Structural Birth Defects Research Articles

Abstract 2464: Gabriella Miller Kids First Data Resource Center: Harmonizing clinical and genomic data to support childhood cancer and structural birth defect research

Abstract Childhood cancers and structural birth defects share a common context of altered developmental biology, but the potential role of shared, genetic alterations and/or pathways across pediatric cancers and birth defects is not well explored. It is increasingly critical that genomic data are paired with high-quality clinical data to drive translational research by elucidating the relationship between genomic alterations, treatments, outcomes, and other phenotypic characteristics. The NIH Common Fund Gabriella Miller Kids First Program represents a first-in-kind national, collaborative initiative focused on large-scale clinical and genomic data sharing for childhood cancers and structural birth defects. As part of this program, the Kids First Data Resource Center (DRC) is charged with empowering collaborative discovery across Kids First datasets. Through newly developed cloud-based platforms, researchers will be able to rapidly and interactively access standardized and harmonized clinical and genomic data. A better understanding of common developmental programs could spur advancements in prevention, detection, and therapeutics that will improve the outcomes of affected children and families. Approximately 8,000 patient samples were available at the launch of the Kids First DRC portal, with an initial focus on whole genome sequencing (WGS) of trios and families. More than 25,000 WGS are expected to be processed by 2019, making the DRC one of the largest pediatric data resources of its kind across a diversity of diseases. The rise of cloud-based computing has greatly reduced the burden on the researcher of large-scale genomic harmonization. In normal operations, the DRC is capable of running two hundred workflows simultaneously with considerable scalability on demand. Additionally, there is a strong focus on harmonizing and structuring seemingly disparate clinical and phenotypic data types to make them more interoperable, discoverable and reusable by using ontologies. The data in the DRC is expertly curated and mapped to existing data standards, including NCI Thesaurus (NCIt), Human Phenotype Ontology (HPO), Monarch Disease Ontology (MONDO), and Uber-anatomy Ontology (Uberon). This allows for increased interoperability and semantic structure of the data. For example, MONDO integrates numerous disease terminologies into a single merged ontology, including the NCIt. The combination of harmonized genomic and clinical data across pediatric cancers and structural birth defect provides a key foundation for exploring and developing new methods to better understand the relationships between germline variants, cancer risk, and associated treatments and outcomes. Community standardization of this modeling is ongoing as part of GA4GH, and is critical for implementation of improved interpretation in EHR systems, for example via HL7 FHIR. Citation Format: Allison P. Heath, Deanne M. Taylor, Yuankun Zhu, Pichai Raman, Jena Lilly, Phillip Storm, Angela J. Waanders, Vincent Ferretti, Christina Yung, Michele Mattioni, Brandi Davis-Dusenbery, Zachary L. Flamig, Robert Grossman, Samuel L. Volchenboum, Sabine Mueller, Javad Nazarian, Nicole Vasilevsky, Melissa A. Haendel, Adam Resnick. Gabriella Miller Kids First Data Resource Center: Harmonizing clinical and genomic data to support childhood cancer and structural birth defect research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2464.

Abstract 5054: Are co-occurring structural birth defects associated with risk of acute lymphoblastic leukemia among children with Down syndrome

Abstract Background: Children with Down syndrome (DS) have a 15- to 20-fold increased risk of developing acute leukemia (ALL). While children with DS typically also present with multiple co-occurring major and minor structural birth defects, very little is known about whether the number and type of these co-occurring birth defects in children with DS are associated with risk of ALL. Methods: The Genetic Overlap Between Anomalies and Cancer in Kids (GOBACK) Study included linking data from population-based birth defects and cancer registries in Texas for the years 1999-2013. We performed a case-control analysis of ALL risk in participants diagnosed with DS. We evaluated the risk of ALL according to the presence of major birth defects in eight organ systems, as well as by the number of birth defects. Results: We identified 7,684 children with DS (controls) and 81 children with DS-ALL (cases) from among 5.7 million live births. There was a high burden of co-occurring birth defects in both the DS and DS-ALL groups, with 97% compared to 98% being diagnosed with at least one co-occurring birth defect (p = 0.39), respectively, and 68% compared to 71% being diagnosed with at least one major birth defect (p = 0.33). Similar to what has been reported among the general population of ALL patients, children with DS and ALL had a significantly higher mean birthweight (3088 vs 2891 g, p <0.001) than children with DS overall, and were born to older parents (mean maternal age 33.7 vs. 31.7 yrs, p = 0.01; mean paternal age 36.6 vs. 33.8 yrs, p = 0.02). Although there were trends towards increased prevalences of major birth defects overall and in most organ systems among the DS-ALL group, none reached statistical significance. Similarly, we identified a non-significantly greater mean number of total birth defects in the DS-ALL group (p = 0.2). Neither number of total birth defects nor number of major birth defects were associated with ALL in multivariable Cox regression models. Conclusions: In this population-based assessment, we did not find strong evidence that co-occurring structural birth defects were related to ALL risk among children with DS. However, the small numbers of children with DS-ALL make it difficult to draw definitive conclusions. Citation Format: Jeremy M. Schraw, Tiffany M. Chambers, John P. Woodhouse, Peter H. Langlois, Mark A. Canfield, Angela E. Scheuerle, Michael E. Scheurer, Sharon E. Plon, Karen R. Rabin, Philip J. Lupo. Are co-occurring structural birth defects associated with risk of acute lymphoblastic leukemia among children with Down syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5054.

