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Down syndrome is associated with genome-wide perturbation of gene expression, which may be mediated by epigenetic changes. We perform an epigenome-wide association study on neonatal bloodspots comparing 196 newborns with Down syndrome and 439 newborns without Down syndrome, adjusting for cell-type heterogeneity, which identifies 652 epigenome-wide significant CpGs ( P  < 7.67 × 10 −8 ) and 1,052 differentially methylated regions. Differential methylation at promoter/enhancer regions correlates with gene expression changes in Down syndrome versus non-Down syndrome fetal liver hematopoietic stem/progenitor cells ( P  < 0.0001). The top two differentially methylated regions overlap RUNX1 and FLI1 , both important regulators of megakaryopoiesis and hematopoietic development, with significant hypermethylation at promoter regions of these two genes. Excluding Down syndrome newborns harboring preleukemic GATA1 mutations ( N  = 30), identified by targeted sequencing, has minimal impact on the epigenome-wide association study results. Down syndrome has profound, genome-wide effects on DNA methylation in hematopoietic cells in early life, which may contribute to the high frequency of hematological problems, including leukemia, in children with Down syndrome. Down syndrome has a high co-morbidity with immune and hematopoietic disorders. Here, the authors perform an epigenome-wide association study in newborns with and without Down syndrome to find differential methylation across the genome, including in hematopoietic regulators RUNX1 and FLI1 .

PurposeCongenital malformations are strong risk factors for childhood cancer. Our objective was to determine whether cancer survival differs by birth defect status among Oklahoma children.MethodsWe used accelerated failure time models to estimate survival time ratios (SRs) and 95% confidence intervals (CIs), adjusted for maternal race/ethnicity and census tract-level poverty, among children diagnosed with cancer and born in Oklahoma from 1997 to 2012 (n = 971), by linking records from birth certificates, birth defects, and cancer registries.ResultsWe observed decreased, though imprecise, survival time among survivors with any birth defect (SR: 0.82, 95% CI: 0.29, 2.31) or chromosomal defects (n = 24) (SR: 0.43, 95% CI: 0.06, 3.30) compared to those without birth defects. We observed no difference in survival time among children with non-chromosomal defects (SR: 0.98, 95% CI: 0.31, 3.12) compared to children with no birth defects.ConclusionOur study did not identify significant differences in cancer survival for children with and without birth defects. Future studies should consider pooling data from multiple states to allow in-depth study of specific birth defects and cancer types and confirm whether survival differs by type and number of birth defects.

Metabolomics may shed light on treatment response in childhood acute lymphoblastic leukemia (ALL), however, most assessments have analyzed bone marrow or cerebrospinal fluid (CSF), which are not collected during all phases of therapy. Blood is collected frequently and with fewer risks, but it is unclear whether findings from marrow or CSF biomarker studies may translate. We profiled end-induction plasma, marrow, and CSF from N = 10 children with B-ALL using liquid chromatography-mass spectrometry. We estimated correlations between plasma and marrow/CSF metabolite abundances detected in ≥ 3 patients using Spearman rank correlation coefficients ( r s ). Most marrow metabolites were detected in plasma (N = 661; 81%), and we observed moderate-to-strong correlations (median r s 0.62, interquartile range [IQR] 0.29–0.83). We detected 328 CSF metabolites in plasma (90%); plasma-CSF correlations were weaker (median r s 0.37, IQR 0.07–0.70). We observed plasma-marrow correlations for metabolites in pathways associated with end-induction residual disease (pyruvate, asparagine) and plasma-CSF correlations for a biomarker of fatigue (gamma-glutamylglutamine). There is considerable overlap between the plasma, marrow, and CSF metabolomes, and we observed strong correlations for biomarkers of clinically relevant phenotypes. Plasma may be suitable for biomarker studies in B-ALL.

Emerging evidence suggests newborn screening analytes may yield insights into the etiologies of birth defects, yet no effort has evaluated associations between a range of newborn screening analytes and birth defects. This population-based study pooled statewide data on birth defects, birth certificates, and newborn screening analytes from Texas occurring between January 1, 2007 and December 31, 2009. Associations between a panel of thirty-six newborn screening analytes, collected by the statewide Texas Newborn Screening Program, and the presence of a birth defect, defined as at least one of 39 birth defects diagnoses recorded by the Texas Birth Defects Registry, were assessed using regression analysis. Of the 27,643 births identified, 20,205 had at least one of the 39 birth defects of interest (cases) as identified by the Texas Birth Defects Registry, while 7,438 did not have a birth defect (controls). Among 1,404 analyte-birth defect associations evaluated, 377 were significant in replication analysis. Analytes most consistently associated with birth defects included the phenylalanine/tyrosine ratio (N = 29 birth defects), tyrosine (N = 28 birth defects), and thyroxine (N = 25 birth defects). Birth defects most frequently associated with a range of analytes included gastroschisis (N = 29 analytes), several cardiovascular defects (N = 26 analytes), and spina bifida (N = 23 analytes). Several significant and novel associations were observed between newborn screening analytes and birth defects. While some findings could be consequences of the defects themselves or to the care provided to infants with these defects, these findings could help to elucidate mechanisms underlying the etiology of some birth defects.

