Neonatal Blood Spots Research Articles

Maternal-neonatal transfer of SARS-CoV-2 immunoglobulin G antibodies among parturient women treated with BNT162b2 messenger RNA vaccine during pregnancy

BACKGROUNDThe exclusion of pregnant women from initial COVID-19 messenger RNA vaccine trials raised hesitancy regarding the benefits of vaccination for pregnant women, hence little is known about vaccines’ efficacy in this population.OBJECTIVETo determine the maternal-neonatal transplacental transfer of SARS-CoV-2 antibodies among vaccinated parturient women. A control group of COVID-19-recovered patients was included to compare the immunoglobulin G levels between vaccinated and recovered patients.STUDY DESIGNThis is a prospective cohort study conducted in a single tertiary medical center in Israel between February and March 2021; parturient women vaccinated with the BNT162b2 messenger RNA vaccine during pregnancy were included and compared with COVID-19-recovered parturient women. SARS-CoV-2 immunoglobulin G antibodies were measured in maternal and cord sera, dried blood spot samples taken from newborns, and breast milk samples. The primary aim was to determine whether neonatal cord and dried blood spot samples were positive for SARS-CoV-2 antibodies and to evaluate the transfer ratio, defined as cord blood immunoglobulin G divided by maternal immunoglobulin G levels.RESULTSThe study included 64 vaccinated parturient women and 11 parturient women who had COVID-19 during pregnancy. All maternal blood sera samples and 98.3% of the cord blood sera samples were positive for SARS-Cov-2 immunoglobulin G with median concentrations of 26.1 (interquartile range, 22.0–39.7) and 20.2 (interquartile range, 12.7–29.0), respectively. Similarly, 96.4% of neonatal blood spot samples and all breast milk samples were positive for SARS-CoV-2 immunoglobulin G with median concentrations of 11.0 (interquartile range, 7.2–12.8) and 4.9 (interquartile range, 3.8–6.0), respectively. There was a significant positive correlation between maternal serum levels of SARS-CoV-2 immunoglobulin G and cord blood (r=0.483; P=.0001), neonatal blood spot (r=0.515; P=.004), and breast milk levels (r=0.396; P=.005) of SARS-CoV-2 immunoglobulin G. The median placental transfer ratio of SARS-COV-2 immunoglobulin G was 0.77. Comparison of vaccinated and recovered COVID-19 patients revealed significantly higher SARS-CoV-2 immunoglobulin G levels in maternal serum and cord blood among vaccinated women (P<.0001).CONCLUSIONOur study demonstrated the efficient transfer of SARS-CoV-2 immunoglobulin G across the placenta in women, vaccinated with the BNT162b2 messenger RNA vaccine during pregnancy, to their neonates, with a positive correlation between maternal serum and cord blood antibody concentrations. In addition to maternal protection against COVID-19, the vaccine may also provide neonatal humoral immunity.

Child serum metabolome and traffic-related air pollution exposure in pregnancy

BackgroundMaternal exposure to traffic-related air pollution during pregnancy has been shown to increase the risk of adverse birth outcomes and childhood disorders. High-resolution metabolomics (HRM) has previously been employed to identify metabolic responses to traffic-related air pollution in adults, including pregnant women. Thus far, no studies have examined metabolic effects of air pollution exposure in utero on neonates. MethodsWe retrieved stored neonatal blood spots for 241 children born in California between 1998 and 2007. These children were randomly selected from all California birth rolls to serve as birth-year matched controls for children with retinoblastoma identified from the California cancer registry for a case control study of childhood cancer. We estimated prenatal traffic-related air pollution exposure (particulate matter less than 2.5 μm (PM2.5)) during the third-trimester using the California Line Source Dispersion Model, version 4 (CALINE4) based on residential addresses recorded at birth. We employed untargeted HRM to obtain metabolic profiles, and metabolites associated with air pollution exposure were identified using partial least squares (PLS) regression and linear regressions. Biological effects were characterized using pathway enrichment analyses adjusting for potential confounders including maternal age, race/ethnicity, and education. ResultsIn total we extracted 4038 and 4957 metabolite features from neonatal blood spots in hydrophilic interaction (HILIC) chromatography (positive ion mode) and C18 reverse phase columns (negative ion mode), respectively. After controlling for confounding factors, partial least square regression (Variable Importance in Projection (VIP) ≥ 2) selected 402 HILIC positive and 182 C18 negative features as statistically significantly associated with increasing third trimester PM2.5 exposure. Using pathway enrichment analysis, we identified metabolites in oxidative stress and inflammation pathways as being altered, primarily involving lipid metabolism. ConclusionThe metabolite features and pathways associated with air pollution exposure in neonates suggest that maternal exposure during late pregnancy contributes to oxidative stress and inflammation in newborn children.