Abstract 2465: Genomic harmonization of the Data Resource Center for Gabriella Miller Kids First Pediatric Research Program

Abstract Gabriella Miller Kids First Pediatric Research Program (GMKF) is a nation-wide, multi-year initiative focused on the integration of large-scale clinically annotated genomic data for childhood cancers and structural birth defects supported by the NIH Common Fund. Awarded by GMKF, the Kids First Data Resource Center (DRC) is tasked to build infrastructure and workflows for data intaking, harmonization, integration and access authorization to empower collaborative discoveries across the GMKF and other integrated datasets. A key challenge for uniform analyses and empowered discovery of large-scale genomic data relates to the diverse genomic processing workflows and methods employed across the sequencing and bioinformatics community. The DRC genomic harmonization team aims to provide “analysis ready” datasets that are “functionally equivalent” across the Kids First datasets and other large-scale genomic data initiatives in order to accelerate the discovery process. Paired with the cloud-based workspace environments of the DRC, such harmonized dataset provide unprecedented opportunities for shared, reproducible discovery by a diverse, collaborative network of researchers. As such, DRC initial pipelines are developed with BWA-MEM alignment on genome build GRCh38 followed by the GATK best practices for germline variant calling and joint genotyping. Common Workflow Language (CWL) is used as the main workflow specification, while Docker technology has been applied to containerize all the tools used by the workflow. Our current workflows are tasked with data harmonization across a number of different experimental platforms including whole genome sequencing, exome sequencing, and RNA-seq. The data processing is done via CAVATICA, an Amazon Web Services (AWS) based cloud computing platform associated with the Kids First DRC Portal co-developed by Seven Bridges Genomics, where workflows feature scatter-gather parallelization and AWS resource optimization. By utilizing such a framework, the DRC team has harmonized over 10,000 WGS and 1,000 RNA-Seq samples across 12 study cohorts within 8 months. This dataset in its current release includes samples from 40 pediatric brain cancers as well as 8 childhood birth defects with the outcome of delivering 150TB harmonized CRAM and 60TB gVCF. With a highly optimized bioinformatics pipeline powered by an efficient cloud-based execution workflow, The DRC platform processes one genome in about 11 hours with an average compute cost of $15 for whole genome alignment and germline variant calling. Here we present our observed challenges and identified opportunities in the analysis and integration of multi-disease pediatric genomic data on a large scale. Citation Format: Yuankun Zhu, Miguel Brown, Batsal Devkota, Bailey Farrow, Bogdan Gavrilovic, Allison Heath, Kyle Hernandez, Avi Kelman, Parimala Killada, Meen Chul Kim, Daniel Kolbman, Mateusz Koptyra, Milan Kovacevic, Maarten Leerkes, Alex Lubneuski, Michele Mattioni, Pichai Raman, Adam Resnick, Nikola Skundric, Deanne Taylor, Junjun Zhang, Bo Zhang, Phillip B. Storm. Genomic harmonization of the Data Resource Center for Gabriella Miller Kids First Pediatric Research Program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2465.

Folic acid supplementation and risk for congenital limb reduction defects in China.

