De novo mutations (DNMs) in protein-coding genes are a well-established cause of developmental disorders (DD). However, known DD-associated genes only account for a minority of the observed excess of such DNMs. To identify novel DD-associated genes, we integrated healthcare and research exome sequences on 31,058 DD parent-offspring trios, and developed a simulation-based statistical test to identify gene-specific enrichments of DNMs. We identified 285 significantly DD-associated genes, including 28 not previously robustly associated with DDs. Despite detecting more DD-associated genes than in any previous study, much of the excess of DNMs of protein-coding genes remains unaccounted for. Modelling suggests that over 1,000 novel DD-associated genes await discovery, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of dominant DDs.

PurposeGiven the rapid pace of discovery in rare disease genomics, it is likely that improvements in diagnostic yield can be made by systematically reanalysing previously generated genomic sequence data in light of new knowledge.MethodsWe tested this hypothesis in the UK-wide Deciphering Developmental Disorders Study, where in 2014 we reported a diagnostic yield of 27% through whole exome sequencing of 1133 children with severe developmental disorders and their parents. We reanalysed existing data using improved variant calling methodologies, novel variant detection algorithms, updated variant annotation, evidence-based filtering strategies, and newly discovered disease-associated genes.ResultsWe are now able to diagnose an additional 182 individuals, taking our overall diagnostic yield to 454/1133 (40%), and another 43 (4%) have a finding of uncertain clinical significance. The majority of these new diagnoses are due to novel developmental disorder-associated genes discovered since our original publication.ConclusionThis study highlights the importance of coupling large-scale research with clinical practice, and of discussing the possibility of iterative reanalysis and recontact with patients and health professionals at an early stage. We estimate that implementing parent-offspring whole exome sequencing as a first line diagnostic test for developmental disorders would diagnose >50% of patients.

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We previously estimated that 42% of patients with severe developmental disorders carry pathogenic de novo mutations in coding sequences. The role of de novo mutations in regulatory elements affecting genes associated with developmental disorders, or other genes, has been essentially unexplored. We identified de novo mutations in three classes of putative regulatory elements in almost 8,000 patients with developmental disorders. Here we show that de novo mutations in highly evolutionarily conserved fetal brain-active elements are significantly and specifically enriched in neurodevelopmental disorders. We identified a significant twofold enrichment of recurrently mutated elements. We estimate that, genome-wide, 1-3% of patients without a diagnostic coding variant carry pathogenic de novo mutations in fetal brain-active regulatory elements and that only 0.15% of all possible mutations within highly conserved fetal brain-active elements cause neurodevelopmental disorders with a dominant mechanism. Our findings represent a robust estimate of the contribution of de novo mutations in regulatory elements to this genetically heterogeneous set of disorders, and emphasize the importance of combining functional and evolutionary evidence to identify regulatory causes of genetic disorders.

Dielectric elastomer transducers consist of thin electrically insulating elastomeric membranes coated on both sides with compliant electrodes. They are a promising electromechanically active polymer technology that may be used for actuators, strain sensors, and electrical generators that harvest mechanical energy. The rapid development of this field calls for the first standards, collecting guidelines on how to assess and compare the performance of materials and devices. This paper addresses this need, presenting standardized methods for material characterisation, device testing and performance measurement. These proposed standards are intended to have a general scope and a broad applicability to different material types and device configurations. Nevertheless, they also intentionally exclude some aspects where knowledge and/or consensus in the literature were deemed to be insufficient. This is a sign of a young and vital field, whose research development is expected to benefit from this effort towards standardisation.