CPSF1 Regulates AML1-ETO Fusion Gene Polyadenylation and Stability in t(8;21) Acute Myelogenous Leukemia

Alternative polyadenylation (APA) can alter the three prime untranslated region (3'UTR) length of mRNA transcripts, a crucial region for regulating mRNA metabolism and gene expression. Despite the prevalence and reported importance of APA post-transcriptional regulation in cancer, changes in 3'UTR usage by APA and its contribution to leukemia development have not been thoroughly studied. In acute myelogenous leukemia (AML), t(8;21) is the most common chromosomal abnormality and encodes the AML1-ETO (AE) fusion gene, which dominantly blocks hematopoietic cell differentiation. Previous studies reported that a small amount of non-leukemic t(8;21)+ hematopoietic stem cells (HSCs) never disappeared in long-term remission bone marrows after chemotherapy. These t(8;21)+ HSCs expressed low AE mRNA compared to diagnostic AML cells and possessed normal differentiation into myeloid cells. Another study also reported that a fraction of pediatric t(8;21) AML patients had AE+ clones in their neonatal Guthrie blood spots samples. These data suggest that acquisition of AE is not sufficient for t(8;21) AML development, AE+ HSCs could be a reservoir for pre-leukemic clones, and AE up-regulation is essential for leukemic transformation. However, the mechanism of AE up-regulation has not been revealed. Uncovering this mechanism is highly significant for preventing leukemia development and relapse after treatment.The AE 3'UTR has a full length of 5.2kb (long 3'UTR) that contains 8 polyadenylation sites (PAS), such that APA can result in several mRNA isoforms with varying 3'UTR lengths. We hypothesize that changes in PAS usage, and thus AE 3'UTR length, can modulate fusion gene expression. Therefore, we first checked AE 3'UTR usage by RNA sequencing and absolute quantification using real-time qPCR. Here, we report that 3'UTR usages of total AE were restricted within 3.7kb (short 3'UTR) in t(8;21) AML (>90% in 4 of primary samples, and >98% in cell lines (Kasumi-1 and SKNO1), respectively). Actinomycin D experiments showed that the half-life of AE with the long 3'UTR was much shorter than that with the short 3'UTR (0.8 hour and 2.8 hours, respectively), supporting our hypothesis that changes in 3'UTR usage regulate AE expression. To confirm the correlation between AE expression and its 3'UTR usage, we next checked single cell gene expression patterns of various cell types in t(8;21) AML diagnostic bone marrow samples. AE mRNA was detected not only in CD34+ AML cells but also in some differentiated monocytes and granulocytes, indicating that AE+ non-leukemic cells coexist with AML cells in the leukemic bone marrow. Moreover, these differentiated AE+ cells expressed much lower levels of AE, compared with AML cells (monocytes, 0.19-fold and granulocytes, 0.11-fold). We then analyzed AE expression and long 3'UTR usage by absolute quantification of each single cell (leukemic and non-leukemic) and observed a significant negative correlation (R2=0.33, p<0.01). These data suggest that AE 3'UTR length affects mRNA stability and is an important indicator of fusion gene mRNA expression in primary patient samples.To find the key regulator of this 3'UTR change, we comprehensively knocked down all APA machinery members by shRNA in t(8;21) AML cell lines. We discovered that CPSF1 (cleavage and polyadenylation specific factor 1) knockdown increased long 3'UTR usage (37% in total AE), and down-regulated overall AE mRNA expression (0.47-fold). Importantly, CPSF1 was highly expressed in t(8;21) AML patients' leukemia cells at diagnosis compared to 5 of healthy CD34+ HSCs (2.7-fold, p = 0.01). CPSF1 knockdown also impacted apoptosis and proliferation. These data suggest that CPSF1 promotes AE 3'UTR shortening, resulting in AE stability and a growth advantage of AML cells.Collectively, we conclude that expression of polyadenylation regulator CPSF1 is significantly enhanced in t(8;21) AML, CPSF1 controls 3'UTR length of AE fusion transcripts, and extending the AE 3'UTR by knocking down CPSF1 expression reduces AE transcript stability and restricts growth of t(8;21) AML cells. These results suggest that 3'UTR shortening of oncogenic fusion gene transcripts contributes to leukemogenesis, and controlling CPSF1 and 3'UTR usage may be a useful approach to inhibit leukemia progression. DisclosuresNo relevant conflicts of interest to declare.