Folic acid (FA) supplementation prevents neural tube defects, but there are mixed results for its ability to prevent limb reduction defects. We examined whether a preventive effect of FA supplementation exists for congenital limb reduction defects in a large population in China. Data from a large population-based cohort study in China were used to evaluate the effects of FA supplementation on birth defects. All births at 20 complete gestational weeks, including live births, stillbirths and pregnancy terminations, and all structural congenital anomalies, regardless of gestational week, were recorded. A total of 247 831 singleton live births delivered at gestational ages of 20-42 weeks to women from northern and southern China with full information on FA intake were included. Limb reduction defects were classified by subtype and maternal FA supplementation. The prevalence of limb reduction defects was 2.7 per 10 000 births among women who took FA compared with 9.7 per 10 000 births among those who did not take FA in northern China; the prevalence was 4.5 and 3.8 per 10 000 births, respectively, in southern China. In both unadjusted and adjusted analyses, the estimated relative risk for upper limb reduction defects [odds ratio (OR) = 0.17, 95% confidence interval (CI): 0.04, 0.63] and total limb reduction defects (OR = 0.24, 95% CI: 0.08, 0.70) in northern China, but not for lower limb reduction defects ,was significantly decreased in association with FA supplementation in northern China. There was no association between FA supplementation and either an increased or decreased risk for limb reduction defects in southern China. FA supplementation successfully reduces the prevalence of limb reduction defects in northern China, whose population has low folate concentrations.

P.048 Characterization of somatic mutations in mTOR pathway genes in focal cortical dysplasias

Background: Focal cortical dysplasias (FCDs) are congenital structural abnormalities of the brain, and represent the most common cause of medication-resistant focal epilepsy in children and adults. Recent studies have shown that somatic mutations (i.e. mutations arising in the embryo) in mTOR pathway genes underlie some FCD cases. Specific therapies targeting the mTOR pathway are available. However, testing for somatic mTOR pathway mutations in FCD tissue is not performed on a clinical basis, and the contribution of such mutations to the pathogenesis of FCD remains unknown. Aim: To investigate the feasibility of screening for somatic mutations in resected FCD tissue and determine the proportion and spatial distribution of FCDs which are due to low-level somatic mTOR pathway mutations. Methods: We performed ultra-deep sequencing of 13 mTOR pathway genes using a custom HaloPlexHS target enrichment kit (Agilent Technologies) in 16 resected histologically-confirmed FCD specimens. Results: We identified causal variants in 62.5% (10/16) of patients at an alternate allele frequency of 0.75–33.7%. The spatial mutation frequency correlated with the FCD lesion’s size and severity. Conclusions: Screening FCD tissue using a custom panel results in a high yield, and should be considered clinically given the important potential implications regarding surgical resection, medical management and genetic counselling.

1394-P: The Role of the Unfolded Protein Response in High Glucose-Induced mESC Pluripotency and Impaired Differentiation

Maternal diabetes is associated with various risks during pregnancy, including structural birth defects. Gene dysregulation and reduced progenitor cell formation and differentiation are two major mechanisms that are implicated in diabetic embryopathy. Our lab has previously shown that E14 mouse embryonic stem cells (mESCs) grown in high glucose conditions have delayed differentiation to both neurons and cardiomyocytes. However, treatment of 4-PBA (4-phenylbutyrate), a chemical chaperone used as an endoplasmic reticulum (ER) stress inhibitor, rescued this delay of differentiation to neurons. On the other hand, high glucose increased mESC pluripotency and activated the unfolded protein response (UPR) in undifferentiated conditions, specifically the protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway. To determine the role of the UPR in enhanced mESC pluripotency by high glucose, E14 mESCs grown in high glucose were treated with or without 4-PBA for 8 days. Untreated E14 mESCs grew in dome-shaped colonies with defined edges, while 4-PBA-treated cells grew in flat colonies with cells emerging out of the colonies, indicative of a more differentiated state. Microarray analysis showed that 4-PBA-treated cells had upregulated expression of primed state markers and downregulated expression of pluripotency markers, compared to untreated cells. Our results suggest that inhibition of the UPR through ER stress inhibition abolishes the stimulatory effect of high glucose on mESC pluripotency, leading to a shift from native state to a more differentiated ESC stage. Disclosure W. Sun: None. P. Yang: None. F. Ye: None. P. Yang: None. Funding National Institutes of Health

1693-P: Rapamycin Reduces Maternal Diabetes-Induced Neural Tube Defects by Suppressing Premature Senescence

