5 research outputs found

    A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

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    Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

    Tool use, communicative gesture and cerebral asymmetries in the modern human brain

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    Determining the brain adaptations that underlie complex tool-use skills is an important component in understanding the physiological bases of human material culture. It is argued here that the ways in which humans skilfully use tools and other manipulable artefacts is possible owing to adaptations that integrate sensory–motor and cognitive processes. Data from brain-injured patients and functional neuroimaging studies suggest that the left cerebral hemisphere, particularly the left parietal cortex, of modern humans is specialized for this purpose. This brain area integrates dynamically representations that are computed in a distributed network of regions, several of which are also left-lateralized. Depending on the nature of the task, these may include conceptual knowledge about objects and their functions, the actor's goals and intentions, and interpretations of task demands. The result is the formation of a praxis representation that is appropriate for the prevailing task context. Recent evidence is presented that this network is organized similarly in the right- and left-handed individuals, and participates in the representation of both familiar tool-use skills and communicative gestures. This shared brain mechanism may reflect common origins of the human specializations for complex tool use and language

    Revealing determinants of two‐phase dynamics of P53 network under gamma irradiation based on a reduced 2D relaxation oscillator model

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    This study proposes a two‐dimensional (2D) oscillator model of p53 network, which is derived via reducing the multidimensional two‐phase dynamics model into a model of ataxia telangiectasia mutated (ATM) and Wip1 variables, and studies the impact of p53‐regulators on cell fate decision. First, the authors identify a 6D core oscillator module, then reduce this module into a 2D oscillator model while preserving the qualitative behaviours. The introduced 2D model is shown to be an excitable relaxation oscillator. This oscillator provides a mechanism that leads diverse modes underpinning cell fate, each corresponding to a cell state. To investigate the effects of p53 inhibitors and the intrinsic time delay of Wip1 on the characteristics of oscillations, they introduce also a delay differential equation version of the 2D oscillator. They observe that the suppression of p53 inhibitors decreases the amplitudes of p53 oscillation, though the suppression increases the sustained level of p53. They identify Wip1 and P53DINP1 as possible targets for cancer therapies considering their impact on the oscillator, supported by biological findings. They model some mutations as critical changes of the phase space characteristics. Possible cancer therapeutic strategies are then proposed for preventing these mutations’ effects using the phase space approach
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