal development was the starting point for secondary hair follicle (SF) development according to tissue morphology and cluster analysis. In SF development, the prolactin signalling pathway and platelet activation played important roles, and 10 miRNAs were potential candidate miRNAs in SF initiation.


Assuntos
Desenvolvimento Fetal/genética , Perfilação da Expressão Gênica , Folículo Piloso/crescimento & desenvolvimento , MicroRNAs/genética , Ovinos/embriologia , Animais , Biologia Computacional , Regulação para Baixo , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Ativação Plaquetária , Prolactina/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Análise de Sequência de RNA/métodos , Transdução de Sinais , Regulação para Cima ,
11.
Lancet ; 393(10173): 747-757, 2019 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-30712880

RESUMO

BACKGROUND: Fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which are detectable by chromosomal microarrays), and pathogenic sequence variants in developmental genes. Testing for aneuploidy and CNVs is routine during the investigation of fetal structural anomalies, but there is little information on the clinical usefulness of genome-wide next-generation sequencing in the prenatal setting. We therefore aimed to evaluate the proportion of fetuses with structural abnormalities that had identifiable variants in genes associated with developmental disorders when assessed with whole-exome sequencing (WES). METHODS: In this prospective cohort study, two groups in Birmingham and London recruited patients from 34 fetal medicine units in England and Scotland. We used whole-exome sequencing (WES) to evaluate the presence of genetic variants in developmental disorder genes (diagnostic genetic variants) in a cohort of fetuses with structural anomalies and samples from their parents, after exclusion of aneuploidy and large CNVs. Women were eligible for inclusion if they were undergoing invasive testing for identified nuchal translucency or structural anomalies in their fetus, as detected by ultrasound after 11 weeks of gestation. The partners of these women also had to consent to participate. Sequencing results were interpreted with a targeted virtual gene panel for developmental disorders that comprised 1628 genes. Genetic results related to fetal structural anomaly phenotypes were then validated and reported postnatally. The primary endpoint, which was assessed in all fetuses, was the detection of diagnostic genetic variants considered to have caused the fetal developmental anomaly. FINDINGS: The cohort was recruited between Oct 22, 2014, and June 29, 2017, and clinical data were collected until March 31, 2018. After exclusion of fetuses with aneuploidy and CNVs, 610 fetuses with structural anomalies and 1202 matched parental samples (analysed as 596 fetus-parental trios, including two sets of twins, and 14 fetus-parent dyads) were analysed by WES. After bioinformatic filtering and prioritisation according to allele frequency and effect on protein and inheritance pattern, 321 genetic variants (representing 255 potential diagnoses) were selected as potentially pathogenic genetic variants (diagnostic genetic variants), and these variants were reviewed by a multidisciplinary clinical review panel. A diagnostic genetic variant was identified in 52 (8·5%; 95% CI 6·4-11·0) of 610 fetuses assessed and an additional 24 (3·9%) fetuses had a variant of uncertain significance that had potential clinical usefulness. Detection of diagnostic genetic variants enabled us to distinguish between syndromic and non-syndromic fetal anomalies (eg, congenital heart disease only vs a syndrome with congenital heart disease and learning disability). Diagnostic genetic variants were present in 22 (15·4%) of 143 fetuses with multisystem anomalies (ie, more than one fetal structural anomaly), nine (11·1%) of 81 fetuses with cardiac anomalies, and ten (15·4%) of 65 fetuses with skeletal anomalies; these phenotypes were most commonly associated with diagnostic variants. However, diagnostic genetic variants were least common in fetuses with isolated increased nuchal translucency (≥4·0 mm) in the first trimester (in three [3·2%] of 93 fetuses). INTERPRETATION: WES facilitates genetic diagnosis of fetal structural anomalies, which enables more accurate predictions of fetal prognosis and risk of recurrence in future pregnancies. However, the overall detection of diagnostic genetic variants in a prospectively ascertained cohort with a broad range of fetal structural anomalies is lower than that suggested by previous smaller-scale studies of fewer phenotypes. WES improved the identification of genetic disorders in fetuses with structural abnormalities; however, before clinical implementation, careful consideration should be given to case selection to maximise clinical usefulness. FUNDING: UK Department of Health and Social Care and The Wellcome Trust.