Maternal diabetes significantly increases the risk of structural birth defects. Senescence occurs after neural tube closure. We aimed to determine whether maternal diabetes induces premature senescence in the developing neuroepithelium. Maternal diabetes induced robust senescence associated β-galactosidase (SAβG) activity in the apical side of the developing neuroepithelium at embryonic day 8.5 (E8.5). The major senescence mediator p21 was induced preceding the SAβG signal at the same region. p21 gene deleted embryos of diabetic dams had a significantly lower neural tube defects (NTDs) incidence (3.6%) compared to wild type litter mates (25.9%). The transcriptional factor Forkhead transcription factor 3a (FoxO3a) is activated in diabetic embryopathy, and Foxo3a knockout reduces maternal diabetes-induced NTDs. Our data showed Foxo3a deletion diminished the signals of SAβG, and abrogated diabetes-increased abundance of p21 and DNA damage response proteins. MicroRNAs have been identified as novel inducers of cellular senescence. Two FoxO3a binding sites were found in the promote region of miR-200c. In vitro study confirmed both FoxO3a and high glucose stimulated miR-200 promoter activity. miR-200c null embryos had a lower NTD rate (4.3%) compared with that of WT embryos (29.2%) from diabetic dams. miR-200c repressed the expression of ZEB1 and ZEB2, which are transcription repressors for p21. In addition to the revelation of the gene regulation pathway in maternal diabetes-induced premature senescence, we found intraperitoneal injection of the senescence inhibitor Rapamycin in diabetic dams during E5.5-E9.5 diminished SAβG signal, and reduced the NTD rate from 24.0% to 4.5%) in diabetic pregnancy. Thus, our study revealed a novel FoxO3a-miR-200c-p21-mediated premature senescence pathway, and provided the mechanistic basis for targeting premature senescence in preventing diabetes-induced NTDs. Disclosure C. Xu: None. P. Yang: None. Funding American Diabetes Association (1-13-BS-220 to P.Y.); National Institutes of Health

Associations between age and sleep apnea risk among newborn infants.

Among older children, sleep-disordered breathing (SDB) is associated with measurable neurocognitive consequences. However, diagnostic SDB thresholds are lacking for infants < 12 months. We sought to evaluate the relationship between SDB indices, gestational age (GA), and postmenstrual age (PMA) for infants who underwent clinically-indicated polysomnograms at a tertiary care center. Every infant < 3-months chronological age whose first clinically-indicated polysomnogram was between 2/2012 and 2/2017 was included. Linear regression was used to evaluate associations between apnea-hypopnea index (AHI), obstructive-apnea index (OAI), and GA and PMA for infants with and without obvious clinical risk factors for SDB (eg, micrognathia and cleft palate). For 53 infants without obvious SDB risk factors (GA 35.6 ± 4.5 weeks; PMA 41.2 ± 4.0 weeks), mean AHI was 27 ± 18 and OAI 2.9 ± 4.5. There was a weak inverse relationship between AHI and PMA (r 2 = 0.12, P = 0.01), but AHI was not predicted by GA (r 2 = 0.04, P = 0.13). Conversely, OAI was more strongly associated with GA (r 2 = 0.33, P < 0.0001) than PMA (r 2 = 0.08, P = 0.036). For 28 infants with congenital structural anomalies that predispose to SDB (GA 38.0 ± 3.1 weeks, PMA 43.1 ± 3.3 weeks, AHI 37.7 ± 30, OAI 8.2 ± 11.8), neither AHI nor OAI were related to PMA or GA. Among infants who received clinically-indicated polysomnograms but did not have obvious structural risk for SDB, AHI declined with advancing PMA, but obstructive-apnea was best predicted by prematurity. In contrast, the SDB risk did not improve with increasing GA or PMA for infants with congenital structural risk factors; such infants may not outgrow their risk for SDB.

Diagnostic Yield of Chromosomal Microarray Analysis in Fetuses With Isolated Increased Nuchal Translucency: A French Multicenter Study

(Abstracted from Ultrasound Obstet Gynecol 2018;52:715–721) Nuchal translucency (NT) is a collection of fluid at the back of the fetal neck; its thickness can be measured by ultrasound between 10 and 13 + 6 weeks of gestation. An increased thickness, often defined as an NT of greater than the 99th centile, which corresponds approximately to a threshold of 3.5 mm, is associated with a risk of chromosomal abnormalities, as well as genetic syndromes such as Noonan and Smith-Lemli-Opitz syndrome, and major structural birth defects.