Neonatal thyrotropin levels and auditory neural maturation in full-term newborns.

ObjectiveThis study aimed to look for a possible relationship between thyrotropin (TSH) values from neonatal bloodspot screening testing and newborn lower auditory pathway myelinization evaluated using the brainstem evoked response audiometry (ABR) test.MethodsSixty-two healthy full-term newborns without perinatal problems were enrolled in the study. TSH results were collected from neonatal bloodspot screening data and were below the test cut-off level (15μUI/mL). The TSH test was performed between three and seven days, and the ABR test was performed in the first 28 days of life. The newborns were divided into two groups: Group 1 (n = 35), TSH between 0 and 5μUI/mL, and group 2 (n = 27), TSH between 5 and 15μUI/mL. Data are presented as mean ± SD, median, or percentage, depending on the variable.ResultsWave latency and interpeak interval values for Groups 1 and 2 were as follows: Wave I: 1.8 ± 0.1 and 1.7 ± 0.1; Wave III: 4.4 ± 0.1 and 4.4 ± 0.1; Wave V: 6.9 ± 0.1 and 6.9 ± 0.1; interval I–III: 2.6 ± 0.1 and 2.6 ± 0.1; interval I–V: 5.1 ± 0.1 and 5.1 ± 0.1; interval III–V: 2.4 ± 0.1 and 2.4 ± 0.1. There were no significant differences in ABR parameters between groups 1 and 2 (p > 0.05). Multiple regression analysis showed a slight significant negative correlation between TSH and wave I values (standardized β = −0.267; p = 0.036), without observing any relationship with the other ABR waves recorded.ConclusionsThis study investigated the relationship of TSH and auditory myelinization evaluated by ABR. It did not show a significant change in lower auditory pathway myelinization according to TSH levels in newborns with TSH screening levels lower than 15 μUI/mL.

Neonatal blood spot screening

This article describes the neonatal or newborn blood spot screening programme (NBSSP) in the United Kingdom. Babies are screened for nine diseases at 5 days of age by a heel prick test. Although midwifes are the primary health practitioner involved in NBSSP, GPs may be consulted antenatally or postnatally for advice. GPs can aid informed decision making for parents concerned about genetic testing, discuss the implications of positive screening, and provide support for families with confirmed diagnoses. This review of the newborn blood spot test will discuss the programme, its limitations, ethical considerations and the diseases screened.

Expanded Neonatal Bloodspot Screening Programmes: An Evaluation Framework to Discuss New Conditions With Stakeholders.

Neonatal bloodspot screening (NBS) programmes that screen for rare but serious conditions are expanding worldwide. Fast developments for testing and treatment put pressure on implementation processes. In 2015 the Netherlands embarked on an NBS expansion from 17 to 31 conditions. An evaluation framework was developed based on international NBS frameworks to gain insight in test properties, clinical findings, follow-up and implementation. A stakeholder process took place with implications for the planning of the expanded NBS panel. The evaluation framework progressed into a go/no go framework to start national screening, and is currently explored as basis for continuous evaluation of the NBS panel. The framework and stakeholder process may serve as an example for other programmes.

