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

PEM Electrolysis in a Stirred‐Tank Bioreactor Enables Autotrophic Growth of Clostridium ragsdalei with CO2 and Electrons

Abstract Acetogenic bacteria produce CO2‐based chemicals in aqueous media by hydrogenotrophic conversion of CO2, but CO is the preferred carbon and electron source. Consequently, coupling CO2 electrolysis with bacterial fermentation within an integrated bio‐electrocatalytical system (BES) is promising, if CO2 reduction catalysts are available for the generation of CO in the complex biotic electrolyte. A standard stirred‐tank bioreactor was coupled to a zero‐gap PEM electrolysis cell for CO2 conversion, allowing voltage control and separation of the anode in one single cell. The cathodic CO2 reduction and the competing hydrogen evolution enabled in‐situ feeding of C. ragsdalei with CO and H2. Proof‐of‐concept was demonstrated in first batch processes with continuous CO2 gassing, as autotrophic growth and acetate formation was observed in the stirred BES in a voltage range of −2.4 to −3.0 V. The setup is suitable also for other bioelectrocatalytic reactions. Increased currents and lower overvoltages are however required. Atomically‐dispersed M−N−C catalysts show promise, if degradation throughout autoclaving can be omitted. The development of selective and autoclavable catalysts resistant to contamination and electrode design for the complex electrolyte will enable efficient bioelectrocatalytic power‐to‐X systems based on the introduced BES