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Anophthalmia and microphthalmia (A/M) are rare birth defects affecting up to 2 per 10,000 live births. These conditions are manifested by the absence of an eye or reduced eye volumes within the orbit leading to vision loss. Although clinical case series suggest a strong genetic component in A/M, few systematic investigations have been conducted on potential genetic contributions owing to low population prevalence. To overcome this challenge, we utilized DNA samples and data collected as part of the National Birth Defects Prevention Study (NBDPS). The NBDPS employed multi-center ascertainment of infants affected by A/M. We performed exome sequencing on 67 family trios and identified numerous genes affected by rare deleterious nonsense and missense variants in this cohort, including de novo variants. We identified 9 nonsense changes and 86 missense variants that are absent from the reference human population (Genome Aggregation Database), and we suggest that these are high priority candidate genes for A/M. We also performed literature curation, single cell transcriptome comparisons, and molecular pathway analysis on the candidate genes and performed protein structure modeling to determine the potential pathogenic variant consequences on PAX6 in this disease.

BackgroundGlobal efforts are needed to elucidate the epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the underlying cause of coronavirus disease 2019 (COVID-19), including seroprevalence, risk factors, and long-term sequelae, as well as immune responses after vaccination across populations and the social dimensions of prevention and treatment strategies.MethodsIn the United States, the National Cancer Institute in partnership with the National Institute of Allergy and Infectious Diseases, established the SARS-CoV-2 Serological Sciences Network (SeroNet) as the nation's largest coordinated effort to study coronavirus disease 2019. The network comprises multidisciplinary researchers bridging gaps and fostering collaborations among immunologists, epidemiologists, virologists, clinicians and clinical laboratories, social and behavioral scientists, policymakers, data scientists, and community members. In total, 49 institutions form the SeroNet consortium to study individuals with cancer, autoimmune disease, inflammatory bowel diseases, cardiovascular diseases, human immunodeficiency virus, transplant recipients, as well as otherwise healthy pregnant women, children, college students, and high-risk occupational workers (including healthcare workers and first responders).ResultsSeveral studies focus on underrepresented populations, including ethnic minorities and rural communities. To support integrative data analyses across SeroNet studies, efforts are underway to define common data elements for standardized serology measurements, cellular and molecular assays, self-reported data, treatment, and clinical outcomes.ConclusionsIn this paper, we discuss the overarching framework for SeroNet epidemiology studies, critical research questions under investigation, and data accessibility for the worldwide scientific community. Lessons learned will help inform preparedness and responsiveness to future emerging diseases.

Previous research on risk factors for obstructive heart defects (OHDs) focused on maternal and infant genetic variants, prenatal environmental exposures, and their potential interaction effects. Less is known about the role of paternal genetic variants or environmental exposures and risk of OHDs. We examined parent-of-origin effects in transmission of alleles in the folate, homocysteine, or transsulfuration pathway genes on OHD occurrence in offspring. We used data on 569 families of liveborn infants with OHDs born between October 1997 and August 2008 from the National Birth Defects Prevention Study to conduct a family-based case-only study. Maternal, paternal, and infant DNA were genotyped using an Illumina Golden Gate custom single nucleotide polymorphism (SNP) panel. Relative risks (RR), 95% confidence interval (CI), and likelihood ratio tests from log-linear models were used to estimate the parent-of-origin effect of 877 SNPs in 60 candidate genes in the folate, homocysteine, and transsulfuration pathways on the risk of OHDs. Bonferroni correction was applied for multiple testing. We identified 3 SNPs in the transsulfuration pathway and 1 SNP in the folate pathway that were statistically significant after Bonferroni correction. Among infants who inherited paternally-derived copies of the G allele for rs6812588 in the RFC1 gene, the G allele for rs1762430 in the MGMT gene, and the A allele for rs9296695 and rs4712023 in the GSTA3 gene, RRs for OHD were 0.11 (95% CI: 0.04, 0.29, P = 9.16x10-7), 0.30 (95% CI: 0.17, 0.53, P = 9.80x10-6), 0.34 (95% CI: 0.20, 0.57, P = 2.28x10-5), and 0.34 (95% CI: 0.20, 0.58, P = 3.77x10-5), respectively, compared to infants who inherited maternally-derived copies of the same alleles. We observed statistically significant decreased risk of OHDs among infants who inherited paternal gene variants involved in folate and transsulfuration pathways. Author summary: Obstructive heart defects are birth defects that cause obstruction to the blood flow of the developing heart. Common OHDs include coarctation of the aorta, aortic stenosis and pulmonary stenosis. While there is a fair amount of literature indicating an association between maternal genetic variants and OHDs, less is known about the role of paternal genetic variants in the etiology of OHDs. We used a genotype clustering algorithm, SNPMClust, that was developed in-house at the Arkansas Center for Birth Defects Research and Prevention to study the role of paternal genetic variants in the folate, homocysteine and transsulfuration pathways. Maternal, paternal, and infant DNA specimens were collected from participants of the National Birth Defects Prevention Study, a large population-based case-control study in the United States, and were genotyped using an Illumina Golden Gate custom single nucleotide polymorphism (SNP) panel. We identified 4 SNPs in the folate and transsulfuration pathways, rs6812588, rs1762430, rs9296695, and rs4712023, that were associated with a statistically significant decreased risk of OHDs for infants who inherited a paternally-derived copy of the variant allele compared to infants who inherited a maternal copy of the variant allele. In conclusion, we observed a significantly decreased risk and less epigenetic influence of paternal genetic variants on OHDs compared to maternally-derived variants. [ABSTRACT FROM AUTHOR]

Background Trichlorophenols (TCPs) are organochlorine compounds which are ubiquitous in the environment and well known for their carcinogenic effects. However, little is known about their neurotoxicity in humans. Objectives Our goal was to examine the association between body burden of TCPs (ie, 2,4,5-TCP and 2,4,6- TCP) and attention deficit hyperactivity disorder (ADHD). Methods We calculated ORs and 95% CIs from logistic regression analyses using data from the 1999-2004 National Health and Nutrition Examination Survey (NHANES) to evaluate the association between urinary TCPs and parent-reported ADHD among 2546 children aged 6-15 years. Results Children with low levels (<3.58 μg/g) and high levels (≥3.58 μg/g) of urinary 2,4,6-TCP had a higher risk of parent-reported ADHD compared to children with levels below the limit of detection (OR 1.54, 95% CI 0.97 to 2.43 and OR 1.77, 95% CI 1.18 to 2.66, respectively; p for trend=0.006) after adjusting for covariates. No association was found between urinary 2,4,5-TCP and parent-reported ADHD. Conclusion Exposure to TCP may increase the risk of behavioural impairment in children. The potential neurotoxicity of these chemicals should be considered in public health efforts to reduce environmental exposures/ contamination, especially in countries where organochlorine pesticides are still commonly used. [ABSTRACT FROM AUTHOR]