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1.
Mol Genet Metab Rep ; 21: 100518, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31641590

RESUMO

Altered vitamin B6 metabolism due to pathogenic variants in the gene PNPO causes early onset epileptic encephalopathy, which can be treated with high doses of vitamin B6. We recently reported that single nucleotide polymorphisms (SNPs) that influence PNPO expression in the brain are associated with genetic generalized epilepsy (GGE). However, it is not known whether any of these GGE-associated SNPs influence vitamin B6 metabolite levels. Such an influence would suggest that vitamin B6 could play a role in GGE therapy. Here, we performed genome-wide association studies (GWAS) to assess the influence of GGE associated genetic variants on measures of vitamin B6 metabolism in blood plasma in 2232 healthy individuals. We also asked if SNPs that influence vitamin B6 were associated with GGE in 3122 affected individuals and 20,244 controls. Our GWAS of vitamin B6 metabolites reproduced a previous association and found a novel genome-wide significant locus. The SNPs in these loci were not associated with GGE. We found that 84 GGE-associated SNPs influence expression levels of PNPO in the brain as well as in blood. However, these SNPs were not associated with vitamin B6 metabolism in plasma. By leveraging polygenic risk scoring (PRS), we found suggestive evidence of higher catabolism and lower levels of the active and transport forms of vitamin B6 in GGE, although these findings require further replication.

2.
Birth Defects Res ; 111(20): 1618-1632, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31328417

RESUMO

BACKGROUND: The National Birth Defects Prevention Study (NBDPS) is a multisite, population-based, case-control study of genetic and nongenetic risk factors for major structural birth defects. Eligible women had a pregnancy affected by a birth defect or a liveborn child without a birth defect between 1997 and 2011. They were invited to complete a telephone interview to collect pregnancy exposure data and were mailed buccal cell collection kits to collect specimens from themselves, their child (if living), and their child's father. Over 23,000 families representing more than 30 major structural birth defects provided DNA specimens. METHODS: To evaluate their utility for exome sequencing (ES), specimens from 20 children with colonic atresia were studied. Evaluations were conducted on specimens collected using cytobrushes stored and transported in open versus closed packaging, on native genomic DNA (gDNA) versus whole genome amplified (WGA) products and on a library preparation protocol adapted to low amounts of DNA. RESULTS: The DNA extracted from brushes in open packaging yielded higher quality sequence data than DNA from brushes in closed packaging. Quality metrics of sequenced gDNA were consistently higher than metrics from corresponding WGA products and were consistently high when using a low input protocol. CONCLUSIONS: This proof-of-principle study established conditions under which ES can be applied to NBDPS specimens. Successful sequencing of exomes from well-characterized NBDPS families indicated that this unique collection can be used to investigate the roles of genetic variation and gene-environment interaction effects in birth defect etiologies, providing a valuable resource for birth defect researchers.

3.
Genet Epidemiol ; 43(1): 102-111, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30334581

RESUMO

Results from association studies are traditionally corroborated by replicating the findings in an independent data set. Although replication studies may be comparable for the main trait or phenotype of interest, it is unlikely that secondary phenotypes will be comparable across studies, making replication problematic. Alternatively, there may simply not be a replication sample available because of the nature or frequency of the phenotype. In these situations, an approach based on complementary pairs stability selection for genome-wide association study (ComPaSS-GWAS), is proposed as an ad-hoc alternative to replication. In this method, the sample is randomly split into two conditionally independent halves multiple times (resamples) and a GWAS is performed on each half in each resample. Similar in spirit to testing for association with independent discovery and replication samples, a marker is corroborated if its p-value is significant in both halves of the resample. Simulation experiments were performed for both nongenetic and genetic models. The type I error rate and power of ComPaSS-GWAS were determined and compared to the statistical properties of a traditional GWAS. Simulation results show that the type I error rate decreased as the number of resamples increased with only a small reduction in power and that these results were comparable with those from a traditional GWAS. Blood levels of vitamin pyridoxal 5'-phosphate from the Trinity Student Study (TSS) were used to validate this approach. The results from the validation study were compared to, and were consistent with, those obtained from previously published independent replication data and functional studies.