Assuntos
Cariótipo Anormal/estatística & dados numéricos , Anormalidades Congênitas/genética , Desenvolvimento Fetal/genética , Feto/anormalidades , Sequenciamento Completo do Exoma/estatística & dados numéricos , Cariótipo Anormal/embriologia , Aborto Eugênico/estatística & dados numéricos , Aborto Espontâneo/epidemiologia , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/epidemiologia , Variações do Número de Cópias de DNA/genética , Feminino , Feto/diagnóstico por imagem , Humanos , Recém-Nascido , Nascimento Vivo/epidemiologia , Masculino , Medição da Translucência Nucal , Pais , Morte Perinatal/etiologia , Gravidez , Estudos Prospectivos , Natimorto/epidemiologia , Sequenciamento Completo do Exoma/métodos
12.
Gene ; 697: 48-56, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-30790652

RESUMO

BACKGROUND: Autosomal recessive disorder is closely correlated with congenital fetal malformation. The mutation of WDR35 may lead to short rib-polydactyly syndrome (SRP), asphyxiating thoracic dystrophy (ATD, Jeune syndrome) and Ellis van Creveld syndrome. The purpose of this study is to investigate the role of WDR35 in fetal anomaly. RESULTS: The fetuses presented malformation with abnormal head shape, cardiac dilatation, pericardial effusion, and non-displayed left pulmonary artery and left lung. After the detection of genomic DNA (gDNA) in amniotic fluid cells (AFC), chromosomal rearrangement was found in arr[hg19] 2p25.3p23.3. It was revealed through multiple PCR-DHPLC that MYCN, WDR35, LPIN1, ODC1, KLF11 and NBAS contained duplicated copy numbers in 2p25.3p23.3. AF-MSCs were mostly positive for CD44, CD105, negative for CD34 and CD14. Western Blot test showed that WDR35-encoded protein was decreased in the patients' AFC compared to that in normal pregnant women. In the patients' amniotic fluid-derived mesenchymal stem cells (AF-MSCs), WDR35 overexpression could repair cilia formation, and the overexpression of WDR35 or Gli2 could significantly enhance ALP activity and expressions of osteogenic differentiation marker genes, including RUNXE2, OCN, BSP and ALP. However, WDR35 silencing in C3H10T1/2 cells could remarkably inhibit cilia formation and osteogenic differentiation. This inhibitory effect could be attenuated by Gli2 overexpression. CONCLUSIONS: The results demonstrated that copy number variation (CNV) of WDR35 may lead to skeletal dysplasia and fetal anomaly, and that down-regulated WDR35 may damage the cilia formation and sequentially indirectly regulate Gli signal, which would eventually result in negative regulation of osteogenic differentiation.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Osteogênese/fisiologia , Proteínas/genética , Adulto , Líquido Amniótico/química , Líquido Amniótico/citologia , Animais , Doenças do Desenvolvimento Ósseo/metabolismo , Diferenciação Celular/fisiologia , Cílios/genética , Cílios/fisiologia , Variações do Número de Cópias de DNA , Feminino , Desenvolvimento Fetal/genética , Humanos , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Endogâmicos C3H , Fenótipo , Polimorfismo de Nucleotídeo Único , Gravidez , Proteínas/metabolismo
13.
Lancet ; 393(10173): 758-767, 2019 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-30712878

RESUMO

BACKGROUND: Identification of chromosomal aneuploidies and copy number variants that are associated with fetal structural anomalies has substantial value. Although whole-exome sequencing (WES) has been applied to case series of a few selected prenatal cases, its value in routine clinical settings has not been prospectively assessed in a large unselected cohort of fetuses with structural anomalies. We therefore aimed to determine the incremental diagnostic yield (ie, the added value) of WES following uninformative results of standard investigations with karyotype testing and chromosomal microarray in an unselected cohort of sequential pregnancies showing fetal structural anomalies. METHODS: In this prospective cohort study, the parents of fetuses who were found to have a structural anomaly in a prenatal ultrasound were screened for possible participation in the study. These participants were predominantly identified in or were referred to the Columbia University Carmen and John Thain Center for Prenatal Pediatrics (New York, NY, USA). Fetuses with confirmed aneuploidy or a causal pathogenic copy number variant were excluded from WES analyses. By use of WES of the fetuses and parents (parent-fetus trios), we identified genetic variants that indicated an underlying cause (diagnostic genetic variants) and genetic variants that met the criteria of bioinformatic signatures that had previously been described to be significantly enriched among diagnostic genetic variants. FINDINGS: Between April 24, 2015, and April 19, 2017, 517 sequentially identified pregnant women found to have fetuses with a structural anomaly were screened for their eligibility for inclusion in our study. 71 (14%) couples declined testing, 87 (17%) trios were missing at least one DNA sample (from either parent or the fetus), 69 (13%) trios had a clinically relevant abnormal karyotype or chromosomal microarray finding, 51 (10%) couples did not consent to WES or withdrew consent, and five (1%) samples were not of good enough quality for analysis. DNA samples from 234 (45%) eligible trios were therefore used for analysis of the primary outcome. By use of trio sequence data, we identified diagnostic genetic variants in 24 (10%) families. Mutations with bioinformatic signatures that were indicative of pathogenicity but with insufficient evidence to be considered diagnostic were also evaluated; 46 (20%) of the 234 fetuses assessed were found to have such signatures. INTERPRETATION: Our analysis of WES data in a prospective cohort of unselected fetuses with structural anomalies shows the value added by WES following the use of routine genetic tests. Our findings suggest that, in cases of fetal anomalies in which assessment with karyotype testing and chromosomal microarray fail to determine the underlying cause of a structural anomaly, WES can add clinically relevant information that could assist current management of a pregnancy. The unique challenges of WES-based prenatal diagnostics require analysis by a multidisciplinary team of perinatal practitioners and laboratory specialists. FUNDING: Institute for Genomic Medicine (Columbia University Irving Medical Center).