Is IVF Linked to Subsequent Childhood Cancer

In vitro fertilization (IVF) has been associated with increased risk for structural birth defects and genomic imprinting disorders in the offspring; is

Prevalence and Association of Congenital Anomalies According to the Maternal Body Mass Index: Cross-Sectional Study

To evaluate and compare the prevalence of structural congenital anomalies (CAs) according to maternal body mass index (BMI). The present cross-sectional study involved pregnant women with fetuses diagnosed with structural CAs through morphological ultrasonography between November 2014 and January 2016. The nutritional status of the pregnant women was classified according to the gross value of the body mass index. The pregnant women were categorized into four groups: low weight, adequate weight, overweight, and obesity. Statistical analysis was performed using Stata/SE version 12.0 (Stata Corporation, College Station, TX), with values of p ≤ 0.05 considered statistically significant. A total of 223 pregnant women had fetuses diagnosed with CAs. The prevalence of structural CAs in pregnant women with low weight was of 20.18%, of 43.50% in pregnant women with adequate weight, of 22.87% in pregnant women with overweight, and of 13.45% in pregnant women with obesity. The prevalence of central nervous system (CNS) anomalies and of genitourinary system anomalies was high for the four groups of pregnant women. A positive association was observed between multiple anomalies in pregnant women with adequate weight (prevalence ratio [PR] = 1.65; p ≤ 0.004) and between anomalies of the lymphatic system in obese pregnant women (PR = 4.04, p ≤ 0.000). The prevalence of CNS and genitourinary system anomalies was high in all of the BMI categories. Obese pregnancies were associated with lymphatic system anomalies. Therefore, screening and identification of the risk factors for CAs are important, regardless of the maternal BMI. Our findings reinforce the importance of discussing with pregnant women maternal nutrition and its effect on fetal development and on neonatal outcome.

Investigating the Origins of Congenital Heart Defects in a Mouse Model of Cornelia de Lange Syndrome

Congenital heart defects (CHDs) are among the most common birth defects and are a major cause of infant mortality. Increasing evidence suggests that CHDs result from the combinatorial effects of variations in the expression of multiple genes throughout the genome. As one approach to understand the multifactorial origins of CHDs, we have generated and studied mouse models of Cornelia de Lange Syndrome (CdLS), a multisystem birth defects disorder that arises in most instances from haplinsufficiency for NIPBL. The NIPBL gene encodes a cohesin binding factor that is also known to have global effects on gene expression, and Nipbl‐deficient vertebrate animal models of CdLS, such as Nipbl‐deficient mice and zebrafish, recapitulate both the large array of structural birth defects observed in CdLS and the global dysregulation of gene expression observed in cells from individuals with CdLS (e.g., Kawauchi et al., 2009, PLoS Genetics; Muto et al., 2011, PLoS Biology). Strikingly, Nipbl+/− mice exhibit CHD at a frequency of ~30%, similar to the level observed in individuals with CdLS. This high degree of penetrance makes such mice an excellent model system for understanding the complex origins of CHDs.In a recent study, we generated an allelic series of Nipbl in the mouse, which allows us to selectively create or rescue Nipbl haploinsufficiency in different tissues (Santos et al., 2016, PLoS Biology). We used this allelic series to understand the tissue origins of CHD in CdLS, and found that defects were apparent from the earliest times of heart development. Specifically, we found deficits in the numbers of developing cardiac progenitor cells; defects in right ventricle development during early heart development; defects in ventricular septation during mid‐gestation; and a high incidence (~30%) of atrial septal defects (ASDs) at perinatal stages of heart development (ibid). The results of these and other studies (Chea, Calof, unpublished observations) suggested that, in CdLS, the origins of CHD lie at the earliest stages of heart development, during the initial allocation of cardiac progenitors to the first and second heart fields (FHF, SHF). Because the SHF contributes cells that make up the bulk of the right ventricle, and defects in the SHF can lead to defects in outflow tract and atrial septum development, we are particularly interested in whether Nipbl deficiency in the SHF specifically may be responsible for the CHD observed in CdLS. To test this, we are crossing mice carrying SHF‐specific Cre recombinases with NipblFlox mice, in order to generate offspring with Nipbl haploinsufficiency specifically in the SHF and its derivatives. Results from these studies will allow us to determine whether Nipbl deficiency in the SHF and its derivatives is necessary and sufficient for the development of the high incidence of CHD in CdLS.Support or Funding InformationSupported by a grant to ALC and ADL from the National Institute of Heart, Lung, and Blood Disorders (HL138659‐02) of the NIH.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Sociodemographic, health behavioral, and clinical risk factors for anotia/microtia in a population-based case-control study