The genome-wide impact of trisomy 21 on DNA methylation and its implications for hematopoiesis

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.

Neonatal screening program for five conditions in Honduras.

We present the initial results of a neonatal screening program in part of the public health system in Honduras, that is, the Honduran Social Security Institute. The program design includes steps from neonatal bloodspot in the first newborn days to evaluation and treatment when necessary. In 2018 and 2019, 19,911 newborns were tested for hypothyroidism, cystic fibrosis, galactosemia, phenylketonuria, and adrenal hyperplasia. Abnormalities were identified in 18 newborns, corresponding to a prevalence of 9:10,000. Considering all births in Honduras, the estimated coverage of screening ranged between 4.4 and 5.7%. These results reinforce the need to expand and consolidate neonatal screening.

Genome-wide association study identifies 16 genomic regions associated with circulating cytokines at birth.

Circulating inflammatory markers are essential to human health and disease, and they are often dysregulated or malfunctioning in cancers as well as in cardiovascular, metabolic, immunologic and neuropsychiatric disorders. However, the genetic contribution to the physiological variation of levels of circulating inflammatory markers is largely unknown. Here we report the results of a genome-wide genetic study of blood concentration of ten cytokines, including the hitherto unexplored calcium-binding protein (S100B). The study leverages a unique sample of neonatal blood spots from 9,459 Danish subjects from the iPSYCH initiative. We estimate the SNP-heritability of marker levels as ranging from essentially zero for Erythropoietin (EPO) up to 73% for S100B. We identify and replicate 16 associated genomic regions (p < 5 x 10-9), of which four are novel. We show that the associated variants map to enhancer elements, suggesting a possible transcriptional effect of genomic variants on the cytokine levels. The identification of the genetic architecture underlying the basic levels of cytokines is likely to prompt studies investigating the relationship between cytokines and complex disease. Our results also suggest that the genetic architecture of cytokines is stable from neonatal to adult life.

Inhibition of inflammatory signaling in Pax5 mutant cells mitigates B-cell leukemogenesis

PAX5 is one of the most frequently mutated genes in B-cell acute lymphoblastic leukemia (B-ALL), and children with inherited preleukemic PAX5 mutations are at a higher risk of developing the disease. Abnormal profiles of inflammatory markers have been detected in neonatal blood spot samples of children who later developed B-ALL. However, how inflammatory signals contribute to B-ALL development is unclear. Here, we demonstrate that Pax5 heterozygosis, in the presence of infections, results in the enhanced production of the inflammatory cytokine interleukin-6 (IL-6), which appears to act in an autocrine fashion to promote leukemia growth. Furthermore, in vivo genetic downregulation of IL-6 in these Pax5 heterozygous mice retards B-cell leukemogenesis, and in vivo pharmacologic inhibition of IL-6 with a neutralizing antibody in Pax5 mutant mice with B-ALL clears leukemic cells. Additionally, this novel IL–6 signaling paradigm identified in mice was also substantiated in humans. Altogether, our studies establish aberrant IL6 expression caused by Pax5 loss as a hallmark of Pax5-dependent B-ALL and the IL6 as a therapeutic vulnerability for B-ALL characterized by PAX5 loss.

