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

Méthodologie d'accès à des benzolactones de taille moyenne

Les lactones de taille moyenne présentent un grand intérêt en synthèse organique puisqu elles peuvent être utilisées comme intermédiaires dans la préparation de nombreux composés. Ces cycles sont également présents dans des produits naturels et peuvent présenter diverses applications. Les lactones de taille inférieure à six chaînons ou supérieure à 12 chaînons sont obtenues facilement en utilisant quand cela est nécessaire des conditions de hautes dilutions. Par contre l accès aux lactones de taille moyenne reste très difficile. Nous nous sommes intéressés à la préparation de benzolactones de taille moyenne, peu décrites dans la littérature. La première méthode testée suppose une réaction électrochimique intramoléculaire catalysée par des complexes du nickel, sur une molécule aromatique possédant à la fois une liaison C,Br sur le noyau aromatique et une double liaison électrophile. Des essais préliminaires ont montré que l étape électrochimique demeure peu efficace (formation de produits de réduction). Nous avons envisagé une autre approche pour préparer ces composés. Cette stratégie implique le passage par une arylation électrochimique intermoléculaire suivie d une étape de lactonisation. Cette méthode simple et efficace a permis l accès à quatre benzolactones. Afin de diminuer le nombre d étapes de synthèse, et éviter notamment les étapes de protection et déprotection, une seconde méthode a été développée. Elle consiste à introduire par voie électrochimique une chaîne portant la fonction alcool sous la forme d un carbonyle, réduit ultérieurement. Le dérivé ortho-halogéné possédant déjà une fonction ester sera facilement saponifié avant lactonisation. Ces résultats laissent entrevoir la possibilité d accéder à des lactones chirales. Cette seconde approche, très efficace, a permis la préparation de lactones possédant soit une double liaison ou encore des variations structurales sur le noyau aromatique ou hétéroaromatique.Medium ring compounds are important in organic chemistry. They are contained in a large number of natural products. They are also intermediates in many synthetic applications. We have focused on the preparation of benzolactones. Lactones containing up to 6 members are easily prepared. Also, macrocyclic lactones larger than 12-membered rings can be efficiently obtained in high dilution reaction conditions. On the contrary, medium ring lactones, like other medium-size ring compounds, are reported to be the most difficult to prepare by cyclisation. Our purpose was to apply an efficient C,C bond forming electrochemical reaction, involving the nickel catalyzed arylation of activated olefins, to the formation of medium ring benzolactones. The first idea was to perform this reaction intramolecularily. In such a simple route, the activated olefin is first tethered to the aryl moiety before the electrochemical arylation of the C,C-double bond, thus leading to the expected fused benzolactone in only 2 steps. Unfortunately until now, this method is of low efficiency, as the main products in the electrochemical step come from reduction of the starting compound. As an alternative, we could first form the C,C-bond by a bimolecular process before closing the ring by lactonisation. This simple method to access rapidly to medium ring lactones using an electrochemical step is efficient. Benzolactones were obtained in good yield. To decrease the number of steps and notably avoid the protection/deprotection steps we found it quite convenient to first tethered the carboxylic group to the aromatic ring and then introduce an alkyl chain bearing the hydroxyl group precursor in the form of a carbonyl. Apart from reducing the number of steps, this enables access to chiral lactones. Other benzolactones have been prepared having notably a heteroaryl ring or a double bond in the lactone ring.PARIS12-CRETEIL BU Multidisc. (940282102) / SudocSudocFranceF

α-Methylation of ketones with methanol catalyzed by Ni/SiO2-Al2O3

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Direct arylation : alternative to classic cross-coupling chemistry and a fruitful synthetic tool for the access to novative bioactive molecules.

International audienceThis account will discuss the advances performed in our group on direct arylation of heterocyclic systems regarded as critical scaffolds of pharmaceutical industries due to their wide-ranging biological and therapeutical properties. Applications to larger molecules devoted to pharmaceutical, material or agrochemical industries should bring significant improvement, getting rid of the preliminary step of prefunctionalization

Synthesis of Dipentaerythritol from Pentaerythritol under Acidic Conditions

International audienceThe direct synthesis of dipentaerythritol (DPE) from pentaerythritol (PE) was studied under acidic conditions. After optimization of the reaction parameters in a batch reactor, DPE was obtained with 50% selectivity when 50% PE was converted. This process, using PE in suspension in sulfolane (PE/sulfolane ratio = 2333 g/L) at 175 °C for 60 min, required a low amount of sulfuric acid (0.5 mol %). The optimized conditions were transposed to a 140 grams scale process. Finally, DPE was isolated with 16% yield (72% gas chromatography, GC purity) for 28% conversion of PE that corresponds to 57% DPE selectivity

Solvent-free direct α-alkylation of ketones by alcohols catalyzed by nickel supported on silica–alumina

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Access to a new family of medium ring aromatic lactones

We report a new method for preparation of hydroxyacids as precursors of benzolactones using a simple and an efficient electrochemical step. This gives in only four steps six-to eleven-membered lactones with high isolated yields from conveniently substituted aryl bromides. The lactonisation was performed according to the Yamamoto's process

Solvent-Free N-Alkylation of Amides with Alcohols Catalyzed by Nickel on Silica-Alumina

International audienceThe N-alkylation of phenylacetamide with benzyl alcohol has been studied using Ni/SiO2-Al2O3. In the optimized conditions, the desired product was isolated in an excellent 98% yield. The reaction could advantageously be performed in neat conditions, with a slight excess of amide and a catalytic amount of base. These conditions were tested on a large range of amides and alcohols, affording 24 compounds in 13 to 99% isolated yields

Eco-conception of highly salt-tolerant alkyl ether carboxylate hydrotropes with a glyceryl spacer

International audienceNew alkyl ether carboxylates including a glyceryl spacer instead of ethylene glycol units have been synthesized using environmentally friendly methodology. A cascade synthesis of acetalisation and hydrogenolysis was developed to obtain products containing an alkyl chain linked to glycerol unit bearing a carboxylate polar head. These products were methylated using trimethyl phosphate to observe the influence of an alcohol free or methoxylated on physicochemical properties. Finally, saponification gave the carboxylate anionic group of the new hydrotropes. The study of the amphiphilicity, the tolerance to sodium and calcium ions and the solubilizing power of these bio-based ionic/nonionic hydrotropes has shown that they exhibit significantly improved application properties compared to similar petro-based hydrotropes

An eco-compatible pathway to new hydrotropes from tetraols

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