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Contains fulltext : 284811.pdf (Publisher’s version ) (Open Access), BACKGROUND: Prior studies have revealed remarkable phenotypic heterogeneity in KCNQ2-related disorders, correlated with effects on biophysical features of heterologously expressed channels. Here, we assessed phenotypes and functional properties associated with KCNQ2 missense variants R144W, R144Q, and R144G. We also explored in vitro blockade of channels carrying R144Q mutant subunits by amitriptyline. METHODS: Patients were identified using the RIKEE database and through clinical collaborators. Phenotypes were collected by a standardized questionnaire. Functional and pharmacological properties of variant subunits were analyzed by whole-cell patch-clamp recordings. FINDINGS: Detailed clinical information on fifteen patients (14 novel and 1 previously published) was analyzed. All patients had developmental delay with prominent language impairment. R144Q patients were more severely affected than R144W patients. Infantile to childhood onset epilepsy occurred in 40%, while 67% of sleep-EEGs showed sleep-activated epileptiform activity. Ten patients (67%) showed autistic features. Activation gating of homomeric Kv7.2 R144W/Q/G channels was left-shifted, suggesting gain-of-function effects. Amitriptyline blocked channels containing Kv7.2 and Kv7.2 R144Q subunits. INTERPRETATION: Patients carrying KCNQ2 R144 gain-of-function variants have developmental delay with prominent language impairment, autistic features, often accompanied by infantile- to childhood-onset epilepsy and EEG sleep-activated epileptiform activity. The absence of neonatal seizures is a robust and important clinical differentiator between KCNQ2 gain-of-function and loss-of-function variants. The Kv7.2/7.3 channel blocker amitriptyline might represent a targeted treatment. FUNDING: Supported by FWO, GSKE, KCNQ2-Cure, Jack Pribaz Foundation, European Joint Programme on Rare Disease 2020, the Italian Ministry for University and Research, the Italian Ministry of Health, the European Commission, the University

Contains fulltext : 218274.pdf (Publisher’s version ) (Closed access), Genetic syndromes frequently present with overlapping clinical features and inconclusive or ambiguous genetic findings which can confound accurate diagnosis and clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA methylation patterns (called "episignatures"). Peripheral blood episignatures can be used for diagnostic testing as well as for the interpretation of ambiguous genetic test results. We present here an approach to episignature mapping in 42 genetic syndromes, which has allowed the identification of 34 robust disease-specific episignatures. We examine emerging patterns of overlap, as well as similarities and hierarchical relationships across these episignatures, to highlight their key features as they are related to genetic heterogeneity, dosage effect, unaffected carrier status, and incomplete penetrance. We demonstrate the necessity of multiclass modeling for accurate genetic variant classification and show how disease classification using a single episignature at a time can sometimes lead to classification errors in closely related episignatures. We demonstrate the utility of this tool in resolving ambiguous clinical cases and identification of previously undiagnosed cases through mass screening of a large cohort of subjects with developmental delays and congenital anomalies. This study more than doubles the number of published syndromes with DNA methylation episignatures and, most significantly, opens new avenues for accurate diagnosis and clinical assessment in individuals affected by these disorders.

Knowledge of exposure to a wide range of chemicals, and the spatio-temporal variability thereof, is urgently needed in the context of protecting and restoring aquatic ecosystems. This paper discusses a computational material flow analysis to predict the occurrence of thousands of man-made organic chemicals on a European scale, based on a novel temporally and spatially resolved modelling framework. The goal was to increase understanding of pressures by emerging chemicals and to complement surface water monitoring data. The ambition was to provide a first step towards a “real-life” mixture exposure situation accounting for as many chemicals as possible. Comparison of simulated concentrations and chemical monitoring data for 226 substance/basin combinations showed that the simulated concentrations were accurate on average. For 65% and 90% of substance/basin combinations the error was within one and two orders of magnitude respectively. An analysis of the relative importance of uncertainties revealed that inaccuracies in use volume or use type information contributed most to the error for individual substances. To resolve this, we suggest better registration of use types of industrial chemicals, investigation of presence/absence of industrial chemicals in wastewater and runoff samples and more scientific information exchange.

