Mutations in STAT3 and IL12RB1 impair the development of human IL-17–producing T cells

The cytokines controlling the development of human interleukin (IL) 17–producing T helper cells in vitro have been difficult to identify. We addressed the question of the development of human IL-17–producing T helper cells in vivo by quantifying the production and secretion of IL-17 by fresh T cells ex vivo, and by T cell blasts expanded in vitro from patients with particular genetic traits affecting transforming growth factor (TGF) β, IL-1, IL-6, or IL-23 responses. Activating mutations in TGFB1, TGFBR1, and TGFBR2 (Camurati-Engelmann disease and Marfan-like syndromes) and loss-of-function mutations in IRAK4 and MYD88 (Mendelian predisposition to pyogenic bacterial infections) had no detectable impact. In contrast, dominant-negative mutations in STAT3 (autosomal-dominant hyperimmunoglobulin E syndrome) and, to a lesser extent, null mutations in IL12B and IL12RB1 (Mendelian susceptibility to mycobacterial diseases) impaired the development of IL-17–producing T cells. These data suggest that IL-12Rβ1– and STAT-3–dependent signals play a key role in the differentiation and/or expansion of human IL-17–producing T cell populations in vivo

AI-based diagnosis in mandibulofacial dysostosis with microcephaly using external ear shapes

IntroductionMandibulo-Facial Dysostosis with Microcephaly (MFDM) is a rare disease with a broad spectrum of symptoms, characterized by zygomatic and mandibular hypoplasia, microcephaly, and ear abnormalities. Here, we aimed at describing the external ear phenotype of MFDM patients, and train an Artificial Intelligence (AI)-based model to differentiate MFDM ears from non-syndromic control ears (binary classification), and from ears of the main differential diagnoses of this condition (multi-class classification): Treacher Collins (TC), Nager (NAFD) and CHARGE syndromes.MethodsThe training set contained 1,592 ear photographs, corresponding to 550 patients. We extracted 48 patients completely independent of the training set, with only one photograph per ear per patient. After a CNN-(Convolutional Neural Network) based ear detection, the images were automatically landmarked. Generalized Procrustes Analysis was then performed, along with a dimension reduction using PCA (Principal Component Analysis). The principal components were used as inputs in an eXtreme Gradient Boosting (XGBoost) model, optimized using a 5-fold cross-validation. Finally, the model was tested on an independent validation set.ResultsWe trained the model on 1,592 ear photographs, corresponding to 1,296 control ears, 105 MFDM, 33 NAFD, 70 TC and 88 CHARGE syndrome ears. The model detected MFDM with an accuracy of 0.969 [0.838–0.999] (p < 0.001) and an AUC (Area Under the Curve) of 0.975 within controls (binary classification). Balanced accuracies were 0.811 [0.648–0.920] (p = 0.002) in a first multiclass design (MFDM vs. controls and differential diagnoses) and 0.813 [0.544–0.960] (p = 0.003) in a second multiclass design (MFDM vs. differential diagnoses).ConclusionThis is the first AI-based syndrome detection model in dysmorphology based on the external ear, opening promising clinical applications both for local care and referral, and for expert centers

Mutations in STAT3 and IL12RB1 impair the development of human IL-17 producing T cells

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Nephrocalcinosis (enamel renal syndrome) caused by autosomal recessive FAM20A mutations

Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood

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

Impact of Regional Block Failure in Ambulatory Hand Surgery on Patient Management: A Cohort Study

International audienceRegional anesthesia (RA) is an anesthetic technique essential for the performance of ambulatory surgery. Failure rates range from 6% to 20%, and the consequences of these failures have been poorly investigated. We determined the incidence and the impact of regional block failure on patient management in the ambulatory setting. This retrospective cohort study includes all adult patients who were admitted to a French University Hospital (Hôpital Saint-Antoine, AP-HP) between 1 January 2016 and 31 December 2017 for unplanned ambulatory distal upper limb surgery. Univariate and stepwise multivariate analyses were performed to determine factors associated with block failure. Among the 562 patients included, 48 (8.5%) had a block failure. RA failure was associated with a longer surgery duration (p = 0.02), more frequent intraoperative analgesics administration (p 2 (p = 0.03), history of substance abuse (p = 0.01), and performance of the surgery outside of the specific ambulatory surgical unit (p = 0.01). Here, we have documented a significant incidence of block failure in ambulatory hand surgery, with impairment in the organization of care. Identifying patients at risk of failure could help improve their management, especially by focusing on providing care in a dedicated ambulatory circuit

Autosomal Recessive Segregation of a Truncating Mutation of Anti-Müllerian Type II Receptor in a Family Affected by the Persistent Müllerian Duct Syndrome Contrasts with Its Dominant Negative Activity in Vitro.

International audienceAnti-Müllerian hormone belongs to the TGFbeta family whose members exert their effects by signaling through two related serine/threonine kinase receptors. Mutations of the anti-Müllerian hormone type II receptor occur naturally, causing the persistent Müllerian duct syndrome. In a family with two members with persistent Müllerian duct syndrome and one normal sibling, we detected two novel mutations of the anti-Müllerian hormone type II receptor gene. One, transmitted by the mother to her three sons, is a deletion of a single base leading to a stop codon, causing receptor truncation after the transmembrane domain. The other, a missense mutation in the substrate-binding site of the kinase domain, is transmitted by the father to the two sons affected by persistent Müllerian duct syndrome, indicating a recessive autosomal transmission as in other cases of persistent Müllerian duct syndrome. Truncating mutations in receptors of the TGFbeta family exert dominant negative activity, which was seen only when each of the mutant anti-Müllerian hormone receptors was overexpressed in an anti-Müllerian hormone-responsive cell line. We conclude that assessment of dominant activity in vitro, which usually involves overexpression of mutant genes, does not necessarily produce information applicable to clinical conditions, in which mutant and endogenous genes are expressed on a one to one basis

A New Instrument For Kinetics and Branching Ratio Studies of Gas Phase Collisional Processes at Very Low Temperatures

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A new instrument for kinetics and branching ratio studies of gas phase collisional processes at very low temperatures

International audienceA new instrument dedicated to the kinetic study of low-temperature gas phase neutral-neutral reactions, including clustering processes, is presented. It combines a supersonic flow reactor with vacuum ultra-violet synchrotron photoionization time-of-flight mass spectrometry. A photoion-photoelectron coincidence detection scheme has been adopted to optimize the particle counting efficiency. The characteristics of the instrument are detailed along with its capabilities illustrated through a few results obtained at low temperatures (<100 K) including a photoionization spectrum of n-butane, the detection of formic acid dimer formation, and the observation of diacetylene molecules formed by the reaction between the C2H radical and C2H2. © 2021 Author(s)