Assuntos
Cariótipo Anormal/embriologia , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Aneuploidia , Variações do Número de Cópias de DNA/genética , Desenvolvimento Fetal/genética , Feto/anormalidades , Sequenciamento Completo do Exoma/estatística & dados numéricos , Anormalidades Múltiplas/epidemiologia , Amniocentese , Amostra da Vilosidade Coriônica , Feminino , Triagem de Portadores Genéticos , Humanos , Masculino , Gravidez , Estudos Prospectivos , Ultrassonografia Pré-Natal , Sequenciamento Completo do Exoma/métodos
14.
Medicine (Baltimore) ; 98(3): e13971, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30653101

RESUMO

Preeclampsia (PE) is a disorder specific to pregnancy characterized by new-onset hypertension and proteinuria after 20 weeks of gestation. There is no definite treatment for PE except delivery of the placenta. The purpose of this study was to elucidate the biological pathways involved in the development of PE and to discover a novel biomarker for PE by performing global gene expression analysis of amniotic fluid cell-free RNA.The participants were recruited from the Department of Obstetrics and Gynecology of CHA Gangnam Medical Center (Seoul, Korea) between March 2014 and February 2015. Eight samples were collected from 8 subjects at second trimester who were later diagnosed with PE. From the amniotic fluid samples, cell-free RNA extraction was performed and gene expression was analyzed using the GeneChip PrimeView Array. Transcriptome data previously analyzed by our group from 9 euploid mid-trimester amniotic fluid samples were used as the control for comparative analysis. Functional analysis of the probe sets was performed using the online Database for Annotation, Visualization, and Integrated Discovery (DAVID) toolkit 6.7.We identified 1841 differentially expressed genes (DEGs) between the PE group and the control. Of these, 1557 genes were upregulated in the PE group, while 284 genes were upregulated in the control. The functional annotation of DEGs identified specific enriched functions such as "transport," "signal transduction," and "stress response." Functional annotation clustering with enriched genes in the PE group revealed that translation-related genes, cell-cell adhesion genes, and immune-related genes were enriched. KEGG pathway analysis showed that several biological pathways, including the ribosome pathway and various immune pathways, were dysregulated. Several genes, including RPS29, IGF-2, and UBC, were significantly upregulated in PE, up to tenfold.This study provides the first genome-wide expression analysis of amniotic fluid cell-free RNA in PE. The results showed that gene expression involving the ribosome pathway and immunologic pathways are dysregulated in PE. Our results will aid in understanding the underlying pathogenesis of PE.


Assuntos
Líquido Amniótico/metabolismo , Ácidos Nucleicos Livres/genética , Perfilação da Expressão Gênica/métodos , Pré-Eclâmpsia/genética , Adulto , Feminino , Desenvolvimento Fetal/genética , Idade Gestacional , Humanos , Análise em Microsséries/métodos , Pessoa de Meia-Idade , Pré-Eclâmpsia/diagnóstico , Gravidez , Segundo Trimestre da Gravidez , República da Coreia/epidemiologia , Transdução de Sinais/genética , Estresse Fisiológico/genética , Transcriptoma/genética
15.
Dev Psychopathol ; 30(3): 807-824, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30068415

RESUMO

Decades of fetal programming research indicates that we may be able to map the origins of many physical, psychological, and medical variations and morbidities before the birth of the child. While great strides have been made in identifying associations between prenatal insults, such as undernutrition or psychosocial stress, and negative developmental outcomes, far less is known about how adaptive responses to adversity regulate the developing phenotype to match stressful conditions. As the application of epigenetic methods to human behavior has exploded in the last decade, research has begun to shed light on the role of epigenetic mechanisms in explaining how prenatal conditions shape later susceptibilities to mental and physical health problems. In this review, we describe and attempt to integrate two dominant fetal programming models: the cumulative stress model (a disease-focused approach) and the match-mismatch model (an evolutionary-developmental approach). In conjunction with biological sensitivity to context theory, we employ these two models to generate new hypotheses regarding epigenetic mechanisms through which prenatal and postnatal experiences program child stress reactivity and, in turn, promote development of adaptive versus maladaptive phenotypic outcomes. We conclude by outlining priority questions and future directions for the fetal programming field.