Purpose: Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides–Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown. Methods: By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes. Results: Of 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS]). In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains. Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants. Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype. In the remaining six individuals with nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification. Conclusion: We identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS.

Present evaluations of chemical pollution in European surface and groundwater bodies focus on problem description and chemical classification of water quality. Surprisingly, relatively low attention has been paid to solutions of chemical pollution problems when those are encountered. Based on evaluations of current practices and available approaches, we suggest that water quality protection, monitoring, assessment and management of chemical pollution can be improved by implementing an early-stage exploration of the ‘solution space’. This follows from the innovative paradigm of solution-focused risk assessment, which was developed to improve the utility of risk assessments. The ‘solution space’ is defined as the set of potential activities that can be considered to protect or restore the water quality against hazards posed by chemical pollution. When using the paradigm, upfront exploration of solution options and selecting options that would be feasible given the local pollution context would result in comparative risk assessment outcomes. The comparative outcomes are useful for selecting optimal measures against chemical pollution for management prioritization and planning. It is recommended to apply the solution-focused risk assessment paradigm to improve the chemical pollution information for river basin management planning. To operationalize this, the present paper describes a still-growing database and strategy to find and select technical abatement and/or non-technical solution options for chemical pollution of surface waters. The solutions database and strategy can be applied to help prevent and reduce water quality problems. Various case studies show that implementing these can be effective, and how solution scenarios can be evaluated for their efficacy by comparative exposure and effect assessment.

The ecological status of European surface waters may be affected by multiple stressors including exposure to chemical mixtures. Currently, two different approaches are used separately to inform water quality management: the diagnosis of the deterioration of aquatic ecosystems caused by nutrient loads and habitat quality, and assessment of chemical pollution based on a small set of chemicals. As integrated assessments would improve the basis for sound water quality management, it is recommended to apply a holistic approach to integrated water quality status assessment and management. This allows for estimating the relative contributions of exposure to mixtures of the chemicals present and of other stressors to impaired ecological status of European water bodies. Improved component- and effect-based methods for chemicals are available to support this. By applying those methods, it was shown that a holistic diagnostic approach is feasible, and that chemical pollution acts as a limiting factor for the ecological status of European surface waters. In a case study on Dutch surface waters, the impact on ecological status could be traced back to chemical pollution affecting individual species. The results are also useful as calibration of the outcomes of component-based mixture assessment (risk quotients or mixture toxic pressures) on ecological impacts. These novel findings provide a basis for a causal and integrated analysis of water quality and improved methods for the identification of the most important stressor groups, including chemical mixtures, to support integrated knowledge-guided management decisions on water quality.

An analysis of existing regulatory frameworks for chemicals reveals a fragmented situation with a number of regulatory frameworks designed for specific groups of chemicals; for protection of different end-points and covering different parts of the chemicals´ life cycle stages. Lack of- and fragmented information on chemicals (properties, use, emissions as well as fate, occurrence and effects in the environment) limit the ability for assessment and early action, and existing legislation would benefit from more transparency and openness of information and knowledge. To achieve harmonisation of existing legislation and an efficient control of chemical contamination of European waters, a solution-focused approach is proposed including increased ambitions (in monitoring, modelling, and risk assessment), cooperation and dialogue. More holistic and efficient development and implementation of existing legislation can be achieved by better cooperation, harmonisation and information exchange between different regulatory frameworks and by improved science–policy interactions. The introduction of an organisational structure and incentives for cooperation are proposed. Cooperation should focus on harmonisation of advanced monitoring activities, modelling, prioritisation, risk assessment and assessment of risk prevention (‘safe by design’) and minimisation options. A process for dialogue and information exchange between existing policy frameworks and with stakeholders (industry, NGO´s, etc.) should be included to identify feasible options for mitigation as well as regulatory gaps—on local and EU-scales. There is also a need to increase international cooperation and strengthen global agreements to cover the full life cycle of chemicals (produced and consumed globally) and for exchanging knowledge and experiences to allow early action. This recommended action would also provide knowledge and a framework for a shift towards a sustainable chemistry approach for chemical safety based