Assuntos
Estudo de Associação Genômica Ampla , Simulação por Computador , Humanos , Modelos Genéticos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes
5.
JAMA ; 320(24): 2600-2601, 2018 12 25.
Artigo em Inglês | MEDLINE | ID: mdl-30575871
6.
Am J Clin Nutr ; 108(6): 1334-1341, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30339177

RESUMO

Background: Genetic polymorphisms can explain some of the population- and individual-based variations in nutritional status biomarkers. Objective: We sought to screen the entire human genome for common genetic polymorphisms that influence folate-status biomarkers in healthy individuals. Design: We carried out candidate gene analyses and genome-wide association scans in 2232 young, healthy Irish subjects to evaluate which common genetic polymorphisms influence red blood cell folate, serum folate, and plasma total homocysteine. Results: The 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C→T (rs1801133) variant was the major genetic modifier of all 3 folate-related biomarkers in this Irish population and reached genome-wide significance for red blood cell folate (P = 1.37 × 10-17), serum folate (P = 2.82 × 10-11), and plasma total homocysteine (P = 1.26 × 10-19) concentrations. A second polymorphism in the MTHFR gene (rs3753584, P = 1.09 × 10-11) was the only additional MTHFR variant to exhibit any significant independent effect on red blood cell folate. Other MTHFR variants, including the 1298A→C variant (rs1801131), appeared to reach genome-wide significance, but these variants shared linkage disequilibrium with MTHFR 677C→T and were not significant when analyzed in MTHFR 677CC homozygotes. No additional non-MTHFR modifiers of red blood cell or plasma folate were detected. Two additional genome-wide significant modifiers of plasma homocysteine were found in the region of the dipeptidase 1 (DPEP1) gene on chromosome 16 and the Twist neighbor B (TWISTNB) gene on chromosome 7. Conclusions: The MTHFR 677C→T variant is the predominant genetic modifier of folate status biomarkers in this healthy Irish population. It is not necessary to determine MTHFR 677C→T genotype to evaluate folate status because its effect is reflected in concentrations of standard folate biomarkers. The MTHFR 1298A→C variant had no independent effect on folate status biomarkers. To our knowledge, this is the first genome-wide association study report on red blood cell folate and the first report of an association between homocysteine and TWISTNB.


Assuntos
Biomarcadores/sangue , Ácido Fólico/sangue , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Estado Nutricional/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Eritrócitos/química , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Homocisteína/sangue , Humanos , Irlanda , Desequilíbrio de Ligação , Masculino , Adulto Jovem
7.
J Biol Chem ; 293(45): 17606-17621, 2018 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-30237171

RESUMO

In humans, transport of food-derived cobalamin (vitamin B12) from the digestive system into the bloodstream involves three paralogous proteins: transcobalamin (TC), haptocorrin (HC), and intrinsic factor (IF). Each of these proteins contains two domains, an α-domain and a ß-domain, which together form a cleft in which cobalamin binds. Zebrafish (Danio rerio) are thought to possess only a single cobalamin transport protein, referred to as Tcn2, which is a transcobalamin homolog. Here, we used CRISPR/Cas9 mutagenesis to create null alleles of tcn2 in zebrafish. Fish homozygous for tcn2-null alleles were viable and exhibited no obvious developmentally or behaviorally abnormal phenotypes. For this reason, we hypothesized that previously unidentified cobalamin-carrier proteins encoded in the zebrafish genome may provide an additional pathway for cobalamin transport. We identified genes predicted to code for two such proteins, Tcn-beta-a (Tcnba) and Tcn-beta-b (Tcnbb), which differ from all previously characterized cobalamin transport proteins as they lack the α-domain. These ß-domain-only proteins are representative of an undescribed class of cobalamin-carrier proteins that are highly conserved throughout the ray-finned fishes. We observed that the genes encoding the three cobalamin transport homologs, tcn2, tcnba, and tcnbb, are expressed in unique spatial and temporal patterns in the developing zebrafish. Moreover, exogenously expressed recombinant Tcnba and Tcnbb bound cobalamin with high affinity, comparable with binding by full-length Tcn2. Taken together, our results suggest that this noncanonical protein structure has evolved to fully function as a cobalamin-carrier protein, thereby allowing for a compensatory cobalamin transport mechanism in the tcn2 -/- zebrafish.