Neonatal and carrier screening for rare diseases: how innovation challenges screening criteria worldwide

Screening for rare diseases first began more than 50 years ago with neonatal bloodspot screening (NBS) for phenylketonuria, and carrier screening for Tay-Sachs disease, sickle cell anaemia and β-thalassaemia. NBS’s primary aim is health gain for children, while carrier screening enables autonomous reproductive choice. While screening can be beneficial, it also has the potential to cause harm and thus decisions are needed on whether a specific screening is worthwhile. These decisions are usually based on screening principles and criteria. Technological developments, both treatment driven and test driven, have led to expansions in neonatal screening and carrier screening. This article demonstrates how the dynamics and expansions in NBS and carrier screening have challenged four well-known screening criteria (treatment, test, target population and programme evaluation), and the decision-making based on them. We show that shifting perspectives on screening criteria for NBS as well as carrier screening lead to converging debates in these separate fields. For example, the child is traditionally considered to be the beneficiary in NBS, but the family and society can also benefit. Vice versa, carrier screening may be driven by disease prevention, rather than reproductive autonomy, raising cross-disciplinary questions regarding potential beneficiaries and which diseases to include. In addition, the stakeholders from these separate fields vary: Globally NBS is often governed as a public health programme while carrier screening is usually available via medical professionals. The article concludes with a call for an exchange of vision and knowledge among all stakeholders of both fields to attune the dynamics of screening.

Parents\u2019 Perspectives and Societal Acceptance of Implementation of Newborn Screening for SCID in the Netherlands

PurposeWhile neonatal bloodspot screening (NBS) for severe combined immunodeficiency (SCID) has been introduced more than a decade ago, implementation in NBS programs remains challenging in many countries. Even if high-quality test methods and follow-up care are available, public uptake and parental acceptance are not guaranteed. The aim of this study was to describe the parental perspective on NBS for SCID in the context of an implementation pilot. Psychosocial aspects have never been studied before for NBS for SCID and are important for societal acceptance, a major criterion when introducing new disorders in NBS programs.MethodsTo evaluate the perspective of parents, interviews were conducted with parents of newborns with abnormal SCID screening results (N = 17). In addition, questionnaires about NBS for SCID were sent to 2000 parents of healthy newborns who either participated or declined participation in the SONNET-study that screened 140,593 newborns for SCID.ResultsSupport for NBS for SCID was expressed by the majority of parents in questionnaires from both a public health perspective and a personal perspective. Parents emphasized the emotional impact of an abnormal screening result in interviews. (Long-term) stress and anxiety can be experienced during and after referral indicating the importance of uniform follow-up protocols and adequate information provision.ConclusionThe perspective of parents has led to several recommendations for NBS programs that are considering screening for SCID or other disorders. A close partnership of NBS programs’ stakeholders, immunologists, geneticists, and pediatricians-immunologists in different countries is required for moving towards universal SCID screening for all infants.

Retrospective analysis of pediatric primary immunodeficiencies with congenital heart defects

Around 20,000 children with heart defects are born annually in the Russian Federation, among which around 5,000 children are manifested by its critical course that requires surgical correction within the first days after birth. Although timely pre- and postnatal diagnostics of congenital heart pathology allows to provide proper therapeutic and surgical assistance for such patients, it is hard to minimize severe complications at any stage of the child’s treatment. Quite often, post-surgery patients are unable to cope with serious complications caused by infectious diseases of the respiratory tract, endocardium and meninges. A special place is taken by cases of severe postoperative period: long-term non-healing postoperative wounds and septic disorders leading to patient death. Here we put forward an idea that congenital heart disease may serve as a marker of primary immunodeficiency characterized by lowered parameters of cellular and humoral immunity. Current retrospective study included 29 children died within the first year of life, whose medical records demonstrated confirmed congenital heart disease and manifested signs of immune-dependent pathology. There were analyzed data regarding pregnancy course in order to identify factors contributing to early diagnostics of immune-related pathology associated with CHD. The analysis of existing problems affecting proper diagnostics and treatment of children with congenital heart disease coupled to “covert” PID form was performed. It was noted that among twenty described syndromes manifested with congenital heart disease, seven are currently referred to the group of primary immunodeficiencies. Types of congenital heart defects in the study group ranged from disorders of the valve apparatus to the non-functional opening between heart chambers. Signs of immune-related pathology included decreased thymus size revealed by ultrasound examination as well as lowered value of genetic markers TREC and KREC, retrospectively obtained from neonatal dry blood spots. Finally, we name a key element for successful differential diagnostics of PID with congenital heart disease – awareness of various medical workers about such pathology for developing algorithms for their interaction with regard to management of such comorbid patients.