ObjectiveAnotia and microtia are congenital malformations of the external ear with few known risk factors. We conducted a comprehensive assessment of a wide range of potential risk factors using data from the National Birth Defects Prevention Study (NBDPS), a population-based case-control study of non-chromosomal structural birth defects in the United States. MethodsMothers of 699 infants with anotia or microtia (cases) and 11,797 non-malformed infants (controls) delivered between 1997 and 2011 were interviewed to obtain information about sociodemographic, health behavioral, and clinical characteristics. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated with logistic regression. ResultsInfants with anotia/microtia were more likely to be male (aOR, 1.29; 95% CI, 1.10–1.50) and from a multifetal pregnancy (aOR, 1.68; 95% CI, 1.16–2.42). Cases were also more likely to have parents of Hispanic ethnicity (maternal aOR, 3.19; 95% CI, 2.61–3.91; paternal aOR, 2.11; 95% CI, 1.54–2.88), and parents born outside the United States (maternal aOR, 1.29; 95% CI, 1.06–1.57; paternal aOR, 1.92; 95% CI, 1.53–2.41). Maternal health conditions associated with increased odds of anotia/microtia included obesity (aOR, 1.31; 95% CI, 1.06–1.61) and pre-pregnancy diabetes (type I aOR, 9.89; 95% CI, 5.46–17.92; type II aOR, 4.70; 95% CI, 2.56–8.63). Reduced odds were observed for black mothers (aOR, 0.57; 95% CI, 0.38–0.85) and mothers reporting daily intake of folic acid-containing supplements (aOR, 0.59; 95% CI, 0.46–0.76). ConclusionWe identified several risk factors for anotia/microtia, some which have been previously reported (e.g., diabetes) and others which we investigate for perhaps the first time (e.g., binge drinking) that warrant further investigation. Our findings point to some potentially modifiable risk factors and provide further leads toward understanding the etiology of anotia/microtia.

Prevalence of structural birth defects in IVF-ICSI pregnancies resulting from autologous and donor oocytes in Indian sub-continent: Results from 2444 births.

This study was conducted to evaluate and compare the incidence of birth defects in In-Vitro Fertilization-Intra Cytoplasmic Sperm Injection (IVF-ICSI) pregnancies with autologous and donor oocytes. As a secondary outcome, the prevalence of birth defects in IVF-ICSI pregnancies was compared with those from spontaneous conceptions in India. This retrospective study included 2444 births resulting from IVF-ICSI cycles from autologous (n=1743) and donor oocytes (n=701) during a 3-year period in an Indian infertility center. Birth defects, if any, were noted antenatally and followed till the neonatal period, in case of live birth. The overall prevalence of birth defects in IVF-ICSI pregnancies in this study was 29/2444 (118.6/10000 births) and the most common congenital anomaly was cardiac malformation (32.7/10000 births) followed by genitourinary (28.6/10000 births). The risks of birth defects resulting from autologous and donor oocytes did not differ (114.7/10000 vs 128.38/10000; P>0.05). However, pregnancies resulting from autologous oocytes had a higher trend of gastrointestinal birth defects (20.5/10000 births vs 0), though not statistically significant. The risk of cardiovascular birth defects resulting from IVF-ICSI pregnancies was much higher compared with the natural conceptions in India (32.7/10000 vs 12.7/10000 births; P=0.03), whereas the risk of central nervous system malformations was much lower (8.1/10000 vs 60.18/10000 births; P=0.005). Overall, there was no significant difference in birth defects resulting from IVF-ICSI with autologous or donor oocytes. The births resulting from IVF-ICSI pregnancies did not tend to have a higher rate of birth defects a compared with natural conceptions. The differences in the prevalence of certain birth defects (cardiovascular or central nervous system) reported in IVF-ICSI pregnancies may be due to improved surveillance modalities and early detection in pregnancies following IVF-ICSI. A study with larger number of sample size will give us better understanding of the prevalence of reported incidence in this study.

Application of quality indicators to data from the National Network of Congenital Anomalies of Argentina.