Assuntos
Transcobalaminas , Peixe-Zebra , Animais , Sistemas CRISPR-Cas , Domínios Proteicos , Transcobalaminas/química , Transcobalaminas/genética , Transcobalaminas/metabolismo , Vitamina B 12/química , Vitamina B 12/genética , Vitamina B 12/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/química , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
10.
Hum Mol Genet ; 27(20): 3627-3640, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30124850

RESUMO

In humans, poor nutrition, malabsorption and variation in cobalamin (vitamin B12) metabolic genes are associated with hematological, neurological and developmental pathologies. Cobalamin is transported from blood into tissues via the transcobalamin (TC) receptor encoded by the CD320 gene. We created mice carrying a targeted deletion of the mouse ortholog, Cd320. Knockout (KO) mice lacking this TC receptor have elevated levels of plasma methylmalonic acid and homocysteine but are otherwise healthy, viable, fertile and not anemic. To challenge the Cd320 KO mice we maintained them on a vitamin B12-deficient diet. After 5 weeks on this diet, reproductive failure develops in Cd320 KO females but not males. In vitro, homozygous Cd320 KO embryos from cobalamin-deficient Cd320 KO dams develop normally to embryonic day (E) 3.5, while in vivo, few uterine decidual implantation sites are observed at E7.5, suggesting that embryos perish around the time of implantation. Dietary restriction of vitamin B12 induces a severe macrocytic anemia in Cd320 KO mice after 10-12 months while control mice on this diet are anemia-free up to 2 years. Despite the severe anemia, cobalamin-deficient KO mice do not exhibit obvious neurological symptoms. Our results with Cd320 KO mice suggest that an alternative mechanism exists for mice to transport cobalamin independent of the Cd320 encoded receptor. Our findings with deficient diet are consistent with historical and epidemiological data suggesting that low vitamin B12 levels in humans are associated with infertility and developmental abnormalities. Our Cd320 KO mouse model is an ideal model system for studying vitamin B12 deficiency.


Assuntos
Anemia/etiologia , Modelos Animais de Doenças , Receptores de Superfície Celular/genética , Reprodução , Deficiência de Vitamina B 12/genética , Animais , Dieta , Feminino , Masculino , Camundongos , Camundongos Knockout , Deficiência de Vitamina B 12/complicações , Deficiência de Vitamina B 12/metabolismo , Deficiência de Vitamina B 12/fisiopatologia
11.
Mol Genet Metab Rep ; 16: 20-22, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29988937

RESUMO

The glycine cleavage system (GCS) is a complex of four enzymes enabling glycine to serve as a source of one-carbon units to the cell. We asked whether concentrations of glycine, dimethylglycine, formate, and serine in blood are influenced by variation within GCS genes in a sample of young, healthy individuals. Fifty-two variants tagging (r2 < 0.9) the four GCS genes were tested; one variant, GLDC rs2297442-G, was significantly associated (p = .0007) with decreased glycine concentrations in serum.