The European Union Water Framework Directives aims at achieving good ecological status in member states’ water bodies. Insufficient ecological status could be the result of different interacting stressors, among them the presence of many thousands of chemicals. The diagnosis of the likelihood that these chemicals negatively affect the ecological status of surface waters or human health, and the subsequent development of abatement measures usually relies on water quality monitoring. This gives an incomplete picture of chemicals’ contamination, due to the limited number of monitoring stations, samples and substances. Information gaps thus limit the possibilities to protect against and effectively manage chemicals in aquatic ecosystems. The EU FP7 SOLUTIONS project has developed and validated a collection of integrated models (“Model Train”) to increase our understanding of issues related to emerging chemicals in Europe’s river basins and to complement information and knowledge derived from field data. Unlike pre-existing models, the Model Train is suitable to model mixtures of thousands of chemicals, to better approach a “real-life” mixture exposure situation. It can also be used to model new chemicals at a stage where not much is known about them. The application of these models on a European scale provides temporally and spatially variable concentration data to fill gaps in the space, time and substance domains left open by water quality monitoring, and it provides homogeneous data across Europe where water quality data from monitoring are missing. Thus, it helps to avoid overlooking candidate chemicals and possible hot spots for management intervention. The application of the SOLUTIONS Model Train on a European scale presents a relevant line of evidence for water system level prognostic and diagnostic impact assessment related to chemical pollution. The application supports the design of cost-effective programmes of measures by helping to identify the most affected

To meet the United Nations (UN) sustainable development goals and the European Union (EU) strategy for a non-toxic environment, water resources and ecosystems management require cost-efficient solutions for prevailing complex contamination and multiple stressor exposures. For the protection of water resources under global change conditions, specific research needs for prediction, monitoring, assessment and abatement of multiple stressors emerge with respect to maintaining human needs, biodiversity, and ecosystem services. Collaborative European research seems an ideal instrument to mobilize the required transdisciplinary scientific support and tackle the large-scale dimension and develop options required for implementation of European policies. Calls for research on minimizing society’s chemical footprints in the water–food–energy–security nexus are required. European research should be complemented with targeted national scientific funding to address specific transformation pathways and support the evaluation, demonstration and implementation of novel approaches on regional scales. The foreseeable pressure developments due to demographic, economic and climate changes require solution-oriented thinking, focusing on the assessment of sustainable abatement options and transformation pathways rather than on status evaluation. Stakeholder involvement is a key success factor in collaborative projects as it allows capturing added value, to address other levels of complexity, and find smarter solutions by synthesizing scientific evidence, integrating governance issues, and addressing transition pathways. This increases the chances of closing the value chain by implementing novel solutions. For the water quality topic, the interacting European collaborative projects SOLUTIONS, MARS and GLOBAQUA and the NORMAN network provide best practice examples for successful applied collaborative research including multi-stakeholder involvement. They provided innovative conceptual, mode

Current prioritisation procedures under the EU Water Framework Directive (WFD) do not account for risks from chemical mixtures. SOLUTIONS proposes a multiple-lines-of-evidence approach to tackle the problem effectively. The approach merges all available evidence from co-exposure modelling, chemical monitoring, effect-based monitoring, and ecological monitoring. Full implementation of the proposed methodology requires changes in the legal text in adaptation to scientific progress.

Chemical pollution of surface waters is a societal concern around the globe. Key problems in current water quality protection, assessment and management are the narrow focus on a small fraction of the chemicals in commerce, concerns for increasingly diverse chemical emissions, and lack of effective diagnosis and management approaches. In reply, three key concepts to address these challenges were developed and tested. The approaches were developed in the context of the European Union Water Framework Directive, based on principles such as the DPSIR-causal framework (Drivers, Pressure, Status, Impact and Response) and the basic feature that water protection and management should be based on a water-system level approach. Collaborative actions of researchers and stakeholders resulted in: (1) an operationalization and implementation of the solution-focused risk assessment paradigm as proposed in 2009, to improve the utility of risk assessments, (2) the provision of a large set of tools and services to prevent, monitor, assess and manage complex mixture pollution problems, and (3) a strategy and a database on intervention options. These three elements were recognized as core elements to help protecting and improving water quality. Although the methods were developed in the context of water quality problems in Europe, the three elements can be applied globally in water quality protection and management.

