Exome copy number variant detection, analysis, and classification in a large cohort of families with undiagnosed rare genetic disease.

Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and, with new innovative methods, can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the Genomics Research to Elucidate the Genetics of Rare Diseases consortium and analyzed using the seqr platform. The addition of CNV detection to exome analysis identified causal CNVs for 171 families (2.6%). The estimated sizes of CNVs ranged from 293 bp to 80 Mb. The causal CNVs consisted of 140 deletions, 15 duplications, 3 suspected complex structural variants (SVs), 3 insertions, and 10 complex SVs, the latter two groups being identified by orthogonal confirmation methods. To classify CNV variant pathogenicity, we used the 2020 American College of Medical Genetics and Genomics/ClinGen CNV interpretation standards and developed additional criteria to evaluate allelic and functional data as well as variants on the X chromosome to further advance the framework. We interpreted 151 CNVs as likely pathogenic/pathogenic and 20 CNVs as high-interest variants of uncertain significance. Calling CNVs from existing exome data increases the diagnostic yield for individuals undiagnosed after standard testing approaches, providing a higher-resolution alternative to arrays at a fraction of the cost of genome sequencing. Our improvements to the classification approach advances the systematic framework to assess the pathogenicity of CNVs.

Genome Sequencing for Diagnosing Rare Diseases.

BACKGROUND: Genetic variants that cause rare disorders may remain elusive even after expansive testing, such as exome sequencing. The diagnostic yield of genome sequencing, particularly after a negative evaluation, remains poorly defined. METHODS: We sequenced and analyzed the genomes of families with diverse phenotypes who were suspected to have a rare monogenic disease and for whom genetic testing had not revealed a diagnosis, as well as the genomes of a replication cohort at an independent clinical center. RESULTS: We sequenced the genomes of 822 families (744 in the initial cohort and 78 in the replication cohort) and made a molecular diagnosis in 218 of 744 families (29.3%). Of the 218 families, 61 (28.0%) - 8.2% of families in the initial cohort - had variants that required genome sequencing for identification, including coding variants, intronic variants, small structural variants, copy-neutral inversions, complex rearrangements, and tandem repeat expansions. Most families in which a molecular diagnosis was made after previous nondiagnostic exome sequencing (63.5%) had variants that could be detected by reanalysis of the exome-sequence data (53.4%) or by additional analytic methods, such as copy-number variant calling, to exome-sequence data (10.8%). We obtained similar results in the replication cohort: in 33% of the families in which a molecular diagnosis was made, or 8% of the cohort, genome sequencing was required, which showed the applicability of these findings to both research and clinical environments. CONCLUSIONS: The diagnostic yield of genome sequencing in a large, diverse research cohort and in a small clinical cohort of persons who had previously undergone genetic testing was approximately 8% and included several types of pathogenic variation that had not previously been detected by means of exome sequencing or other techniques. (Funded by the National Human Genome Research Institute and others.).

Beyond the exome: What's next in diagnostic testing for Mendelian conditions.

Despite advances in clinical genetic testing, including the introduction of exome sequencing (ES), more than 50% of individuals with a suspected Mendelian condition lack a precise molecular diagnosis. Clinical evaluation is increasingly undertaken by specialists outside of clinical genetics, often occurring in a tiered fashion and typically ending after ES. The current diagnostic rate reflects multiple factors, including technical limitations, incomplete understanding of variant pathogenicity, missing genotype-phenotype associations, complex gene-environment interactions, and reporting differences between clinical labs. Maintaining a clear understanding of the rapidly evolving landscape of diagnostic tests beyond ES, and their limitations, presents a challenge for non-genetics professionals. Newer tests, such as short-read genome or RNA sequencing, can be challenging to order, and emerging technologies, such as optical genome mapping and long-read DNA sequencing, are not available clinically. Furthermore, there is no clear guidance on the next best steps after inconclusive evaluation. Here, we review why a clinical genetic evaluation may be negative, discuss questions to be asked in this setting, and provide a framework for further investigation, including the advantages and disadvantages of new approaches that are nascent in the clinical sphere. We present a guide for the next best steps after inconclusive molecular testing based upon phenotype and prior evaluation, including when to consider referral to research consortia focused on elucidating the underlying cause of rare unsolved genetic disorders.

Bi-allelic loss-of-function variants in WBP4, encoding a spliceosome protein, result in a variable neurodevelopmental syndrome.