12.
Sci Rep ; 8(1): 7208, 2018 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-29725037

RESUMO

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

13.
Am J Clin Nutr ; 107(3): 345-354, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29566195

RESUMO

Background: Formate is an important metabolite that serves as a donor of one-carbon groups to the intracellular tetrahydrofolate pool. However, little is known of its circulating concentrations or of their determinants. Objective: This study aimed to define formate concentrations and their determinants in a healthy young population. Design: Serum formate was measured in 1701 participants from the Trinity Student Study. The participants were men and women, aged 18 to 28 y, enrolled at Trinity College, Dublin. Formate concentrations were compared with other one-carbon metabolites, vitamin status, potential formate precursors, genetic polymorphisms, and lifestyle factors. Results: Serum formate concentrations ranged from 8.7 to 96.5 µM, with a mean of 25.9 µM. Formate concentrations were significantly higher in women than in men; oral contraceptive use did not further affect them. There was no effect of smoking or of alcohol ingestion, but the TT genotype of the methylenetetrahydrofolate reductase (MTHFR) 677C→T (rs1801133) polymorphism was associated with a significantly decreased formate concentration. Formate was positively associated with potential metabolic precursors (serine, methionine, tryptophan, choline) but not with glycine. Formate concentrations were positively related to serum folate and negatively related to serum vitamin B-12. Conclusions: Formate concentrations were sensitive to the concentrations of metabolic precursors. In view of the increased susceptibility of women with the TT genotype of MTHFR to give birth to infants with neural tube defects as well as the effectiveness of formate supplementation in decreasing the incidence of folate-resistant neural tube defects in susceptible mice, it will be important to understand how this genotype decreases the serum formate concentration. This trial was registered at www.clinicaltrials.gov as NCT03305900.


Assuntos
Formiatos/sangue , Estilo de Vida , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Adolescente , Adulto , Colina/sangue , Estudos Transversais , Feminino , Técnicas de Genotipagem , Humanos , Incidência , Masculino , Metionina/sangue , Polimorfismo de Nucleotídeo Único , Serina/sangue , Triptofano/sangue , Adulto Jovem
14.
NPJ Genom Med ; 3: 7, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29479477

RESUMO

Clinical testing of BRCA1 and BRCA2 began over 20 years ago. With the expiration and overturning of the BRCA patents, limitations on which laboratories could offer commercial testing were lifted. These legal changes occurred approximately the same time as the widespread adoption of massively parallel sequencing (MPS) technologies. Little is known about how these changes impacted laboratory practices for detecting genetic alterations in hereditary breast and ovarian cancer genes. Therefore, we sought to examine current laboratory genetic testing practices for BRCA1/BRCA2. We employed an online survey of 65 questions covering four areas: laboratory characteristics, details on technological methods, variant classification, and client-support information. Eight United States (US) laboratories and 78 non-US laboratories completed the survey. Most laboratories (93%; 80/86) used MPS platforms to identify variants. Laboratories differed widely on: (1) technologies used for large rearrangement detection; (2) criteria for minimum read depths; (3) non-coding regions sequenced; (4) variant classification criteria and approaches; (5) testing volume ranging from 2 to 2.5 × 105 tests annually; and (6) deposition of variants into public databases. These data may be useful for national and international agencies to set recommendations for quality standards for BRCA1/BRCA2 clinical testing. These standards could also be applied to testing of other disease genes.

15.
Nat Rev Genet ; 19(3): 175-185, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29151588

RESUMO

Recent studies have highlighted the imperatives of including diverse and under-represented individuals in human genomics research and the striking gaps in attaining that inclusion. With its multidecade experience in supporting research and policy efforts in human genomics, the National Human Genome Research Institute is committed to establishing foundational approaches to study the role of genomic variation in health and disease that include diverse populations. Large-scale efforts to understand biology and health have yielded key scientific findings, lessons and recommendations on how to increase diversity in genomic research studies and the genomic research workforce. Increased attention to diversity will increase the accuracy, utility and acceptability of using genomic information for clinical care.


