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Background Tatton- Brown- Rahman syndrome (TBRS; OMIM 615879), also known as DNA methyltransferase 3 alpha (DNMT3A)- overgrowth syndrome (DOS), was first described by Tatton- Brown in 2014. This syndrome is characterised by overgrowth, intellectual disability and distinctive facial features and is the consequence of germline loss- of- function variants in DNMT3A, which encodes a DNA methyltransferase involved in epigenetic regulation. Somatic variants of DNMT3A are frequently observed in haematological malignancies, including acute myeloid leukaemia (AML). To date, 100 individuals with TBRS with de novo germline variants have been described. We aimed to further characterise this disorder clinically and at the molecular level in a nationwide series of 24 French patients and to investigate the correlation between the severity of intellectual disability and the type of variant. Methods We collected genetic and medical information from 24 individuals with TBRS using a questionnaire released through the French National AnDDI- Rares Network. Results Here, we describe the first nationwide French cohort of 24 individuals with germline likely pathogenic/ pathogenic variants in DNMT3A, including 17 novel variants. We confirmed that the main phenotypic features were intellectual disability (100% of individuals), distinctive facial features (96%) and overgrowth (87%). We highlighted novel clinical features, such as hypertrichosis, and further described the neurological features and EEG results. Conclusion This study of a nationwide cohort of individuals with TBRS confirms previously published data and provides additional information and clarifies clinical features to facilitate diagnosis and improve care. This study adds value to the growing body of knowledge on TBRS and broadens its clinical and molecular spectrum. [ABSTRACT FROM AUTHOR]

Coupled human-water systems (CHWS) are diverse and have been studied across a wide variety of disciplines. Integrating multiple disciplinary perspectives on CHWS provides a comprehensive and actionable understanding of these complex systems. While interdisciplinary integration has often remained elusive, specific combinations of disciplines might be comparably easier to integrate (compatible), and/or their combination might be particularly likely to uncover previously unobtainable insights (complementary). This paper systematically identifies such promising combinations by mapping disciplines along a common set of topical, philosophical, and methodological dimensions. It also identifies key challenges and lessons for multidisciplinary research teams seeking to integrate highly promising (complementary) but poorly compatible disciplines. Applied to eight disciplines that span the environmental physical sciences and the quantitative and qualitative social sciences, we found that promising combinations of disciplines identified by the typology broadly reproduce patterns of recent interdisciplinary collaborative research revealed by a bibliometric analysis. We also found that some disciplines are centrally located within the typology by being compatible and complementary to multiple other disciplines along distinct dimensions. This points to the potential for these disciplines to act as catalysts for wider interdisciplinary integration. This article is categorized under: Engineering Water > Methods Human Water > Methods Science of Water > Methods [ABSTRACT FROM AUTHOR]

Simple Summary: Osteoarthritis is a debilitating and painful joint disease affecting mainly aging animals and people. Previous results indicated that Efemp1, a protein present in the extracellular matrix that surrounds each cell, is increased in the blood, urine, and bone of osteoarthritic patients. We used the zebrafish as a model system to investigate the role of the Efemp1 protein in skeletal development and homeostasis. We showed that the efemp1 gene is expressed in the brain, the pharyngeal cartilage, and the developing notochord which will later form the vertebral column. We generated a mutant in this gene, devoid of a functional Efemp1 protein, to show that this mutant presents transient deformities in its head cartilage at early stages. More importantly, adult mutants expressed a phenotype characterized by a smaller distance between vertebrae and ruffled edges (bone spurs) at the vertebral ends. This defect is reminiscent of that observed in spinal osteoarthritis; we therefore propose the efemp1−/− mutant line as the first zebrafish model to study this condition. Osteoarthritis is a degenerative articular disease affecting mainly aging animals and people. The extracellular matrix protein Efemp1 was previously shown to have higher turn-over and increased secretion in the blood serum, urine, and subchondral bone of knee joints in osteoarthritic patients. Here, we use the zebrafish as a model system to investigate the function of Efemp1 in vertebrate skeletal development and homeostasis. Using in situ hybridization, we show that the efemp1 gene is expressed in the brain, the pharyngeal arches, and in the chordoblasts surrounding the notochord at 48 hours post-fertilization. We generated an efemp1 mutant line, using the CRISPR/Cas9 method, that produces a severely truncated Efemp1 protein. These mutant larvae presented a medially narrower chondrocranium at 5 days, which normalized later at day 10. At age 1.5 years, µCT analysis revealed an increased tissue mineral density and thickness of the vertebral bodies, as well as a decreased distance between individual vertebrae and ruffled borders of the vertebral centra. This novel defect, which has, to our knowledge, never been described before, suggests that the efemp1 mutant represents the first zebrafish model for spinal osteoarthritis. [ABSTRACT FROM AUTHOR]