IntrAnat Electrodes: A Free Database and Visualization Software for Intracranial Electroencephalographic Data Processed for Case and Group Studies

In some cases of pharmaco-resistant and focal epilepsies, intracranial recordings performed epidurally (electrocorticography, ECoG) and/or in depth (stereoelectroencephalography, SEEG) can be required to locate the seizure onset zone and the eloquent cortex before surgical resection. In SEEG, each electrode contact records brain’s electrical activity in a spherical volume of 3 mm diameter approximately. The spatial coverage is around 1% of the brain and differs between patients because the implantation of electrodes is tailored for each case. Group studies thus need a large number of patients to reach a large spatial sampling, which can be achieved more easily using a multicentric approach such as implemented in our F-TRACT project (f-tract.eu). To facilitate group studies, we developed a software—IntrAnat Electrodes—that allows to perform virtual electrode implantation in patients’ neuroanatomy and to overlay results of epileptic and functional mapping, as well as resection masks from the surgery. IntrAnat Electrodes is based on a patient database providing multiple search criteria to highlight various group features. For each patient, the anatomical processing is based on a series of software publicly available. Imaging modalities (Positron Emission Tomography (PET), anatomical MRI pre-implantation, post-implantation and post-resection, functional MRI, diffusion MRI, Computed Tomography (CT) with electrodes) are coregistered. The 3D T1 pre-implantation MRI gray/white matter is segmented and spatially normalized to obtain a series of cortical parcels using different neuroanatomical atlases. On post-implantation images, the user can position 3D models of electrodes defined by their geometry. Each electrode contact is then labeled according to its position in the anatomical atlases, to the class of tissue (gray or white matter, cerebro-spinal fluid) and to its presence inside or outside the resection mask. Users can add more functionally informed labels on contact, such as clinical responses after electrical stimulation, cortico-cortical evoked potentials, gamma band activity during cognitive tasks or epileptogenicity. IntrAnat Electrodes software thus provides a means to visualize multimodal data. The contact labels allow to search for patients in the database according to multiple criteria representing almost all available data, which is to our knowledge unique in current SEEG software. IntrAnat Electrodes will be available in the forthcoming release of BrainVisa software and tutorials can be found on the F-TRACT webpage

Evaluation Of Population-Varieties Developed Within A Wheat Participatory Breeding Program In France: Performances, Diversity, Stability And Adaptation

Modern agricultural systems rely on little crop genetic diversity, especially with the use of homogeneous varieties grown on large areas. However crop genetic diversity within fields is a lever for a more sustainable production, allowing for a greater stability through combined resistances to biotic and abiotic stress, and buffering environmental heterogeneity which characterizes organic systems. In France, a Participatory Plant Breeding (PPB) project has been applied on bread wheat since 2006 involving farmers and facilitators of the farmers' seed network Réseau Semences Paysannes and INRA researchers for the development of populations based on a decentralized selection in farmers' fields. This project leads to the development of heterogeneous populations whose intra-variety genetic diversity should allow them to adapt to farmers' practices and environments. We evaluated the agronomic behavior, genetic diversity, stability and local adaptation of ten populations developed within the PPB program compared to two commercial pure line varieties. Some populations had very interesting responses when considering grain yield, biomass production and protein content, and six of them were not significantly less productive than the two commercial varieties when comparing overall grain yield per population. While no clear evidence of local adaptation was detected, we found that populations' quality and in a lesser extent grain yield were more stable over years than that of commercial varieties. Protein content stability over time was positively correlated to genetic diversity with no significant drawback on protein production

Set up of a methodology for participatory plant breeding in bread wheat in France

In Organic Agriculture, cultivation environments and agronomic practices are very diverse. This diversity can be handled with decentralized selection based on the knowledge of farmers and scientists. A collaborative work between associations from Réseau Semences Paysannes and the DEAP team from INRA du Moulon set up an innovative breeding approach on farm based on decentralization and participation of farmers. This approach makes it possible to (i) create new population varieties of bread wheat locally adapted (genetic innovation) (ii) set up an organizational scheme based on decentralization and co construction between actors (societal innovation) and (iii) develop experimental designs, create statistical and data management tools which stimulate these genetic and societal innovations

Curation and expansion of Human Phenotype Ontology for defined groups of inborn errors of immunity.