Assuntos
Variação Genética , Genoma Humano , Genômica/métodos , Genética Humana/métodos , Medicina de Precisão/métodos , Humanos
16.
PLoS One ; 12(12): e0188168, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29216221

RESUMO

BACKGROUND: Ebstein anomaly (EA) is a rare congenital defect characterized by apical displacement of the septal tricuspid leaflets and atrialization of the right ventricle. The etiology of EA is unclear; however, recurrence in families and the association of EA with genetic syndromes and copy number variants (CNVs) suggest a genetic component. OBJECTIVE: We performed a population-based study to search for recurrent and novel CNVs in a previously unreported set of EA cases. METHODS: We genotyped 60 EA cases identified from all live births (2,891,076) from selected California counties (1991-2010) using the Illumina HumanOmni2.5-8 array. We identified 38 candidate CNVs in 28 (46%) cases and prioritized and validated 11 CNVs based on the genes included. RESULTS: Five CNVs (41%) overlapped or were close to genes involved in early myocardial development, including NODAL, PDLIM5, SIX1, ASF1A and FGF12. We also replicated a previous association of EA with CNVs at 1p34.1 and AKAP12. Finally, we identified four CNVs overlapping or in close proximity to the transcription factors HES3, TRIM71, CUX1 and EIF4EBP2. CONCLUSIONS: This study supports the relationship of genetic factors to EA and demonstrates that defects in cardiomyocytes and myocardium differentiation may play a role. Abnormal differentiation of cardiomyocytes and how genetic factors contribute should be examined for their association with EA.


Assuntos
Variações do Número de Cópias de DNA , Anomalia de Ebstein/genética , Adolescente , Adulto , Mapeamento Cromossômico , Feminino , Genótipo , Humanos , Recém-Nascido , Masculino , Idade Materna , Adulto Jovem
17.
Sci Rep ; 7(1): 17199, 2017 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-29222464

RESUMO

The extent of population structure within Ireland is largely unknown, as is the impact of historical migrations. Here we illustrate fine-scale genetic structure across Ireland that follows geographic boundaries and present evidence of admixture events into Ireland. Utilising the 'Irish DNA Atlas', a cohort (n = 194) of Irish individuals with four generations of ancestry linked to specific regions in Ireland, in combination with 2,039 individuals from the Peoples of the British Isles dataset, we show that the Irish population can be divided in 10 distinct geographically stratified genetic clusters; seven of 'Gaelic' Irish ancestry, and three of shared Irish-British ancestry. In addition we observe a major genetic barrier to the north of Ireland in Ulster. Using a reference of 6,760 European individuals and two ancient Irish genomes, we demonstrate high levels of North-West French-like and West Norwegian-like ancestry within Ireland. We show that that our 'Gaelic' Irish clusters present homogenous levels of ancient Irish ancestries. We additionally detect admixture events that provide evidence of Norse-Viking gene flow into Ireland, and reflect the Ulster Plantations. Our work informs both on Irish history, as well as the study of Mendelian and complex disease genetics involving populations of Irish ancestry.


Assuntos
DNA/genética , Genética Populacional , Fluxo Gênico , Migração Humana , Humanos , Irlanda
18.
Hum Mol Genet ; 26(24): 4975-4988, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29040465

RESUMO

Vitamin B12 deficiency is common in older individuals. Circulating vitamin B12 concentration can be used to diagnose deficiency, but this test has substantial false positive and false negative rates. We conducted genome-wide association studies (GWAS) in which we resolved total serum vitamin B12 into the fractions bound to transcobalamin and haptocorrin: two carrier proteins with very different biological properties. We replicated reported associations between total circulating vitamin B12 concentrations and a common null variant in FUT2. This allele determines the secretor phenotype in which blood group antigens are found in non-blood body fluids. Vitamin B12 bound to haptocorrin (holoHC) remained highly associated with FUT2 rs601338 (p.Trp154Ter). Transcobalamin bound vitamin B12 (holoTC) was not influenced by this variant. HoloTC is the bioactive the form of the vitamin and is taken up by all tissues. In contrast, holoHC is only taken up by the liver. Using holoHC from individuals with known FUT2 genotypes, we demonstrated that FUT2 rs601338 genotype influences the glycosylation of haptocorrin. We then developed an experimental model demonstrating that holoHC is transported into cultured hepatic cells (HepG2) via the asialoglycoprotein receptor (ASGR). Our data challenge current published hypotheses on the influence of genetic variation on this clinically important measure and are consistent with a model in which FUT2 rs601338 influences holoHC by altering haptocorrin glycosylation, whereas B12 bound to non-glycosylated transcobalamin (i.e. holoTC) is not affected. Our findings explain some of the observed disparity between use of total B12 or holoTC as first-line clinical tests of vitamin B12 status.


