Delineating the genotypic and phenotypic spectrum of HECW2-related neurodevelopmental disorders

Background Variants in HECW2 have recently been reported to cause a neurodevelopmental disorder with hypotonia, seizures and impaired language; however, only six variants have been reported and the clinical characteristics have only broadly been defined. Methods Molecular and clinical data were collected from clinical and research cohorts. Massive parallel sequencing was performed and identified individuals with a HECW2-related neurodevelopmental disorder. Results We identified 13 novel missense variants in HECW2 in 22 unpublished cases, of which 18 were confirmed to have a de novo variant. In addition, we reviewed the genotypes and phenotypes of previously reported and new cases with HECW2 variants (n=35 cases). All variants identified are missense, and the majority of likely pathogenic and pathogenic variants are located in or near the C-terminal HECT domain (88.2%). We identified several clustered variants and four recurrent variants (p.(Arg1191Gln);p.(Asn1199Lys);p.(Phe1327Ser);p.(Arg1330Trp)). Two variants, (p.(Arg1191Gln);p.(Arg1330Trp)), accounted for 22.9% and 20% of cases, respectively. Clinical characterisation suggests complete penetrance for hypotonia with or without spasticity (100%), developmental delay/intellectual disability (100%) and developmental language disorder (100%). Other common features are behavioural problems (88.9%), vision problems (83.9%), motor coordination/movement (75%) and gastrointestinal issues (70%). Seizures were present in 61.3% of individuals. Genotype-phenotype analysis shows that HECT domain variants are more frequently associated with cortical visual impairment and gastrointestinal issues. Seizures were only observed in individuals with variants in or near the HECT domain. Conclusion We provide a comprehensive review and expansion of the genotypic and phenotypic spectrum of HECW2 disorders, aiding future molecular and clinical diagnosis and management.Peer reviewe

TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease

Mutations in the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA biology. The TEFM gene encodes the mitochondrial transcription elongation factor responsible for enhancing the processivity of mitochondrial RNA polymerase, POLRMT. We report for the first time that TEFM variants are associated with mitochondrial respiratory chain deficiency and a wide range of clinical presentations including mitochondrial myopathy with a treatable neuromuscular transmission defect. Mechanistically, we show muscle and primary fibroblasts from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts. Finally, tefm knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function, strengthening the genotype-phenotype correlation. Our study highlights that TEFM regulates mitochondrial transcription elongation and its defect results in variable, tissue-specific neurological and neuromuscular symptoms

Political transition and emergent forest-conservation issues in Myanmar.

Political and economic transitions have had substantial impacts on forest conservation. Where transitions are underway or anticipated, historical precedent and methods for systematically assessing future trends should be used to anticipate likely threats to forest conservation and design appropriate and prescient policy measures to counteract them. Myanmar is transitioning from an authoritarian, centralized state with a highly regulated economy to a more decentralized and economically liberal democracy and is working to end a long-running civil war. With these transitions in mind, we used a horizon-scanning approach to assess the 40 emerging issues most affecting Myanmar's forests, including internal conflict, land-tenure insecurity, large-scale agricultural development, demise of state timber enterprises, shortfalls in government revenue and capacity, and opening of new deforestation frontiers with new roads, mines, and hydroelectric dams. Averting these threats will require, for example, overhauling governance models, building capacity, improving infrastructure- and energy-project planning, and reforming land-tenure and environmental-protection laws. Although challenges to conservation in Myanmar are daunting, the political transition offers an opportunity for conservationists and researchers to help shape a future that enhances Myanmar's social, economic, and environmental potential while learning and applying lessons from other countries. Our approach and results are relevant to other countries undergoing similar transitions

Political transition and emergent forest-conservation issues in Myanmar.