Assuntos
Epigênese Genética/genética , Desenvolvimento Fetal/genética , Efeitos Tardios da Exposição Pré-Natal/genética , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença/genética , Humanos , Lactente , Recém-Nascido , Masculino , Modelos Genéticos , Fenótipo , Gravidez
16.
J Genet ; 97(2): 469-475, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29932067

RESUMO

Smooth muscle myosin heavy chain (SM-MHC) is exclusively expresses in smooth muscle, which takes part in smooth muscle cell contraction. Here, we used an insertional mutation mouse whose heavy polypeptide 11 (Myh11) gene has been disrupted and no SM-MHC protein has been detected. Compared to the wild-type and SM-MHC+/- mice, the SM-MHC-/- neonates had large round bellies, thin-walled giant bladders, and large stomachs with huge gas bubbles. Most of it died within 10 h and the rest within 20 h after birth. Further analysis of the developing foetuses from 16.5 days postcoitum (dpc) stage to newborn showed no significant (P<0.05) difference in the ratio of Mendelian inheritance and average body weight among SM-MHC+/+ , SM-MHC+/- and SM-MHC-/- mice, whereas the abnormal exterior appearance was observed in each SM-MHC-/- bladders from 16.5 dpc. Histological analysis showed no difference in stomach tissues but evidently thin-walled smooth muscle layer and a giant cavity in bladders of SM-MHC-/- foetuses at various stages from 15.5 dpc to newborn. The results indicated that the defect of SM-MHC lead to the bladder developing lesions initially at 15.5 dpc stage in mouse and also implied that the SM-MHC loss might result in the gas bubbles in stomach. The study should facilitate further detailed analyses of the potential role of SM-MHC in bladder and stomach development.


Assuntos
Desenvolvimento Fetal/genética , Mucosa Gástrica/metabolismo , Músculo Liso/metabolismo , Cadeias Pesadas de Miosina/genética , Bexiga Urinária/metabolismo , Animais , Animais Recém-Nascidos , Sequência de Bases , Feminino , Masculino , Camundongos , Camundongos Knockout , Músculo Liso/embriologia , Cadeias Pesadas de Miosina/deficiência , Estômago/embriologia , Fatores de Tempo , Bexiga Urinária/embriologia
17.
Adv Exp Med Biol ; 1012: 63-73, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29956195

RESUMO

The placenta is considered to have developed recently in mammalian evolution. While the fundamental function of the placenta, i.e., providing nutrients and oxygen to the fetus and receiving waste products, is the same in all mammals, the morphology of the placenta varies substantially in a species-dependent manner. Therefore, considerable interest exists in understanding placental development and function in mammals from a molecular biological viewpoint. Numerous recent studies have shown that various environmental factors before and during pregnancy, including nutrition, affect placental formation and function and that alterations in placental formation and function can influence the developing fetus and the offspring after birth. To date, the relationship between nutrition and the placenta has been investigated in several species, various model organisms, and humans. In this chapter, we discuss the current knowledge of the placenta and the epigenome and then highlight the effects of nutrition during pregnancy on the placenta and the fetus and on the offspring after birth.


Assuntos
Meio Ambiente , Placentação/fisiologia , Fenômenos Fisiológicos da Nutrição Pré-Natal , Animais , Feminino , Desenvolvimento Fetal/genética , Feto/fisiologia , Interação Gene-Ambiente , Humanos , Placenta/fisiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Fenômenos Fisiológicos da Nutrição Pré-Natal/genética
18.
Adv Exp Med Biol ; 1012: 85-95, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29956197

RESUMO

The developmental origins of health and disease (DOHaD) refers to the concept that environmental stress during pregnancy alters the programmed fetal development and subsequently causes disorders, such as cardiovascular and metabolic diseases, in adulthood. Epigenetics is a gene regulation mechanism that does not depend on DNA sequence but on chemical modifications of DNA. Several lines of evidence suggest that environmental stress in the fetal period alters the epigenetic state of genes, leading to permanent gene dysregulation, which may be associated with disorders that emerge after birth. Such stresses include malnutrition, which may be associated with type 2 diabetes, and mental stress, which may be associated with neurodevelopmental disorders. It has also been demonstrated that environmental stress-induced epigenetic alterations can be transmitted to the next generation via disease phenotypes. However, since epigenetic modification is an internal system based on attachment and detachment of chemical residues on a DNA sequence, it is reversible and potentially treatable. In fact, recent studies demonstrated that some drugs and early interventions are effective at preventing epigenetic disorders. Therefore, preventive and preemptive medicine is possible for disorders caused by alterations in programming during fetal and early periods.