Central nervous system (CNS) tumors are the most common solid tumors in children. Findings on the role of maternal and perinatal factors on the susceptibility or outcome of these tumors are inconclusive. Therefore, we investigated the association between these early-life factors, risk, and survival of pediatric CNS tumors, using data from one of the world’s largest and most diverse cancer registries. Information on pediatric CNS tumor cases ( n  = 1950) for the period 1995–2011 was obtained from the Texas Cancer Registry. Birth certificate controls were frequency-matched on birth year at a ratio of 10:1 for the same period. Evaluated maternal and perinatal variables were obtained from birth records. Unconditional logistic regression was used to generate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for etiological factors. Additionally, Cox proportional hazards regression was employed to assess adjusted hazard ratios (HRs) and 95% CIs for survival factors. The results indicated that Hispanic and non-Hispanic black mothers were less likely to have children with CNS tumors compared to non-Hispanic white mothers (OR 0.88 [95% CI 0.78–0.98] P -value = 0.019; OR 0.79 [95% CI 0.67–0.93 P -value = 0.004], respectively). Infants born large for gestational age (OR 1.26 [95% CI 1.07–1.47] P -value = 0.004) and those delivered pre-term (OR 1.19 [95% CI 1.04–1.38] P -value = 0.013) showed an increased risk of CNS tumors. Infants born by vaginal forceps or vacuum delivery had a higher risk of CNS tumors compared to those born by spontaneous vaginal delivery (OR 1.35 [95% CI 1.12–1.62] P -value = 0.002). Additionally, offspring of Hispanic and non-Hispanic black mothers showed a higher risk of death (HR 1.45 [95% CI 1.16–1.80] P -value = 0.001; HR 1.53 [95% CI 1.12–2.09] P -value = 0.008, respectively). Infants born by cesarean had a higher risk of death compared to those delivered vaginally (HR 1.28 [95% CI 1.05–1.57] P -value = 0.016). These findings indicate the important role of maternal and perinatal characteristics in the etiology and survival of these clinically significant malignancies.

Background Congenital heart defects (CHDs) affect approximately half of individuals with Down syndrome (DS), but the molecular reasons for incomplete penetrance are unknown. Previous studies have largely focused on identifying genetic risk factors associated with CHDs in individuals with DS, but comprehensive studies of the contribution of epigenetic marks are lacking. We aimed to identify and characterize DNA methylation differences from newborn dried blood spots (NDBS) of DS individuals with major CHDs compared to DS individuals without CHDs. Methods We used the Illumina EPIC array and whole-genome bisulfite sequencing (WGBS) to quantitate DNA methylation for 86 NDBS samples from the California Biobank Program: (1) 45 DS-CHD (27 female, 18 male) and (2) 41 DS non-CHD (27 female, 14 male). We analyzed global CpG methylation and identified differentially methylated regions (DMRs) in DS-CHD versus DS non-CHD comparisons (both sex-combined and sex-stratified) corrected for sex, age of blood collection, and cell-type proportions. CHD DMRs were analyzed for enrichment in CpG and genic contexts, chromatin states, and histone modifications by genomic coordinates and for gene ontology enrichment by gene mapping. DMRs were also tested in a replication dataset and compared to methylation levels in DS versus typical development (TD) WGBS NDBS samples. Results We found global CpG hypomethylation in DS-CHD males compared to DS non-CHD males, which was attributable to elevated levels of nucleated red blood cells and not seen in females. At a regional level, we identified 58, 341, and 3938 CHD-associated DMRs in the Sex Combined, Females Only, and Males Only groups, respectively, and used machine learning algorithms to select 19 Males Only loci that could distinguish CHD from non-CHD. DMRs in all comparisons were enriched for gene exons, CpG islands, and bivalent chromatin and mapped to genes enriched for terms related to cardiac and immune functions. Lastly, a greater percentage of CHD-associated DMRs than background regions were differentially methylated in DS versus TD samples. Conclusions A sex-specific signature of DNA methylation was detected in NDBS of DS-CHD compared to DS non-CHD individuals. This supports the hypothesis that epigenetics can reflect the variability of phenotypes in DS, particularly CHDs.

There is evidence that maternal genotypes in folate-related genes are associated with pediatric acute lymphoblastic leukemia (ALL) independent of offspring genotype. We evaluated the relationship between maternal genotypes in methionine synthase (MTR) and DNA methylation status in ALL to better characterize the molecular mechanism underlying this association. We obtained bone marrow samples from 51 patients with ALL at diagnosis and from 6 healthy donors. Mothers of patients provided a saliva sample and were genotyped at 11 tagSNPs in MTR. DNA methylation was measured in bone marrow mononuclear cells of patients and six healthy marrow donors. We used hierarchical clustering to identify patients with a hypermethylator phenotype based on 281 differentially methylated promoter CpGs. We used logistic regression to estimate the effects of maternal genotype on the likelihood of DNA hypermethylation in ALL and Ingenuity Pathway Analysis to identify networks enriched for differentially methylated genes. Twenty-two cases (43%) demonstrated promoter hypermethylation, which was more frequent among those with ETV6-RUNX1 fusion and initial white blood cell count < 50 x 109/L. Maternal rs12759827 was associated with aberrant DNA methylation (odds ratio [OR] 4.67, 95% confidence interval 1.46-16.31); non-significantly elevated ORs were observed for all other SNPs. Aberrantly methylated promoter CpGs aligned to genes with known cancer-related functions. Maternal folate metabolic genotype may be associated with DNA methylation patterns in ALL in their offspring. Therefore, the effect of maternal genotypes on ALL susceptibility may act through aberrant promoter methylation, which may contribute to the in utero origins of ALL.