Assuntos
Fucosiltransferases/genética , Fucosiltransferases/metabolismo , Transcobalaminas/genética , Adulto , Idoso , Transporte Biológico , Feminino , Variação Genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Glicosilação , Células Hep G2/metabolismo , Humanos , Irlanda , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Transcobalaminas/metabolismo , Vitamina B 12/análise , Vitamina B 12/sangue , Vitamina B 12/metabolismo , Deficiência de Vitamina B 12/metabolismo
19.
Am J Hum Genet ; 101(2): 167-176, 2017 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-28777929

RESUMO

With CRISPR/Cas9 and other genome-editing technologies, successful somatic and germline genome editing are becoming feasible. To respond, an American Society of Human Genetics (ASHG) workgroup developed this position statement, which was approved by the ASHG Board in March 2017. The workgroup included representatives from the UK Association of Genetic Nurses and Counsellors, Canadian Association of Genetic Counsellors, International Genetic Epidemiology Society, and US National Society of Genetic Counselors. These groups, as well as the American Society for Reproductive Medicine, Asia Pacific Society of Human Genetics, British Society for Genetic Medicine, Human Genetics Society of Australasia, Professional Society of Genetic Counselors in Asia, and Southern African Society for Human Genetics, endorsed the final statement. The statement includes the following positions. (1) At this time, given the nature and number of unanswered scientific, ethical, and policy questions, it is inappropriate to perform germline gene editing that culminates in human pregnancy. (2) Currently, there is no reason to prohibit in vitro germline genome editing on human embryos and gametes, with appropriate oversight and consent from donors, to facilitate research on the possible future clinical applications of gene editing. There should be no prohibition on making public funds available to support this research. (3) Future clinical application of human germline genome editing should not proceed unless, at a minimum, there is (a) a compelling medical rationale, (b) an evidence base that supports its clinical use, (c) an ethical justification, and (d) a transparent public process to solicit and incorporate stakeholder input.


Assuntos
Edição de Genes , Genoma Humano/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Edição de Genes/ética , Edição de Genes/legislação & jurisprudência , Edição de Genes/métodos , Humanos , Mudança Social
20.
Annu Rev Nutr ; 37: 269-291, 2017 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-28628360

RESUMO

Neural tube defects (NTDs) are the most severe congenital malformations of the central nervous system. The etiology is complex, with both genetic and environmental factors having important contributions. Researchers have known for the past two decades that maternal periconceptional use of the B vitamin folic acid can prevent many NTDs. Though this finding is arguably one of the most important recent discoveries in birth defect research, the mechanism by which folic acid exerts this benefit remains unknown. Research to date has focused on the hypothesis that an underlying genetic susceptibility interacts with folate-sensitive metabolic processes at the time of neural tube closure. Little progress has been made searching for risk-causative variants in candidate genes; therefore, more complex genetic and epigenetic methodologies are now being considered. This article reviews the research to date that has been targeted on this important gene-nutrient locus.


Assuntos
Predisposição Genética para Doença , Defeitos do Tubo Neural/genética , Animais , Feminino , Ácido Fólico/metabolismo , Ácido Fólico/farmacologia , Ácido Fólico/uso terapêutico , Humanos , Masculino , Camundongos , Defeitos do Tubo Neural/prevenção & controle , Fatores de Risco
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