Phosphoglucomutase-1 deficiency: Early presentation, metabolic management and detection in neonatal blood spots

Phosphoglucomutase 1 deficiency is a congenital disorder of glycosylation (CDG) with multiorgan involvement affecting carbohydrate metabolism, N-glycosylation and energy production. The metabolic management consists of dietary D-galactose supplementation that ameliorates hypoglycemia, hepatic dysfunction, endocrine anomalies and growth delay. Previous studies suggest that D-galactose administration in juvenile patients leads to more significant and long-lasting effects, stressing the urge of neonatal diagnosis (0–6 months of age).Here, we detail the early clinical presentation of PGM1-CDG in eleven infantile patients, and applied the modified Beutler test for screening of PGM1-CDG in neonatal dried blood spots (DBSs).All eleven infants presented episodic hypoglycemia and elevated transaminases, along with cleft palate and growth delay (10/11), muscle involvement (8/11), neurologic involvement (5/11), cardiac defects (2/11). Standard dietary measures for suspected lactose intolerance in four patients prior to diagnosis led to worsening of hypoglycemia, hepatic failure and recurrent diarrhea, which resolved upon D-galactose supplementation. To investigate possible differences in early vs. late clinical presentation, we performed the first systematic literature review for PGM1-CDG, which highlighted respiratory and gastrointestinal symptoms as significantly more diagnosed in neonatal age.The modified Butler-test successfully identified PGM1-CDG in DBSs from seven patients, including for the first time Guthrie cards from newborn screening, confirming the possibility of future inclusion of PGM1-CDG in neonatal screening programs.In conclusion, severe infantile morbidity of PGM1-CDG due to delayed diagnosis could be prevented by raising awareness on its early presentation and by inclusion in newborn screening programs, enabling early treatments and galactose-based metabolic management.

Using a knowledge exchange event to assess study participants' attitudes to research in a rapidly evolving research context.

Background: The UK hosts some of the world's longest-running longitudinal cohort studies, which make repeated observations of their participants and use these data to explore health outcomes. An alternative method for data collection is record linkage; the linking together of electronic health and administrative records. Applied nationally, this could provide unrivalled opportunities to follow a large number of people in perpetuity. However, public attitudes to the use of data in research are currently unclear. Here we report on an event where we collected attitudes towards recent opportunities and controversies within health data science. Methods: The event was attended by ~250 individuals (cohort members and their guests), who had been invited through the offices of their participating cohort studies. There were a series of presentations describing key research results and the audience participated in 15 multiple-choice questions using interactive voting pads. Results: Our participants showed a high level of trust in researchers (87% scoring them 4/5 or 5/5) and doctors (81%); but less trust in commercial companies (35%). They supported the idea of researchers using information from both neonatal blood spots (Guthrie spots) (97% yes) and from electronic health records (95% yes). Our respondents were willing to wear devices like a 'Fit-bit' (88% agreed) or take a brain scan that might predict later mental illness (73%). However, they were less willing to take a new drug for research purposes (45%). They were keen to encourage others to take part in research; whether that be offering the opportunity to pregnant mothers (97% agreed) or extending invitations to their own children and grandchildren (98%). Conclusions: Our participants were broadly supportive of research access to data, albeit less supportive when commercial interests were involved. Public engagement events that facilitate two-way interactions can influence and support future research and public engagement efforts.