Over two dozen spliceosome proteins are involved in human diseases, also referred to as spliceosomopathies. WW domain-binding protein 4 (WBP4) is part of the early spliceosomal complex and has not been previously associated with human pathologies in the Online Mendelian Inheritance in Man (OMIM) database. Through GeneMatcher, we identified ten individuals from eight families with a severe neurodevelopmental syndrome featuring variable manifestations. Clinical manifestations included hypotonia, global developmental delay, severe intellectual disability, brain abnormalities, musculoskeletal, and gastrointestinal abnormalities. Genetic analysis revealed five different homozygous loss-of-function variants in WBP4. Immunoblotting on fibroblasts from two affected individuals with different genetic variants demonstrated a complete loss of protein, and RNA sequencing analysis uncovered shared abnormal splicing patterns, including in genes associated with abnormalities of the nervous system, potentially underlying the phenotypes of the probands. We conclude that bi-allelic variants in WBP4 cause a developmental disorder with variable presentations, adding to the growing list of human spliceosomopathies.

"It's hard to wait": Provider Perspectives on Current Genomic Care in Safety-Net NICUs.

PURPOSE: Critically ill infants from marginalized populations disproportionately receive care in neonatal intensive care units (NICUs) that lack access to state-of-the-art genomic care, leading to inequitable outcomes. We sought provider perspectives to inform our implementation study (VIGOR) providing rapid genomic sequencing within these settings. METHODS: We conducted semi-structured focus groups with neonatal and genetics providers at five NICUs at safety-net hospitals, informed by the Promoting Action on Research Implementation in Health Services framework, which incorporates evidence, context, and facilitation domains. We iteratively developed codes and themes until thematic saturation was reached. RESULTS: Regarding evidence, providers felt that genetic testing benefits infants and families. Regarding context, the major barriers identified to genomic care were genetic testing cost, lack of genetics expertise for disclosure and follow-up, and navigating the complexity of selecting and ordering genetic tests. Providers had negative feelings about the current status quo and inequity in genomic care across NICUs. Regarding facilitation, providers felt that a virtual support model like VIGOR would address major barriers and foster family-centered care and collaboration. CONCLUSION: NICU providers at safety-net hospitals believe that access to state-of-the-art genomic care is critical for optimizing infant outcomes, yet substantial barriers exist that the VIGOR study may address.

Potato Consumption and All-Cause and Cardiovascular Disease Mortality - A Long-Term Follow-Up of a Norwegian Cohort.

BACKGROUND: Potatoes are a staple food in many traditional cuisines, yet their impact on long-term risk of cardiovascular disease (CVD) and mortality is unclear, hampering evidence-based dietary guidelines. OBJECTIVES: This study aimed to examine the association between potato consumption and all-cause and CVD-specific death over a substantial follow-up period within a cohort predominantly consuming boiled potatoes. METHODS: Adults from 3 Norwegian counties were invited to 3 health screenings in 1974-1988 (>80% attendance). Dietary data were collected using semiquantitative food frequency questionnaires at each screening to categorize weekly potato consumption (≤6, 7-13, or ≥14 potatoes/wk) and calculate daily cumulative mean intakes (grams/day). Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox regression to estimate HRs and 95% CIs for the association between potato consumption and risk of death from all causes, CVD, ischemic heart disease (IHD), and acute myocardial infarction (AMI). RESULTS: Among 77,297 participants with a mean baseline age of 41.1 y (range: 18.0-63.9 y), we observed 27,848 deaths, including 9072 deaths due to CVD, over a median follow-up of 33.5 y. Participants who consumed ≥14 potatoes/wk had a lower risk of all-cause death compared with those consuming ≤6 potatoes/wk (HR: 0.88; 95% CI: 0.84, 0.93). Potato consumption was associated with a minor, inverse risk of death due to CVD, IHD, and AMI. In continuous analyses of cumulative intakes, each 100 g/d increment was associated with 4% lower risk of death from all causes (HR: 0.96; 95% CI: 0.94, 0.98), CVD (HR: 0.96; 95% CI: 0.93, 0.99), IHD (HR: 0.96; 95% CI: 0.91, 1.00), and AMI (HR: 0.96, 95% CI: 0.91, 1.01). CONCLUSIONS: In this cohort with a generally high consumption of predominantly boiled potatoes, we find modest, inverse associations between potato consumption and death from all causes, CVD, and IHD.

Associations and predictive power of dietary patterns on metabolic syndrome and its components.

