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Objectives: To explore associations between maternal pre-pregnancy exposure to arsenic in diet and non-cardiac birth defects. Design: This is a population-based, case–control study using maternal responses to a dietary assessment and published arsenic concentration estimates in food items to calculate average daily total and inorganic arsenic exposure during the year before pregnancy. Assigning tertiles of total and inorganic arsenic exposure, logistic regression analysis was used to estimate OR for middle and high tertiles, compared to the low tertile. Setting: US National Birth Defects Prevention Study, 1997–2011. Participants: Mothers of 10 446 children without birth defects and 14 408 children diagnosed with a non-cardiac birth defect. Results: Maternal exposure to total dietary arsenic in the middle and high tertiles was associated with a threefold increase in cloacal exstrophy, with weak positive associations (1·2–1·5) observed either in both tertiles (intercalary limb deficiency) or the high tertile only (encephalocele, glaucoma/anterior chamber defects and bladder exstrophy). Maternal exposure to inorganic arsenic showed mostly weak, positive associations in both tertiles (colonic atresia/stenosis, oesophageal atresia, bilateral renal agenesis/hypoplasia, hypospadias, cloacal exstrophy and gastroschisis), or the high (glaucoma/anterior chamber defects, choanal atresia and intestinal atresia stenosis) or middle (encephalocele, intercalary limb deficiency and transverse limb deficiency) tertiles only. The remaining associations estimated were near the null or inverse. Conclusions: This exploration of arsenic in diet and non-cardiac birth defects produced several positive, but mostly weak associations. Limitations in exposure assessment may have resulted in exposure misclassification. Continued research with improved exposure assessment is recommended to identify if these associations are true signals or chance findings. [ABSTRACT FROM AUTHOR]

Introduction: Arsenic crosses the placenta and accumulates in fetal tissues. In the United States, diet is the predominant route of arsenic exposure, but epidemiologic data are sparse regarding this exposure and development of birth defects. Using data from a large case‐control study, we explored associations between maternal dietary arsenic exposure and congenital heart defects (CHDs), the most prevalent birth defects. Methods: We used maternal self‐reported dietary assessments and arsenic concentration estimates in food items to estimate average daily exposure to dietary arsenic during the year before pregnancy for mothers of 10,446 unaffected control children and 6,483 case children diagnosed with CHDs. Using tertiles of dietary exposure to total arsenic (all species) and inorganic arsenic, we applied logistic regression analysis to estimate associations for middle and high tertiles, compared with the low tertile. Results: Positive associations (odds ratio [OR] ≥ 1.2) for total arsenic were observed in both tertiles for perimembranous ventricular septal defect (VSD) and high tertile only for double outlet right ventricle‐transposition of the great arteries (DORV‐TGA), partial anomalous pulmonary venous return (PAPVR), and tricuspid atresia. Positive associations were also observed in both tertiles (tricuspid atresia) and high tertile only (DORV‐TGA, conoventricular VSD, PAPVR, and pulmonary atresia) for inorganic arsenic. Most remaining associations were near or below unity. Discussion: Exploration of maternal dietary exposure to total and inorganic arsenic and CHDs produced few positive associations but was limited by available food item concentrations. Future research requires expanded collection of dietary data, improved estimates of concentrations, and consideration of nondietary sources of arsenic exposure. [ABSTRACT FROM AUTHOR]

Background: Congenital diaphragmatic hernia (CDH) occurs when abnormal diaphragm development allows herniation of abdominal organs into the thoracic cavity. Its etiopathogenesis is not well understood, but cigarette smoking and alcohol exposure may impact diaphragm development. Using data from a large, population‐based case–control study, we examined associations between maternal cigarette smoking and alcohol consumption and CDH in offspring. Methods: We analyzed maternal interview reports of cigarette smoking and alcohol consumption during early pregnancy for 831 children with CDH and 11,416 children without birth defects with estimated dates of delivery during 1997–2011. Generalized linear mixed effects models with a random intercept for study site were used to estimate associations between measures of exposure to smoking (any, type, frequency, duration) and alcohol (any, quantity, frequency, variability, type) for all CDH combined and selected subtypes (Bochdalek and Morgagni). Results: Mothers of 280 (34.0%) case and 3,451 (30.3%) control children reported early pregnancy exposure to cigarette smoking. Adjusted odds ratios for all CDH were increased for any (1.3; 95% confidence interval 1.1–1.5), active (1.3, 1.0–1.7), and passive (1.4, 1.1–1.7) smoking. Early pregnancy alcohol consumption was reported by mothers of 286 (34.9%) case and 4,200 (37.0%) control children; odds were near the null for any consumption (0.9, 0.8–1.1) and consumption with (0.9, 0.7, 1.1) or without (0.9, 0.8, 1.1) binging. Estimates for smoking and alcohol tended to be higher for Bochdalek CDH and Morgagni CDH than those for all CDH. Conclusions: Findings suggest that maternal early pregnancy exposure to cigarette smoking, but less so to alcohol consumption, contributes to CDH. These findings need to be replicated in additional large studies that use systematic case ascertainment and classification, detailed exposure assessment, and examine subtype‐specific associations. [ABSTRACT FROM AUTHOR]