BACKGROUND: Accurate, detailed, and standardized phenotypic descriptions are essential to support diagnostic interpretation of genetic variants and to discover new diseases. The Human Phenotype Ontology (HPO), extensively used in rare disease research, provides a rich collection of vocabulary with standardized phenotypic descriptions in a hierarchical structure. However, to date, the use of HPO has not yet been widely implemented in the field of inborn errors of immunity (IEIs), mainly due to a lack of comprehensive IEI-related terms. OBJECTIVES: We sought to systematically review available terms in HPO for the depiction of IEIs, to expand HPO, yielding more comprehensive sets of terms, and to reannotate IEIs with HPO terms to provide accurate, standardized phenotypic descriptions. METHODS: We initiated a collaboration involving expert clinicians, geneticists, researchers working on IEIs, and bioinformaticians. Multiple branches of the HPO tree were restructured and extended on the basis of expert review. Our ontology-guided machine learning coupled with a 2-tier expert review was applied to reannotate defined subgroups of IEIs. RESULTS: We revised and expanded 4 main branches of the HPO tree. Here, we reannotated 73 diseases from 4 International Union of Immunological Societies-defined IEI disease subgroups with HPO terms. We achieved a 4.7-fold increase in the number of phenotypic terms per disease. Given the new HPO annotations, we demonstrated improved ability to computationally match selected IEI cases to their known diagnosis, and improved phenotype-driven disease classification. CONCLUSIONS: Our targeted expansion and reannotation presents enhanced precision of disease annotation, will enable superior HPO-based IEI characterization, and hence benefit both IEI diagnostic and research activities

Intriguing Relationships Between Cancer and Systemic Sclerosis: Role of the Immune System and Other Contributors

Systemic sclerosis (SSc) is an autoimmune connective tissue disorder, characterized by multisystem involvement, vasculopathy, and fibrosis. An increased risk of malignancy is observed in SSc (including breast and lung cancers), and in a subgroup of patients with specific autoantibodies (i.e., anti-RNA polymerase III and related autoantibodies), SSc could be a paraneoplastic syndrome and might be directly related to an immune response against cancer. Herein, we reviewed the literature, focusing on the most recent articles, and shed light onto the potential relationship between cancer and scleroderma regarding temporal and immunological dimensions

The "extreme phenotype approach" applied to male breast cancer allows the identification of rare variants of ATR as potential breast cancer susceptibility alleles

In oncogenetics, some patients could be considered as "extreme phenotypes", such as those with very early onset presentation or multiple primary malignancies, unusually high numbers of cancers of the same spectrum or rare cancer types in the same parental branch. For these cases, a genetic predisposition is very likely, but classical candidate gene panel analyses often and frustratingly remains negative. In the framework of the EX2TRICAN project, exploring unresolved extreme cancer phenotypes, we applied exome sequencing on rare familial cases with male breast cancer, identifying a novel pathogenic variant of ATR (p.Leu1808*). ATR has already been suspected as being a predisposing gene to breast cancer in women. We next identified 3 additional ATR variants in a cohort of both male and female with early onset and familial breast cancers (c.7762-2A>C; c.2078+1G>A; c.1A>G). Further molecular and cellular investigations showed impacts on transcripts for variants affecting splicing sites and reduction of ATR expression and phosphorylation of the ATR substrate CHEK1. This work further demonstrates the interest of an extended genetic analysis such as exome sequencing to identify very rare variants that can play a role in cancer predisposition in extreme phenotype cancer cases unexplained by classical cancer gene panels testing