BACKGROUND AND AIMS: Metabolic syndrome (MetS) defines important risk factors in the development of cardiovascular diseases and other serious health conditions. This study aims to investigate the influence of different dietary patterns on MetS and its components, examining both associations and predictive performance. METHODS AND RESULTS: The study sample included 10,750 participants from the seventh survey of the cross-sectional, population-based Tromsø Study in Norway. Diet intake scores were used as covariates in logistic regression models, controlling for age, educational level and other lifestyle variables, with MetS and its components as response variables. A diet high in meat and sweets was positively associated with increased odds of MetS and elevated waist circumference, while a plant-based diet was associated with decreased odds of hypertension in women and elevated levels of triglycerides in men. The predictive power of dietary patterns derived by different dimensionality reduction techniques was investigated by randomly partitioning the study sample into training and test sets. On average, the diet score variables demonstrated the highest predictive power in predicting MetS and elevated waist circumference. The predictive power was robust to the dimensionality reduction technique used and comparable to using a data-driven prediction method on individual food variables. CONCLUSIONS: The strongest associations and highest predictive power of dietary patterns were observed for MetS and its single component, elevated waist circumference.

The perceived impact of climate change on mental health and suicidality in Kenyan high school students.

BACKGROUND: Climate change has psychological impacts but most of the attention has been focused on the physical impact. This study was aimed at determining the association of climate change with adolescent mental health and suicidality as reported by Kenyan high school students. METHODS: This was a cross sectional study with a sample size of 2,652. The participants were high school students selected from 10 schools in 3 regions of Kenya. A questionnaire was used to assess climate change experiences, mental health problems, and suicidality of the youth. Data were analyzed descriptively and with logistic regression to determine various associations of the different variables and the predictors of the various scores of SDQ and suicidality at 95% CI. RESULTS: Significant differences were observed between gender and two of the threats of climate change - worry and being afraid as subjectively experienced by the participants. Females were more worried and afraid of climate change than males. On univariate and multivariate logistic regression, we found that various experiences of climate change were significantly associated with various scores of SDQ and much fewer of the experiences predicted SDQ scores. The same pattern was reflected in suicidality. CONCLUSION: Climate change appears to be associated with mental health concerns and suicidality according to Kenyan high school students' reports with gender differences in some associations.

Evaluation of a digital FFQ using 24 h recalls as reference method, for assessment of habitual diet in women with South Asian origin in Norway.

OBJECTIVE: Dietary assessment tools should be designed for the target population. We developed an FFQ designed to assess diet in South Asian women in Norway. The study objective was to evaluate this FFQ using 24-h dietary recalls as reference method. DESIGN: Approximately 3 weeks after the participants (n 40) had filled in the FFQ, the first of three non-consecutive 24-h dietary recalls was completed. The recalls were telephone-based, unannounced and performed by a trained dietitian, with 2-3 weeks between each interview. SETTING: The DIASA 1 study, in Oslo, Norway. PARTICIPANTS: Women of South Asian ethnic origin participating in the DIASA 1 study were invited to participate in the evaluation study. RESULTS: The WebFFQasia significantly overestimated the absolute intake of energy, protein, fat and carbohydrates compared with the 24-h dietary recalls. Absolute intakes of sugar, starch and fibre did not differ significantly between the methods. For energy percentages (E%), there were no significant differences, except for monounsaturated fat. Correlations were strong for E% from sugar and saturated fat and moderate for E% from fibre, carbohydrate, total fat and protein. Fourteen food groups out of twenty three were not significantly different compared with the reference method, and sixteen groups showed strong to moderate correlations. CONCLUSION: The WebFFQasia may be used to assess E% from habitual diet and can adequately estimate intakes and rank participants according to nutrient intake and main food categories at group level.

Demographic disparities in the limited awareness of alcohol use as a breast cancer risk factor: empirical findings from a cross-sectional study of U.S. women.