Sedaghatian-type spondylometaphyseal dysplasia: Whole exome sequencing in neonatal dry blood spots enabled identification of a novel variant in GPX4

Accumulation of lipid peroxides causes membrane damage and cell death. Glutathione peroxidase 4 (GPX4) acts as a hydroperoxidase which prevents accumulation of toxic oxidized lipids and blocks ferroptosis, an iron-dependent, non-apoptotic mode of cell death. GPX4 deficiency causes Sedaghatian-type spondylo-metaphyseal dysplasia (SSMD), a lethal autosomal recessive disorder, featuring skeletal dysplasia, cardiac arrhythmia and brain anomalies with only three pathogenic GPX4 variants reported in two SSMD patients. Our objective was to identify the underlying genetic cause of neonatal death of two siblings presenting with hypotonia, cardiorespiratory failure and SSMD. Whole exome sequencing (WES) was performed in DNA samples from two siblings and their parents. Since “critical samples” were not available from the patients, DNA was extracted from dry blood spots (DBS) retrieved from the Israeli newborn-screening center. Sanger sequencing and segregation analysis followed the WES. Homozygous novel GPX4 variant, c.153_160del; p.His52fs*1 causing premature truncation of GPX4 was detected in both siblings; their parents were heterozygotes. Segregation analysis confirmed autosomal recessive inheritance. This report underscores the importance of DBS WES in identifying the genes and mutations causing devastating rare diseases. Obtaining critical samples from a dying patient is crucial for enabling genetic diagnosis.

M94. NO EVIDENCE OF ASSOCIATIONS BETWEEN GENETIC LIABILITY FOR SCHIZOPHRENIA RISK OF CANNABIS USE DISORDER

BackgroundCannabis use and cannabis use disorder (CUD) is increased in patients with schizophrenia. It is important to establish if this is explained by non-causal factors, such as shared genetic vulnerability. We aimed to investigate whether the polygenic risk scores (PRS) for schizophrenia and other psychiatric disorders would predict CUD in controls, patients with schizophrenia, and patients with other psychiatric disorders.MethodsWe linked nationwide Danish registers and genetic information obtained from dried neonatal bloodspots in an observational analysis. We included people with schizophrenia, other psychiatric disorders, and controls. The exposures of interest were the polygenic risk scores for schizophrenia, ADHD autism spectrum disorder, and anorexia nervosa. The main outcome of interest was diagnosis of cannabis use disorder.ResultsThe study included 88,637 individuals. PRS for schizophrenia did not predict CUD in controls (hazard ratio (HR)=1.16, 95% CI 0.95–1.43 per standard-deviation increase in PRS, or HR=1.47, 95% CI 0.72–3.00 comparing highest versus remaining decile), but PRS for ADHD did (HR=1.27, 95% CI 1.08–1.50 per standard-deviation increase, or HR=2.02, 95% CI 1.27–3.22 for the highest decile of PRS). . Among cases with schizophrenia, the PRS for schizophrenia was associated with CUD. While CUD was a strong predictor of schizophrenia (HR=4.91 (95% CI 4.36–5.53)), the inclusion of various PRS did not appreciably alter this association.DiscussionThe PRS for schizophrenia was not associated with CUD in controls or patients with other psychiatric disorders than schizophrenia. This speaks against the hypothesis that shared genetic vulnerability would explain the association between cannabis and schizophrenia.

Using a knowledge exchange event to assess study participants’ attitudes to research in a rapidly evolving research context

Background: The UK hosts some of the world’s longest-running longitudinal cohort studies, which make repeated observations of their participants and use these data to explore health outcomes. An alternative method for data collection is record linkage; the linking together of electronic health and administrative records. Applied nationally, this could provide unrivalled opportunities to follow a large number of people in perpetuity. However, public attitudes to the use of data in research are currently unclear. Here we report on an event where we collected attitudes towards recent opportunities and controversies within health data science. Methods: The event was attended by ~250 individuals (cohort members and their guests), who had been invited through the offices of their participating cohort studies. There were a series of presentations describing key research results and the audience participated in 15 multiple-choice questions using interactive voting pads. Results: Our participants showed a high level of trust in researchers (87% scoring them 4/5 or 5/5) and doctors (81%); but less trust in commercial companies (35%). They supported the idea of researchers using information from both neonatal blood spots (Guthrie spots) (97% yes) and from electronic health records (95% yes). Our respondents were willing to wear devices like a ’Fit-bit’ (88% agreed) or take a brain scan that might predict later mental illness (73%). However, they were less willing to take a new drug for research purposes (45%). They were keen to encourage others to take part in research; whether that be offering the opportunity to pregnant mothers (97% agreed) or extending invitations to their own children and grandchildren (98%). Conclusions: Our participants were broadly supportive of research access to data, albeit less supportive when commercial interests were involved. Public engagement events that facilitate two-way interactions can influence and support future research and public engagement efforts.