In Argentina, birth defects are a leading cause of infant deaths. In 2009, the National Network for Congenital Anomalies of Argentina (RENAC) was established as a hospital-based surveillance system of major structural birth defects. To assess and enhance the system's data quality, we previously developed data quality indicators (DQI). Our aim was to evaluate quality indicators in RENAC. We applied the DQI presented in a related publication to the 2016 RENAC data. Among the DQI of description, spina bifida coverage and talipes had the lowest results. Regarding prevalence of hypospadias, it was lower than the defined threshold. RENAC did not achieve the ascertainment threshold of a prevalence of 21.5 per 10,000 for critical congenital heart defects. There was a high ratio of spina bifida to anencephaly. DQI provide a focus for improving quality, making decisions, and advocating for interventions. Examples include advocating for newborn screening of critical congenital heart defects with pulse oximetry; developing training programs for clinicians to improve the detection of isolated hypospadias; and developing visual tools and checklists to improve the completeness and accuracy of case description for spina bifida, talipes, and other major malformations. After the interventions, it is important to track the impact by measuring again the DQI.

Noncoding rare variants of TBX6 in congenital anomalies of the kidney and urinary tract.

Congenital anomalies of the kidney and urinary tract (CAKUT) are a wide range of congenital structural renal defects. CAKUT is the leading cause of chronic renal failure and end-stage renal disease in children. Studies in humans and animal models have confirmed the large genetic contribution to CAKUT. The previous evidence suggested that human TBX6 coding mutations might cause CAKUT via gene-dosage insufficiency. However, the potential involvement of TBX6 noncoding mutations in CAKUT remains to be elucidated. Here, we described DNA sequencing and copy-number analysis of TBX6 in 269 Chinese subjects with CAKUT. Interestingly, we identified two heterozygous noncoding variants of TBX6 in sporadic subjects with CAKUT: one is c.769-7delT, from a subject with duplex renal and collecting system, and the other is a 3' untranslated region (3'-UTR) variant (c.1392C>T) from a subject with unilateral renal hypoplasia. These two TBX6 noncoding variants are novel and extremely rare, respectively, in human populations archived in the ExAC database. The mini-gene splicing assay showed that the TBX6 c.769-7delT variant significantly reduced the splicing efficiency of TBX6 intron 5 when compared to the wild-type control. In this work, we identified a novel splicing variant of TBX6 in human CAKUT. Our experimental observations suggested that the TBX6 noncoding variant can affect gene expression and may potentially be involved in human CAKUT.

Alobar holoprosencephaly in one of twin neonates

Holoprosencephaly (HPE) is a congenital structural anomaly of the forebrain which is often diagnosed prenatally, usually in singleton pregnancies. This is a case of alobar HPE affecting one of 19-day-old twin neonates which was only detected postnatally. The other twin was unaffected. The anomaly was not diagnosed in utero because a prenatal sonogram was not performed. This case is presented to reemphasize the need for thorough routine prenatal/obstetrics sonography. After birth, transfontanelle ultrasonography is a useful imaging modality for diagnosing this debilitating cerebral structural anomaly, but definitive classification requires cross-sectional brain imaging with computed tomography or magnetic resonance imaging.

Birth defects in Tarnaveni area, Romania - preliminary study results.

Background and aimsIn the development of any human body, defects may occur, resulting in the occurrence of congenital malformations, also referred to as birth defects. The aim of this preliminary study was to assess the prevalence of birth defects registered during a period of 5 years in Tarnaveni area. As Tarnaveni is located in close proximity to a former chemical plant, a recognized hazardous waste site, we conducted this pilot study to assess the prevalence of birth defects, in order to evaluate the need for a more comprehensive investigation of a potential relation between the exposure to toxic metals contaminating the environmental media as a result of the past industrial activities, and the prevalence of the birth defects in this area.MethodsWe abstracted birth information (gestational age at delivery (GA), birth weight (BW), birth length (BL), head circumference (HC), and major structural birth defects), from medical records at “Dr. Gheorghe Marinescu“ Tarnaveni Municipal Hospital, of the 2010–2014 period. We expressed BW as Z-scores relative to expected mean values at each gestational age for a reference population, calculated the ponderal index, and determined the 5 years birth defects prevalence among live births during the study interval.ResultsThe 5 years (2010–2014) prevalence of birth defects, was 3.3% (95% confidence interval (CI): 2.47, 4.09). There were n = 163 (8.7%) preterm deliveries (less than 37 weeks of gestation at delivery), mean birth weight was 3108.3 g (standard deviation (SD) = 517.1), ranging from 450–4600 g, and n = 187 (10%) were low birth weight (LBW) (less than 2500 g). The ponderal index was 2.2 g/cm3 on average (SD = 0.5), with range 1.2–20.7 g/cm3.ConclusionsWhile preliminary, our data show a 5 years (2010–2014) prevalence of major structural birth defects among newborns from Tarnaveni area of 3.3%. These pilot results indicate the need for a more comprehensive investigation of a potential relation between the exposure to toxic metals contaminating the environmental media as a result of the past industrial activities and the prevalence of the birth defects in Tarnaveni area.