BACKGROUND: Alcohol use is an established yet modifiable risk factor for breast cancer. However, recent research indicates that the vast majority of U.S. women are unaware that alcohol use is a risk factor for breast cancer. There is limited information about the sociodemographic characteristics and alcohol use correlates of awareness of the alcohol use and breast cancer link, and this is critically important for health promotion and intervention efforts. In this study, we assessed prevalence of the awareness of alcohol use as a risk factor for breast cancer among U.S. women and examined sociodemographic and alcohol use correlates of awareness of this link. METHODS: We conducted a 20-minute online cross-sectional survey, called the ABLE (Alcohol and Breast Cancer Link Awareness) survey, among U.S. women aged 18 years and older (N = 5,027) in the fall of 2021. Survey questions assessed awareness that alcohol use increases breast cancer risk (yes, no, don't know/unsure); past-year alcohol use and harmful drinking via the Alcohol Use Disorders Identification Test (AUDIT); and family, health, and sociodemographic characteristics. We conducted multivariate multinomial regression analysis to identify correlates of awareness that alcohol use increases breast cancer risk. RESULTS: Overall, 24.4% reported that alcohol use increased breast cancer risk, 40.2% reported they were unsure, and 35.4% reported that there was no link between alcohol use and breast cancer. In adjusted analysis, awareness of alcohol use as a breast cancer risk factor, compared to not being aware or unsure, was associated with being younger (18-25 years old), having a college degree, and having alcohol use disorder symptoms. Black women were less likely than white women to report awareness of the alcohol use and breast cancer link. CONCLUSIONS: Overall, only a quarter of U.S. women were aware that alcohol use increases breast cancer risk, although 40% expressed uncertainty. Differences in awareness by age, level of education, race and ethnicity and level of alcohol use offer opportunities for tailored prevention interventions, while the overall low level of awareness calls for widespread efforts to increase awareness of the breast cancer risk from alcohol use among U.S. women.

Genomic insights and advanced machine learning: characterizing autism spectrum disorder biomarkers and genetic interactions.

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by altered brain connectivity and function. In this study, we employed advanced bioinformatics and explainable AI to analyze gene expression associated with ASD, using data from five GEO datasets. Among 351 neurotypical controls and 358 individuals with autism, we identified 3,339 Differentially Expressed Genes (DEGs) with an adjusted p-value (≤ 0.05). A subsequent meta-analysis pinpointed 342 DEGs (adjusted p-value ≤ 0.001), including 19 upregulated and 10 down-regulated genes across all datasets. Shared genes, pathogenic single nucleotide polymorphisms (SNPs), chromosomal positions, and their impact on biological pathways were examined. We identified potential biomarkers (HOXB3, NR2F2, MAPK8IP3, PIGT, SEMA4D, and SSH1) through text mining, meriting further investigation. Additionally, we shed light on the roles of RPS4Y1 and KDM5D genes in neurogenesis and neurodevelopment. Our analysis detected 1,286 SNPs linked to ASD-related conditions, of which 14 high-risk SNPs were located on chromosomes 10 and X. We highlighted potential missense SNPs associated with FGFR inhibitors, suggesting that it may serve as a promising biomarker for responsiveness to targeted therapies. Our explainable AI model identified the MID2 gene as a potential ASD biomarker. This research unveils vital genes and potential biomarkers, providing a foundation for novel gene discovery in complex diseases.

Short-term responses of littoral phytoplankton in a large shallow subtropical lake.

The littoral zone is an essential compartment for lake biota because of its high productivity and diversity. Moreover, phytoplankton is expected to have non-equilibrium dynamics on it. The study's aimed to explore phytoplankton in the littoral zone of a shallow lake over a short-term scale. Daily sampling was conducted for 25 consecutive summer days in 2016, at two marginal points of a continuously warm, polymictic, and oligo-mesotrophic subtropical lake (Lake Mangueira, Brazil). Cyanobacteria and Chlorophyta contributed 86% of total biomass. We observed high variability in phytoplankton structure, with species turnover over diel cycles. Redundancy analysis indicated spatial differentiation for phytoplankton structure in relation to abiotic conditions. Nutrient dynamics and humic substances were significant drivers for phytoplankton variability. Phytoplankton was positively correlated with SRP and negatively with humic substances. Our results showed a non- equilibrium state for the littoral phytoplankton of Lake Mangueira, given the high variability of abiotic conditions, even at short distances. Due to its high temporal and spatial variability, the littoralzone seems to contribute to the recruitment and maintenance of phytoplankton biodiversity in shallow lakes. Further studies should consider the functional attributes of species and the complex biological interactions of phytoplankton and macrophytes along the littoral zone.

Thyroid Ethanol and Radiofrequency Ablation: A Call for Patient-Friendly Online Resources.

