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

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

Mill’s radical end of laissez-faire: A review essay of the political economy of progress: John Stuart Mill and modern radicalism

Can John Stuart Mill’s radicalism achieve liberal egalitarian ends? Joseph Persky’s The Political Economy of Progress is a provocative and compelling discussion of Mill’s economic thought. It is also a defense of radical political economy. Providing valuable historical context, Persky traces Mill’s intellectual journey as an outspoken proponent of laissez-faire to a cautious supporter of co-operative socialism. I propose two problems with Persky’s optimistic take on radical social reform. First, demands for substantive equality have led past radicals to endorse exclusionary nationalist and eugenics policies. It pushes some contemporary radicals towards illiberal interventions into intimate social life. Second, the radical critique of capitalism relies on an account of profit that neglects the epistemic function of private-property markets. Once this is acknowledged, capitalism retains some progressive credentials against radical alternatives

Experimental investigations into the impact of the void fraction on the condensation characteristics of R134a refrigerant in minichannels under conditions of periodic instability

This paper present the results of experimental investigations of condensation of R134a refrigerant in pipe minichannels with internal diameters 0.64, 0.90, 1.40, 1.44, 1.92 and 3.30 mm subject to periodic pressure instabilities. It was established that as in conventional channels, the displacement velocity of the pressure instabilities distinctly depends on the frequency of their hydrodynamic generation. The void fraction distinctly influences the velocity of the pressure instabilities. The form of this relationship depends on the internal diameter of the minichannels and on the method of calculating the void fraction