Integrated metabolome analysis reveals novel connections between maternal fecal metabolome and the neonatal blood metabolome in women with gestational diabetes mellitus

Gestational Diabetes Mellitus (GDM), which is correlated with changes in the gut microbiota, is a risk factor for neonatal inborn errors of metabolism (IEMs). Maternal hyperglycemia exerts epigenetic effects on genes that encode IEM-associated enzymes, resulting in changes in the neonatal blood metabolome. However, the relationship between maternal gut microbiota and the neonatal blood metabolome remains poorly understood. This study aimed at understanding the connections between maternal gut microbiota and the neonatal blood metabolome in GDM. 1H-NMR-based untargeted metabolomics was performed on maternal fecal samples and targeted metabolomics on the matched neonatal dry blood spots from a cohort of 40 pregnant women, including 22 with GDM and 18 controls. Multi-omic association methods (including Co-Inertia Analysis and Procrustes Analysis) were applied to investigate the relationship between maternal fecal metabolome and the neonatal blood metabolome. Both maternal fecal metabolome and the matched neonatal blood metabolome could be separated along the vector of maternal hyperglycemia. A close relationship between the maternal and neonatal metabolomes was observed by multi-omic association approaches. Twelve out of thirty-two maternal fecal metabolites with altered abundances from 872 1H- NMR features (Bonferroni-adjusted P < 0.05) in women with GDM and the controls were identified, among which 8 metabolites contribute (P < 0.05 in a 999-step permutation test) to the close connection between maternal and the neonatal metabolomes in GDM. Four of these eight maternal fecal metabolites, including lysine, putrescine, guanidinoacetate, and hexadecanedioate, were negatively associated (Spearman rank correlation, coefficient value < −0.6, P < 0.05) with maternal hyperglycemia. Biotin metabolism was enriched (Bonferroni-adjusted P < 0.05 in the hypergeometric test) with the four-hyperglycemia associated fecal metabolites. The results of this study suggested that maternal fecal metabolites contribute to the connections between maternal fecal metabolome and the neonatal blood metabolome and may further affect the risk of IEMs.

Using a knowledge exchange event to assess study participants' attitudes to research in a rapidly evolving research context.

Background: The UK hosts some of the world's longest-running longitudinal cohort studies, who make repeated observations of their participants and use these data to explore health outcomes. An alternative method for data collection is record linkage; the linking together of electronic health and administrative records. Applied nationally, this could provide unrivalled opportunities to follow a large number of people in perpetuity. However, public attitudes to the use of data in research are currently unclear. Here we report on an event where we collected attitudes towards recent opportunities and controversies within health data science. Methods: The event was attended by ~250 individuals (cohort members and their guests), who had been invited through the offices of their participating cohort studies. There were a series of presentations describing key research results and the audience participated in 15 multiple-choice questions using interactive voting pads. Results: Our participants showed a high level of trust in researchers (87% scoring them 4/5 or 5/5) and doctors (81%); but less trust in commercial companies (35%). They supported the idea of researchers using information from both neonatal blood spots (Guthrie spots) (97% yes) and from electronic health records (95% yes). Our respondents were willing to wear devices like a 'Fit-bit' (78% agreed) or take a brain scan that might predict later mental illness (73%). However, they were less willing to take a new drug for research purposes (45%). They were keen to encourage others to take part in research; whether that be offering the opportunity to pregnant mothers (97% agreed) or extending invitations to their own children and grandchildren (98%). Conclusions: Our participants were broadly supportive of research access to data, albeit less supportive when commercial interests were involved. Public engagement events that facilitate two-way interactions can influence and support future research and public engagement efforts.