INTRODUCTION: The multiple treatment options available to patients with thyroid nodules can generate uncertainty and confusion. Radiofrequency ablation (RFA) and ethanol ablation (EA) are two alternative modalities to manage thyroid nodules. As patients more frequently utilize online resources to guide their decision-making, the quality of such resources must be evaluated. The goal of this study was to assess the quality of online patient materials relating to RFA and EA compared to standard thyroidectomy. METHODS: The terms "thyroidectomy," "thyroid radiofrequency ablation," and "thyroid ethanol ablation" were searched on Google. Flesch Reading Ease (FRE), Flesch-Kincaid Grade Level (FKGL), Simple Measure of Gobbledygook (SMOG), and Patient Education Materials Assessment Tool (PEMAT) understandability and actionability were calculated for each website. Statistical analysis was conducted on SPSS Statistics. Google trends were used to determine search interest for each term (May 2016 - May 2021). RESULTS: Of the 77 websites that met our inclusion criteria (30 thyroidectomy sites, 30 RFA sites, and 17 EA sites), the average FRE, FKGL, and SMOG scores of the RFA websites were significantly worse than those of the thyroidectomy websites (p < 0.05). The FKGL and SMOG scores of the EA websites were significantly worse than those of the thyroidectomy websites (p < 0.05). The average understandability and actionability scores for thyroidectomy websites were significantly higher than those of RFA and EA websites (p < 0.05). CONCLUSION: Ablation websites have lower search interest, readability, validity, understandability, and actionability scores in comparison to traditional thyroidectomy websites. Our findings emphasize the need to consider readability and PEMAT scores when developing online educational resources for ablative alternatives to thyroidectomy to allow for greater patient accessibility.

The Pandemic Arc: Expanded Narratives in the History of Global Health.

Using the examples of plague, smallpox, and HIV/AIDS, the present essay argues for the benefits of incorporating the evolutionary histories of pathogens, beyond visible epidemic spikes within human populations, into our understanding of what pandemics actually are as epidemiological phenomena. The pandemic arc - which takes the pathogen as the defining "actor" in a pandemic, from emergence to local proliferation to globalization - offers a framework capable of bringing together disparate aspects not only of the manifestations of disease but also of human involvement in the pandemic process. Pathogens may differ, but there are common patterns in disease emergence and proliferation that distinguish those diseases that become pandemic, dispersed through human communities regionally or globally. The same methods of genomic analysis that allow tracking the evolutionary development of a modern pathogen such as SARS-CoV-2 also allow us to trace pandemics into the past. Reconstruction of these pandemic arcs brings new elements of these stories into view, recovering the experiences of regions and populations hitherto overlooked by Eurocentric narratives. This expanded global history of infectious diseases, in turn, lays a groundwork for reconceiving what ambitions a truly global health might aim for.

Violence Exposure, Self-Reported Mental Health Concerns and Use of Alcohol and Drugs for Coping among Youth in the Slums of Kampala, Uganda.

This study aimed to a) compute the prevalence of violence exposure types, polyvictimization, and self-reported depression, anxiety, and using substances to cope among youth ages 12 to 18 years living on the streets or in the slums of Kampala, Uganda, (b) examine the independent associations among orphan status, violence exposure types, and self-reported mental health concerns, and c) explore the association between polyvictimization and mental health concerns. Data are from a 2014 cross-sectional survey of service-seeking youth ages 12 to 18 years (N = 1134) in Kampala, Uganda. Violence exposure types explored in this study were: witnessing family physical violence, direct physical abuse by a parent, any rape history, and physical dating violence. We used descriptive statistics and multivariable logistic regression to test study objectives. Over half of the sample (60.5%) reported experiencing at least one type of violence exposure; many youth endorsed self-reported depression (57.8%), anxiety (76.8%), and substance use to cope (37.0%). Exposure to violence was associated with higher odds for self-reported depression, anxiety, and using substances to cope. These findings underscore the urgent need to implement evidence-based interventions among this young, underserved population and their families to prevent violence, improve mental health outcomes, and promote resilience.

Re: "Next generation sequencing in neonatology: what does it mean for the next generation?"

Available evidence does not support limiting the use of rapid or ultra-rapid exome or genome sequencing in critically ill neonates to cases of predicted high diagnostic yield. Such testing is best positioned to improve neonatal care when test utilization is conceptualized within the total care of the family with a goal of rapid resolution of the diagnostic odyssey.

Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects.