Integrated models addressing microplastic (MP) generation, terrestrial distribution, and freshwater transport are useful tools characterizing the export of MP to marine waters. In Part I of this study, a baseline watershed-scale MP mass balance model was developed for tire and road wear particles (TRWP) in the Seine watershed. In Part II, uncertainty and sensitivity analysis (SA) methods were used to identify the parameters that determine the transport of these particles to the estuary. Local differential, local range and global first-order variance-based SA identified similar key parameters. The global SA (1000 Monte Carlo simulations) indicated that most of the variance in TRWP exported to the estuary can be apportioned to TRWP diameter (76%), TRWP density (5.6%), the fraction of TRWP directed to combined sewers with treatment (3.9%), and the fraction of TRWP distributed to runoff (versus roadside soil; 2.2%). The export fraction was relatively insensitive to heteroaggregation processes and the rainfall intensity threshold for road surface washoff. The fraction of TRWP exported to estuary in the probabilistic assessment was centered on the baseline estimate of 2%. This fraction ranged from 1.4 to 4.9% (central tendency defined as 25th to 75th percentile) and 0.97% to 13% (plausible upper bound defined as 10th to 90th percentiles). This study emphasizes the importance of in situ characterization of TRWP diameter and density, and confirms the baseline mass balance presented in Part I, which indicated an appreciable potential for capture of TRWP in freshwater sediment.

Human and ecological exposure to micro- and nanoplastic materials (abbreviated as MP, < 5 mm) occurs in both aquatic and terrestrial environments. Recent reviews prioritize the need for assessments linking spatially distributed MP releases with terrestrial and freshwater transport processes, thereby providing a better understanding of the factors affecting MP distribution to the sea. Tire and road wear particles (TRWP) have an estimated generation rate of 1 kg tread inhabitant −1 year −1 in Europe, but the fate of this MP source in watersheds has not been systematically assessed. An integrated temporally and geospatially resolved watershed-scale MP modeling methodology was applied to TRWP fate and transport in the Seine (France) watershed. The mass balance considers TRWP generation and terrestrial transport to soil, air, and roadways, as well as freshwater transport processes including particle heteroaggregation, degradation and sedimentation within subcatchments. The per capita TRWP mass release estimate in the Seine watershed was 1.8 kg inhabitant −1 yr −1 . The model estimates indicated that 18% of this release was transported to freshwater and 2% was exported to the estuary, which demonstrated the potential for appreciable capture, degradation, and retention of TRWP prior to export. The modeled pseudo-steady state sediment concentrations were consistent with measurements from the Seine watershed supporting the plausibility of the predicted trapping efficiency of approximately 90%. The approach supported the efficient completion of local and global sensitivity analyses presented in Part II of this study, and can be adapted to the assessment of other MPs.

Humans and wildlife are exposed to an intractably large number of different combinations of chemicals via food, water, air, consumer products, and other media and sources. This raises concerns about their impact on public and environmental health. The risk assessment of chemicals for regulatory purposes mainly relies on the assessment of individual chemicals. If exposure to multiple chemicals is considered in a legislative framework, it is usually limited to chemicals falling within this framework and co-exposure to chemicals that are covered by a different regulatory framework is often neglected. Methodologies and guidance for assessing risks from combined exposure to multiple chemicals have been developed for different regulatory sectors, however, a harmonised, consistent approach for performing mixture risk assessments and management across different regulatory sectors is lacking. At the time of this publication, several EU research projects are running, funded by the current European Research and Innovation Programme Horizon 2020 or the Seventh Framework Programme. They aim at addressing knowledge gaps and developing methodologies to better assess chemical mixtures, by generating and making available internal and external exposure data, developing models for exposure assessment, developing tools for in silico and in vitro effect assessment to be applied in a tiered framework and for grouping of chemicals, as well as developing joint epidemiological-toxicological approaches for mixture risk assessment and for prioritising mixtures of concern. The projects EDC-MixRisk, EuroMix, EUToxRisk, HBM4EU and SOLUTIONS have started an exchange between the consortia, European Commission Services and EU Agencies, in order to identify where new methodologies have become available and where remaining gaps need to be further addressed. This paper maps how the different projects contribute to the data needs and assessment methodologies and identifies remaining challenges to be fu