Political and economic transitions have had substantial impacts on forest conservation. Where transitions are underway or anticipated, historical precedent and methods for systematically assessing future trends should be used to anticipate likely threats to forest conservation and design appropriate and prescient policy measures to counteract them. Myanmar is transitioning from an authoritarian, centralized state with a highly regulated economy to a more decentralized and economically liberal democracy and is working to end a long-running civil war. With these transitions in mind, we used a horizon-scanning approach to assess the 40 emerging issues most affecting Myanmar's forests, including internal conflict, land-tenure insecurity, large-scale agricultural development, demise of state timber enterprises, shortfalls in government revenue and capacity, and opening of new deforestation frontiers with new roads, mines, and hydroelectric dams. Averting these threats will require, for example, overhauling governance models, building capacity, improving infrastructure- and energy-project planning, and reforming land-tenure and environmental-protection laws. Although challenges to conservation in Myanmar are daunting, the political transition offers an opportunity for conservationists and researchers to help shape a future that enhances Myanmar's social, economic, and environmental potential while learning and applying lessons from other countries. Our approach and results are relevant to other countries undergoing similar transitions

CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

Purpose: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). Methods: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. Results: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. Conclusion: We significantly broaden the mutational and clinical spectrum of CTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.Peer reviewe

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

High-throughput DNA sequencing for the identification of the molecular basis of Mendelian pathologies : opportunities and challenges

L'avènement du séquençage à haut-débit a révolutionné l’élucidation des bases moléculaires des pathologies mendéliennes, malgré ces avancées près d’une personne sur deux présentant une pathologie suspecte d’être mendélienne reste dans une situation d’impasse diagnostique. La combinaison de progrès pour le séquençage, pour l’interprétation et pour la caractérisation fonctionnelle des variants est à même de surmonter une partie de ces impasses. La prise en compte des limites inhérentes aux approches utilisées (cohortes cas/témoins, modèle in vitro ou in vivo) pour élucider les bases moléculaires des pathologies est cruciale pour adopter des stratégies de recherche efficaces. L’interprétation des variants non-codants et la confirmation de pathologies oligogéniques s’annoncent comme des défis majeurs à surmonter et plaident pour le renforcement des collaborations internationales et interdisciplinaires. L’élucidation des bases moléculaires des pathologies devient d’autant plus importante que le développement de thérapies ciblées innovantes permet d’orienter la prise en charge thérapeutique en fonction des bases moléculaires.The advent of high-throughput sequencing revolutionized the elucidation of the molecular basis of Mendelian diseases. However, nearly one out of two people with a suspected Mendelian disease remains without diagnosis. The combination of progress in sequencing, interpretation and functional characterization of variants can overcome some of these diagnostic odysseys. Considering the inherent limitations of the methods (case/control cohorts, in vitro or in vivo model) used to elucidate the molecular basis of pathologies is key to define successful research strategy. The interpretation of non-coding variants and the confirmation of oligogenic diseases are major challenges to be overcome and plead for the strengthening of international and interdisciplinary collaborations. The elucidation of the molecular basis of genetic diseases becomes even more important as the implementation of innovative targeted therapies relies on a good understanding of these molecular basi

A snapshot of some pLI score pitfalls

International audienceThe pLI score reflects the tolerance of a given gene to the loss of function on the basis of the number of protein truncating variants, that is, the frameshift, splice donor, splice acceptor, and stop-gain variants referenced for this gene in control databases weighted by the size of the gene and the sequencing coverage. It is frequently used to prioritize candidate genes when analyzing whole exome or whole genome data. We list here the main pitfalls to consider before using this score. Concrete illustrations are given for each of these pitfalls.</p

The educative posture, a cornerstone in the service of therapeutic patient education!

Introduction: The educative posture (EP) is considered by several authors as the cornerstone for serving the development of the skills of health professionals in therapeutic patient education (TPE) and more broadly the integration of this TPE into professional practices. However, the concept of EP remains to be clarified in view of the polysemic definitions, or simply lack of definition of EP. Objectives/contributions: This article describes the issues around the definition, recognition and development of the concept of EP. It also proposes a pragmatic characterization of the concept organized around 7 dimensions: The relation to time ("the right moment, the time it takes"), the benefits of the practice of TPE (well-being of health professionals), emotions and feelings (quality of the exchanges, sharing), the professional character of TPE (biomedical and educational required competences), the global and interdisciplinary approach (complexity of the person, interest of a team work), the educational aspect of the care relationship (education integrated with care) and the ethical dimension (thought to be essential). Discussion/conclusion: This study opens perspectives of transformations of the professional trainings, as well as research oriented on the educational interventions to make of this EP a learning object in its own right. © 2018 EDP Sciences, SETE