Assuntos
Epigênese Genética/fisiologia , Epigenômica/métodos , Desenvolvimento Fetal/genética , Cuidado Pré-Natal/métodos , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Medicina Preventiva/métodos , Feminino , Humanos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/psicologia , Estresse Psicológico/complicações , Estresse Psicológico/genética
19.
Nihon Eiseigaku Zasshi ; 73(2): 105-109, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-29848859

RESUMO

In Japan, the prevalence of low birth weight (< 2,500 g) has been increasing, probably owing to leanness, exposure to toxic chemicals and smoking. Epidemiological studies revealed that low birth weight poses risks of hypertension, coronary heart diseases and diabetes. Although the precise mechanism has not been understood, there is an urgent need for appropriate public health interventions. MicroRNA (miRNA) is a small RNA consisting of approximately 22 nucleotides and distributed in a wide variety of organs and body fluids. miRNAs are involved in the pathogenesis of various human diseases and expected to be their potential biomarkers. The interest on the study on miRNA in the research field of developmental origins of health and disease (DOHaD) has been growing, and the number of related papers has been increasing. There are several molecular epidemiological studies on the relationship between maternal miRNA and fetal development. The effects of smoking and dietary factors on miRNA expression and fetal development have been investigated in epidemiological and experimental studies. However, the role of maternal miRNA in fetal development has not been well understood so far. In this review, the current status of studies on miRNA expression in DOHaD research is described and future perspectives are discussed.


Assuntos
Dieta , Desenvolvimento Fetal , Recém-Nascido de Baixo Peso , Troca Materno-Fetal/genética , Troca Materno-Fetal/fisiologia , MicroRNAs , Animais , Doença das Coronárias/etiologia , Diabetes Mellitus/etiologia , Feminino , Desenvolvimento Fetal/genética , Expressão Gênica , Humanos , Hipertensão/etiologia , Japão/epidemiologia , MicroRNAs/genética , MicroRNAs/fisiologia , Gravidez , Risco , Fumar/efeitos adversos
20.
Acta Med Okayama ; 72(2): 115-119, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29674759

RESUMO

We devised biomathematics-based formulae to estimate the standard values of fetal growth of Japanese after 22 weeks' gestation. The growth rates of bi-parietal diameter (BPD), abdominal circumference (AC), femur length (FL), and estimated fetal body weight (EFBW) at the time of gestation were assumed to be proportional to the product of the value at the time and the rest value of an unknown maximum value, respectively. The EFBW was also assumed to follow a multiple logistic function of BPD, AC and FL to fit the standard values of Japanese fetuses published by the Japan Society of Ultrasonics in Medicine. The Mann-Whitney test was used for statistical analysis. The values as a function of gestational day, t, were as follows: BPD(t)=99.6/(1+exp (2.725-0.01837*t)) (mm); AC(t)=39.7/(1+exp (2.454-0.01379*t)) (cm); FL(t)=79.6/(1+exp (2.851-0.01710*t)) (mm); EFBW(t)=8045.1/(1+exp (6.028-0.06582*BPD(t)-0.1469*AC(t)+ 0.07377*FL(t))) (g). EFBW as a function of BPD, AC and FL was as follows: EFBW=8045.1/(1+exp (4.747+ 0.02584*BPD+0.1010*AC-0.1416*FL)) (g). When the BPD, AC and FL were at -2 standard deviation (SD), -1SD, mean and + 2SD, the EFBW values calculated by the formula were statistically closer to the standard values than conventional formulas with p-values of 4.871×10-7, 4.228×10-7, 9.777×10-7 and 0.028, respectively. The formulae based on biomathematics might be useful to estimate the fetal growth standard values.


Assuntos
Antropometria/métodos , Desenvolvimento Fetal/fisiologia , Idade Gestacional , Grupo com Ancestrais do Continente Asiático , Feminino , Desenvolvimento Fetal/genética , Humanos , Gravidez
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