Von Hippel Lindau(VHL)syndrome presents with cerebellar and spinal hemangioblastomas, renal cell cancer, neuroendocrine pancreatic tumor, and pheochromocytoma and it is caused by germline mutations in the VHL gene. Pathogenic germline variants in the succinate dehydrogenase A (SDHA) gene are associated with paraganglioma and pheochromocytoma. Here we report co-occurrence of germline pathogenic variants in both VHL and SDHA genes in a patient who presented with pancreatic neuroendocrine tumor. As these genes converge on the pseudo-hypoxia signaling pathway, further studies are warranted to determine the significance of co-occurrence of these variants in relation to tumor penetrance, disease severity, treatment response and clinical outcomes in this selected group of patients. [ABSTRACT FROM AUTHOR]

The systematic evaluation of ligands by exponential enrichment (SELEX) was utilized to systematically identify additional DNA sequences important for binding of FOXO1A, a transcription factor protein with proapoptotic activities which contribute to insulin and growth factor signaling. The results showed that binding ability of FOXO1A is enhanced to 9-fold through 1-to-1 binding stoichiometry by two additional sequence elements, the reverse complement (5'GT(A/C)AACA-3') and the flanking sequence (5'-ACAACA-3').

Objectives: To explore associations between maternal pre-pregnancy exposure to arsenic in diet and non-cardiac birth defects., Design: This is a population-based, case-control study using maternal responses to a dietary assessment and published arsenic concentration estimates in food items to calculate average daily total and inorganic arsenic exposure during the year before pregnancy. Assigning tertiles of total and inorganic arsenic exposure, logistic regression analysis was used to estimate OR for middle and high tertiles, compared to the low tertile., Setting: US National Birth Defects Prevention Study, 1997-2011., Participants: Mothers of 10 446 children without birth defects and 14 408 children diagnosed with a non-cardiac birth defect., Results: Maternal exposure to total dietary arsenic in the middle and high tertiles was associated with a threefold increase in cloacal exstrophy, with weak positive associations (1·2-1·5) observed either in both tertiles (intercalary limb deficiency) or the high tertile only (encephalocele, glaucoma/anterior chamber defects and bladder exstrophy). Maternal exposure to inorganic arsenic showed mostly weak, positive associations in both tertiles (colonic atresia/stenosis, oesophageal atresia, bilateral renal agenesis/hypoplasia, hypospadias, cloacal exstrophy and gastroschisis), or the high (glaucoma/anterior chamber defects, choanal atresia and intestinal atresia stenosis) or middle (encephalocele, intercalary limb deficiency and transverse limb deficiency) tertiles only. The remaining associations estimated were near the null or inverse., Conclusions: This exploration of arsenic in diet and non-cardiac birth defects produced several positive, but mostly weak associations. Limitations in exposure assessment may have resulted in exposure misclassification. Continued research with improved exposure assessment is recommended to identify if these associations are true signals or chance findings.

Activating Signal Cointegrator 1 Complex, Subunit 3 (ASCC3) is part of the four-part ASC-1 transcriptional cointegrator complex. This complex includes ASCC1 (associated with spinal muscular atrophy with congenital bone fractures 2), TRIP4 (associated with spinal muscular atrophy with congenital bone fractures 1), and ASCC2 (not yet associated with human disease.) ASCC3 encodes a DNA helicase responsible for generating single-stranded DNA as part of the DNA damage response. Interestingly, ASCC3 expresses coding and non-coding isoforms, which act in opposition to balance the recovery of gene transcription after UV-induced DNA damage. Here we report the discovery of ASCC3 as the cause of a neuromuscular syndrome in seven unreported individuals from six unrelated families and updates on the one previously reported family. All the individuals share a neurologic phenotype that ranges from severe developmental delay to muscle fatigue. There appears to be genotype-phenotype correlation, as the most mildly affected individual is homozygous for a rare missense variant, while the more severely affected individuals are compound heterozygotes for a missense and a presumed loss-of-function (LOF) variant. There are no individuals with biallelic presumed LOF variants in our cohort or in gnomAD, as this genotype may not be compatible with life. In summary we report a syndrome in these eleven individuals from seven families with biallelic variants in ASCC3 ., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)