KDM4B is a lysine-specific demethylase with a preferential activity on H3K9 tri/di-methylation (H3K9me3/2)-modified histones. H3K9 tri/di-demethylation is an important epigenetic mechanism responsible for silencing of gene expression in animal development and cancer. However, the role of KDM4B on human development is still poorly characterized. Through international data sharing, we gathered a cohort of nine individuals with mono-allelic de novo or inherited variants in KDM4B. All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had anomalies on brain imaging ranging from agenesis of the corpus callosum with hydrocephalus to cystic formations, abnormal hippocampi, and polymicrogyria. In mice, lysine demethylase 4B is expressed during brain development with high levels in the hippocampus, a region important for learning and memory. To understand how KDM4B variants can lead to GDD in humans, we assessed the effect of KDM4B disruption on brain anatomy and behavior through an in vivo heterozygous mouse model (Kdm4b+/-), focusing on neuroanatomical changes. In mutant mice, the total brain volume was significantly reduced with decreased size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly. This report demonstrates that variants in KDM4B are associated with GDD/ intellectual disability and neuroanatomical defects. Our findings suggest that KDM4B variation leads to a chromatinopathy, broadening the spectrum of this group of Mendelian disorders caused by alterations in epigenetic machinery.

Hospital-level variation in genetic testing in children's hospitals' neonatal intensive care units from 2016 to 2021.

PURPOSE: This study aimed to examine variation in genetic testing between neonatal intensive care units (NICUs) across hospitals over time. METHODS: We performed a multicenter large-scale retrospective cohort study using NICU discharge data from the Pediatric Hospital Information System database between 2016 and 2021. We analyzed the variation in the percentage of NICU patients who had any genetic testing across hospitals and over time. We used a multivariable multilevel logistic regression model to investigate the potential association between patient characteristics and genetic testing. RESULTS: The final analysis included 207,228 neonates from 38 hospitals. Overall, 13% of patients had at least 1 genetic test sent, although this varied from 4% to 50% across hospitals. Over the study period, the proportion of patients tested increased, with the increase disproportionately borne by hospitals already testing high proportions of patients. On average, patients who received genetic testing had higher illness severity. Controlling for severity, however, only minimally reduced the degree of hospital-level variation in genetic testing. CONCLUSION: The percentage of NICU patients who undergo genetic testing varies among hospitals and increasingly so over time. Variation is largely unexplained by differences in severity between hospitals. The degree of variation suggests that clearer guidelines for NICU genetic testing are warranted.

Provision and availability of genomic medicine services in Level IV neonatal intensive care units.

PURPOSE: To describe variation in genomic medicine services across level IV neonatal intensive care units (NICUs) in the United States and Canada. METHODS: We developed and distributed a novel survey to the 43 level IV NICUs belonging to the Children's Hospitals Neonatal Consortium, requesting a single response per site from a clinician with knowledge of the provision of genomic medicine services. RESULTS: Overall response rate was 74% (32/43). Although chromosomal microarray and exome or genome sequencing (ES or GS) were universally available, access was restricted for 22% (7/32) and 81% (26/32) of centers, respectively. The most common restriction on ES or GS was requiring approval by a specialist (41%, 13/32). Rapid ES/GS was available in 69% of NICUs (22/32). Availability of same-day genetics consultative services was limited (41%, 13/32 sites), and pre- and post-test counseling practices varied widely. CONCLUSION: We observed large inter-center variation in genomic medicine services across level IV NICUs: most notably, access to rapid, comprehensive genetic testing in time frames relevant to critical care decision making was limited at many level IV Children's Hospitals Neonatal Consortium NICUs despite a significant burden of genetic disease. Further efforts are needed to improve access to neonatal genomic medicine services.

Jansen-de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families.

Jansen-de Vries syndrome (JdVS) is a neurodevelopmental condition attributed to pathogenic variants in Exons 5 and 6 of PPM1D. As the full phenotypic spectrum and natural history remain to be defined, we describe a large cohort of children and adults with JdVS. This is a retrospective cohort study of 37 individuals from 34 families with disease-causing variants in PPM1D leading to JdVS. Clinical data were provided by treating physicians and/or families. Of the 37 individuals, 27 were male and 10 female, with median age 8.75 years (range 8 months to 62 years). Four families document autosomal dominant transmission, and 32/34 probands were diagnosed via exome sequencing. The facial gestalt, including a broad forehead and broad mouth with a thin and tented upper lip, was most recognizable between 18 and 48 months of age. Common manifestations included global developmental delay (35/36, 97%), hypotonia (25/34, 74%), short stature (14/33, 42%), constipation (22/31, 71%), and cyclic vomiting (6/35, 17%). Distinctive personality traits include a hypersocial affect (21/31, 68%) and moderate-to-severe anxiety (18/28, 64%). In conclusion, JdVS is a clinically recognizable neurodevelopmental syndrome with a characteristic personality and distinctive facial features. The association of pathogenic variants in PPM1D with cyclic vomiting bears not only medical attention but also further pathogenic and mechanistic evaluation.