Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities

The contribution of X-linked coding variation to severe developmental disorders

Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Tranexamic Acid

https://scholarlycommons.pacific.edu/phs-facbooks/1047/thumbnail.jp

Australian sonographer competency-A new framework

Sonographers possess a unique and complex body of knowledge and skills, providing real health benefits to the community. The value of competency frameworks rests on their capacity to support and facilitate professional practice in the interests of public safety. The commitment to act in the service of others carries with it a professional and ethical obligation to practice within the boundaries of accepted competency standards. The well-accepted Australasian Sonographers Association (ASA) competency standards for entry-level Australian sonographers were introduced a decade ago. At this time, ultrasound technology, its application and the sonographer's role as a critical interface to this technology continue to evolve. The article provides an overview of research used to develop a contemporary competency framework for sonographers. It describes each framework component and how these components have a potential role in sonographer education and clinical practice at different levels of expertise. Sonographer competencies were developed via a national collaborative research project led by a multi-institutional research team of academic and industry professionals. A Delphi study design elicited consensus on multiple competency characteristics from an expert panel of 55 sonographers. The expert panel contained representatives from all Australian states and territories and represented all domains of practice. The resulting project outcome consisted of a competency framework containing four significant components: sonographer competency standards, sonographer knowledge, sonographer attitudes and a holistic competency matrix

Insect pollinators: linking research and policy. Workshop report.

EXECUTIVE SUMMARY Pollinators interact with plants to underpin wider biodiversity, ecosystem function, ecosystem services to agricultural crops and ultimately human nutrition. The conservation of pollinators is thus an important goal. Pollinators and pollination represent a tractable example of how biodiversity can be linked to an ecosystem service. This represents a case study for exploring the impacts of various policy instruments aiming to halt/reverse the loss of ecosystem services. There is a need to understand how multiple pressures (e.g. habitat loss, fragmentation and degradation, climate change, pests and diseases, invasive species and environmental chemicals) can combine or interact to affect diversity, abundance and health of different pollinator groups. Decision makers need to balance consideration of the effects of single pressures on pollinators against the suite of other pressures on pollinators. For instance, the threat from pesticide use (with its high public and media profile) also needs to be considered in the context of the other threats facing pollinators and balanced against the need for food security. An independent review of the balance of risks across pollinator groups from pesticide use would help synthesise current knowledge into an accessible form for decision makers. To manage or lessen these threats to pollinators (wild and managed) and pollination requires improved knowledge about their basic ecology. We still need to know where and in what numbers different pollinator species occur, how they use different environments, how they interact with each other through shared plants and diseases and how wild pollinator abundance is changing. Decision makers need clear factual evidence for i) the relative contribution of different managed and wild pollinator groups to wildflower and crop pollination and ii) how this varies across different land-uses, ecosystems and regions. Addressing these basic and applied questions will improve our ability to forecast impacts on pollination service delivery to agricultural crops arising from current and future environmental changes, pesticide use and emerging diseases. The development of a long-term, multi-scale monitoring scheme to monitor trends in pollinator (wild and managed) population size and delivery of pollination services (ideally tied to data collection on land-use, pesticide applications and disease incidence at relevant spatial scales) would provide the evidence base for developing the effectiveness of policy and management interventions over time. Such a monitoring scheme would benefit from including research council organisations (e.g. CEH), governmental departments (e.g. Fera), universities, museums and NGOs (e.g. BBKA,SBA, Bumblebee Conservation Trust etc) Insect Pollinators: linking research and policy Workshop Report | 5 In the context of agricultural intensification and conservation we need to establish what type, quality and quantity of interventions (e.g. agri-environment schemes, protected areas) are needed, where to place them and how they can sustain different pollinator populations and effective pollination services. Current monitoring of the risks from diseases and pesticides requires broadening to consider other insects aside from honey bees, unless we can demonstrate that honey bees are good surrogates for all other pollinators. There is a need to increase confidence in regulatory risk assessments pertaining to pathogens and pesticides by incorporating other pollinator species, investigating chronic exposure to multiple chemicals and using field relevant dosages (specific to regions, not using other data sources as surrogates). At present the effects of spatial, social and temporal scales on the benefits stakeholders receive from pollination services are only beginning to be understood. Economic valuation of pollination services can help optimise the cost-effectiveness of service management measures and offer new opportunities to incentivise action or raise awareness among stakeholders. Novel tools and instruments (e.g. education and training) are needed to translate broad international (e.g. CBD, EU Biodiversity Strategy) and national (e.g. England‟s Biodiversity Strategy) policies into local actor (e.g. beekeeper, farmer, citizen scientist) contributions to meet biodiversity commitments Refocusing some public funding to link basic science to development of practical solutions (e.g. better crop protection products, improved disease resistance or treatment) could help science deliver better-targeted evidence for pollinator protection. Scientists need to make more use of opportunities (e.g. POSTnotes1; practitioner guides) to transfer knowledge to a broad audience in order to better influence decision maker and practitioner behaviours. Improved knowledge exchange between scientists and decision makers is important to combating threats to pollination. Central to this is improved understanding of the respective positions of policy makers and scientists. For instance, policy-makers usually need to be presented with a range of options to balance against other areas of policy. Science does not always arrive at a consensus due to uncertainties in data or models. Policy-makers need to understand that scientists are communicating the “best available knowledge at present” and that consequently it is not always possible to give a definitive answer

Epigenetic aging of humpback whales in three oceans

Age is a key parameter in population ecology, but rarely known in whale populations. We used an epigenetic assay based on DNA methylation levels at three CpG sites to estimate the age of 1,013 humpback whales skin samples obtained from 1993 through 2014. The assay was calibrated with 76 individuals of known age (<1 to 30 years) and had an R2=0.718 (p=2.88e-22) and a standard deviation of 3.562 years. Samples of unknown exact age were obtained from one feeding ground (the Gulf of Maine, n=609), one extralimital wintering area off the southeast U.S. (n=33) and breeding grounds in the North Atlantic (West Indies, n=122), the North Pacific (Hawaii, n=41) and the South Pacific (American Samoa, n=115). The maximum estimated age at the time of sampling was 50.9 years. Two females, both from the Gulf of Maine, reached the maximum observed age of 64 years when later re-sighted (one with a dependent calf in 2016). Whales of both sexes in the Gulf of Maine were younger on average than in those in the West Indies, and whales sampled off the southeast U.S. coast in winter were younger than both North Atlantic feeding and breeding populations. Together, these results suggest a lower tendency of juveniles to undertake or complete migration to the breeding grounds. Age frequency differences among oceanic breeding populations were generally consistent with historical exploitation histories, but not clearly indicative of recovery. This is the first study of age in live humpback whales based on large sample sizes and multiple populations. Epigenetic aging has broad potential to advance understanding of whale biology and ecology and to facilitate conservation. Despite its average precision, we recommend caution when applying this assay to small sample sizes and individual case studie