Fifteen years of research on oral–facial–digital syndromes: from 1 to 16 causal genes

Oral–facial–digital syndromes (OFDS) gather rare genetic disorders characterised by facial, oral and digital abnormalities associated with a wide range of additional features (polycystic kidney disease, cerebral malformations and several others) to delineate a growing list of OFDS subtypes. The most frequent, OFD type I, is caused by a heterozygous mutation in the OFD1 gene encoding a centrosomal protein. The wide clinical heterogeneity of OFDS suggests the involvement of other ciliary genes. For 15 years, we have aimed to identify the molecular bases of OFDS. This effort has been greatly helped by the recent development of whole-exome sequencing (WES). Here, we present all our published and unpublished results for WES in 24 cases with OFDS. We identified causal variants in five new genes (C2CD3, TMEM107, INTU, KIAA0753 and IFT57) and related the clinical spectrum of four genes in other ciliopathies (C5orf42, TMEM138, TMEM231 and WDPCP) to OFDS. Mutations were also detected in two genes previously implicated in OFDS. Functional studies revealed the involvement of centriole elongation, transition zone and intraflagellar transport defects in OFDS, thus characterising three ciliary protein modules: the complex KIAA0753-FOPNL-OFD1, a regulator of centriole elongation; the Meckel-Gruber syndrome module, a major component of the transition zone; and the CPLANE complex necessary for IFT-A assembly. OFDS now appear to be a distinct subgroup of ciliopathies with wide heterogeneity, which makes the initial classification obsolete. A clinical classification restricted to the three frequent/well-delineated subtypes could be proposed, and for patients who do not fit one of these three main subtypes, a further classification could be based on the genotype

De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits:report of 25 new individuals and review of the literature

TBR1, a T-box transcription factor expressed in the cerebral cortex, regulates the expression of several candidate genes for autism spectrum disorders (ASD). Although TBR1 has been reported as a high-confidence risk gene for ASD and intellectual disability (ID) in functional and clinical reports since 2011, TBR1 has only recently been recorded as a human disease gene in the OMIM database. Currently, the neurodevelopmental disorders and structural brain anomalies associated with TBR1 variants are not well characterized. Through international data sharing, we collected data from 25 unreported individuals and compared them with data from the literature. We evaluated structural brain anomalies in seven individuals by analysis of MRI images, and compared these with anomalies observed in TBR1 mutant mice. The phenotype included ID in all individuals, associated to autistic traits in 76% of them. No recognizable facial phenotype could be identified. MRI analysis revealed a reduction of the anterior commissure and suggested new features including dysplastic hippocampus and subtle neocortical dysgenesis. This report supports the role of TBR1 in ID associated with autistic traits and suggests new structural brain malformations in humans. We hope this work will help geneticists to interpret TBR1 variants and diagnose ASD probands

Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths

Publisher Copyright: © 2021 The Authors, some rights reserved.Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/ml; in plasma diluted 1:10) of IFN-alpha and/or IFN-omega are found in about 10% of patients with critical COVID-19 (coronavirus disease 2019) pneumonia but not in individuals with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-alpha and/or IFN-omega (100 pg/ml; in 1:10 dilutions of plasma) in 13.6% of 3595 patients with critical COVID-19, including 21% of 374 patients >80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1124 deceased patients (aged 20 days to 99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-beta. We also show, in a sample of 34,159 uninfected individuals from the general population, that auto-Abs neutralizing high concentrations of IFN-alpha and/or IFN-omega are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of individuals carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals 80 years. By contrast, auto-Abs neutralizing IFN-beta do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over 80s and total fatal COVID-19 cases.Peer reviewe

Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-alpha 2 in 10 patients: IFN-alpha 2 only in three, IFN-alpha 2 plus IFN-omega in five, and IFN-alpha 2, IFN-omega plus IFN-beta in two; IFN-omega only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-alpha 2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-omega in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-alpha 2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-. only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-omega and/or IFN-alpha 2