Prolonged antibiotic exposure causes dangerous hematologic side effects, including neutropenia, in up to 34% of patients. Murine studies established a link between the intestinal microbiota and hematopoiesis. To identify factors that predispose to neutropenia in pediatric patients, we evaluated changes in microbiota‐derived metabolites and intestinal microbiota composition after prolonged courses of antibiotics. In this multi‐center study, patients with infections requiring anticipated antibiotic treatment of two or more weeks were enrolled. Stool samples were obtained at the start and completion of antibiotics or at neutropenia onset (prospective arm). Some patients were enrolled in a retrospective arm in which a stool sample was collected at the time of neutropenia during antibiotic therapy and 2–4 weeks after completion of antibiotics with recovery of blood counts. We identified 10 patients who developed neutropenia on antibiotics and 29 controls matched for age, sex, race, and ethnicity. Clinical data demonstrated no association between neutropenia and the type of infection or antibiotic used; however, patients with neutropenia were admitted to the intensive care unit more often and received longer courses of antibiotics. Reduced intestinal microbiome richness and, specifically, decreased abundance of Lachnospiraceae family members correlated with neutropenia. Untargeted stool metabolomic profiling revealed several metabolites that were depleted exclusively in patients with neutropenia, including members of the urea cycle pathway, pyrimidine metabolism, and fatty acid metabolism that are known to be produced by Lachnospiraceae. Our study shows a relationship between intestinal microbiota disruption and abnormal hematopoiesis and identifies taxa and metabolites likely to contribute to microbiota‐sustained hematopoiesis.

BackgroundSome assessments indicate the prevalence of certain birth defects varies by urban–rural status. We evaluated associations between urban–rural residence and a spectrum of birth defects, using a phenome-wide association study approach in Texas, a state with large urban centers and expansive rural areas.MethodsData for birth defects and livebirths during 1999–2015 were obtained from the Texas Birth Defects Registry and the Center for Health Statistics. Maternal residence was classified as urban or rural, and prevalence ratios (PR) and 95% confidence intervals (CI) were calculated for any defect and 140 specific defects by Poisson regression.ResultsOverall, birth defects were less frequent in rural compared to urban counties (PR = 0.88, 95% CI: 0.87–0.89). Twelve specific defects were less prevalent in rural counties, including ventricular septal defects (VSDs; PR = 0.76, 95% CI: 0.73–0.79) and hypospadias (PR = 0.86, 95% CI: 0.82–0.89). For some birth defects, including VSDs, there was evidence of decreasing prevalence with decreasing population size.ConclusionsIn our large population-based assessment, we demonstrated that several birth defects were less prevalent in rural counties, suggesting that characteristics of urban settings may be relevant to their etiologies, diagnosis, or surveillance. Further research is needed to identify specific exposures underlying these associations.ImpactThere are few studies of birth defects prevalence in urban versus rural settings. To address this, we investigated a comprehensive range of birth defects, including several rare defects that have not been previously studied, in a large and diverse population.We identified 12 structural birth defects that were less prevalent in rural areas.Findings suggest possible differential exposures among urban and rural women, and/or possible underdiagnosis of certain birth defects in rural areas.Findings highlight the need for further study of geographically referenced risk factors for birth defects, and of the completeness of birth defects ascertainment in rural areas.

Birth defects prevalence may vary seasonally, but previous studies have focused on a few commonly occurring phenotypes. We performed a phenome-wide association study (PheWAS) in order to evaluate the associations between season of conception and a broad range of birth defects. Date of conception was estimated for all livebirths and birth defect cases in Texas from 1999–2015 using data from vital records, provided by the Texas Department of State Health Services Center for Health Statistics. Birth defects diagnoses were obtained from the Texas Birth Defects Registry, a statewide, active surveillance system. We estimated prevalence ratios (PRs) for phenotypes with ≥50 cases according to conception in spring (March-May), summer (June–August) or fall (September–November) relative to winter (December–February), using Poisson regression. Season of conception was associated with 5% of birth defects studied in models adjusted for maternal age, education, race/ethnicity, and number of previous livebirths. Specifically, summer conception was associated with any monitored birth defect (PR 1.03, 95% CI 1.02–1.04) and five specific phenotypes, most notably Hirschsprung disease (PR 1.46, 95% CI 1.22–1.75). These findings suggest that seasonally variable exposures influence the development of several birth defects and may assist in identifying novel environmental risk factors.