Maternal residential exposure to specific agricultural pesticide active ingredients and birth defects in a 2003-2005 North Carolina birth cohort.

Previously we observed elevated odds ratios (ORs) for total pesticide exposure and 10 birth defects: three congenital heart defects and structural defects affecting the gastrointestinal, genitourinary and musculoskeletal systems. This analysis examines association of those defects with exposure to seven commonly applied pesticide active ingredients. Cases were live-born singleton infants from the North Carolina Birth Defects Monitoring Program linked to birth records for 2003-2005; noncases served as controls (total n = 304,906). Pesticide active ingredient exposure was assigned using a previously constructed metric based on crops within 500 m of residence, dates of pregnancy, and likely chemical application dates for each pesticide-crop combination. ORs (95% CI) were estimated with logistic regression for categories of exposure compared to unexposed. Models were adjusted for maternal race/ethnicity, age at delivery, education, marital status, and smoking status. Associations varied by birth defect and pesticide combinations. For example, hypospadias was positively associated with exposures to 2,4-D (OR50th to <90th percentile : 1.39 [1.18, 1.64]), mepiquat (OR50th to <90th percentile : 1.10 [0.90, 1.34]), paraquat (OR50th to <90th : 1.14 [0.93, 1.39]), and pendimethalin (OR50th to <90th : 1.21 [1.01, 1.44]), but not S-metolachlor (OR50th to <90th : 1.00 [0.81, 1.22]). Whereas atrial septal defects were positively associated with higher levels of exposure to glyphosate, cyhalothrin, S-metolachlor, mepiquat, and pendimethalin (ORs ranged from 1.22 to 1.35 for 50th to <90th exposures, and 1.72 to 2.09 for >90th exposures); associations with paraquat were null or inconsistent (OR 50th to <90th: 1.05 (0.87, 1.27). Our results suggest differing patterns of association for birth defects with residential exposure to seven pesticide active ingredients in North Carolina.

Risk factors of congenital anomalies in Karbala

BACKGROUND; Congenital anomalies can be defined as structural or functional abnormalities present at birth. They are an important cause of morbidity and mortality in infants. Various risk factors have been identified as contributing factors to these defects. The objectives of the present study are to determine the frequency of different structural congenital anomalies and possible risk factors responsible for these anomalies.&#x0D; METHODS; This case - control study was carried out in the neonatal intensive care unit of Kerbala teaching hospital for children in Karbala / Iraq. The study was conducted over 18 month’s period from January 1, 2014 to May 31, 2015. All babies admitted to neonatal care unit with congenital anomalies during this period were included apart from neonate with suspicion of inborn error of metabolism and those with chromosomal abnormalities because there are no facilities for definite diagnosis of these diseases.&#x0D; Seventy seven newborns with congenital anomalies included in this study, males 47(61.04%) and females 30 (38.96%) and 100 newborn without congenital anomalies, male 59 (59%) and female 41 (41%), selected randomly as a control.&#x0D; The statistical method which used to signify the risk factors is relative risk (RR). [RR = 1 no effect, RR &gt; 1 is a risk factor, and RR &lt; 1 is protective]&#x0D; RESULTS; In present study, the congenital anomalies related to the cardiovascular system (CVS) were the most common 33(42.86%). Males 47(61.04%) were more commonly affected than females 30 (38.96%). Cases of congenital anomaly were found in 60 (77.92%) of multiparas, whereas 17 (22.08%) in primiparas. It has been seen that 45 (58.44%) of the mothers were 20 - 30 years old, 15 (19.48%) of the mothers were between 30 - 40 years old, and 6 (7.79%) of the mothers were over the 40 years old.&#x0D; In the present study, 54 (70.13%) mothers of babies delivered with congenital anomalies had a history of consanguinity. Also, 6 (7.79%) mothers of babies delivered with congenital anomalies had a history of diabetes mellitus. CONCLUSION; The congenital anomalies were cardiovascular system (CVS) 33(42.86%), gastrointestinal system 25 (32.47%), and central nervous system 14 (18.18%).&#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; The main risk factors were consanguinity and maternal diabetes.