Quelles sont les variations asymptomatiques crâniennes, post-crâniennes et dentaires effectivement répétables et reproductibles, dans le cadre d’un échantillon bioarchéologique ?

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Proposition d’une démarche commune pour la sélection de variations asymptomatiques osseuses et dentaires répétables et reproductibles en anthropologie biologique

International audienceAsymptomatic variations (AV) in bones and teeth are widely used in biological anthropology, particularly to understand intra- and inter-population affinities.This study focuses on the first step of any study: the repeatability and reproducibility of the method implemented. Using the Kappa coefficient, the reliability of 198 variables divided into three anatomical areas (cranial, post-cranial and teeth) was analyzed. The sample used was selected among the best represented and best preserved individuals of the Notre-Dame-du-Bourg osteo-archaeological collection (Digne-les-Bains, medieval and modern period). The analyses were performed after four rounds of scoring (three observers), and when more than 20 observations of polymorphic variations were obtained. The quality of agreement was established according to the Fleiss et al. scale (2003). Although missing data were a hindrance in this study, several proposals were made to overcome the problem. We also highlight and discuss the fact that experience has an impact on the observation of qualitative variables. The outcome is a proposal for a protocol based on selecting repeatable and reproducible AVs to normalize comparisons between studies in both osteoarchaeological and forensic contexts.Les variations asymptomatiques (VA) osseuses et dentaires sont grandement utilisées en anthropologie biologique, notamment pour appréhender les affinités intra- et inter-populationnelles. Cette étude se concentre sur la première étape de toute étude : la répétabilité et la reproductibilité de la méthode mise en place. À partir de l’utilisation du coefficient de Kappa la fiabilité de 198 variables réparties en trois zones anatomiques (crâne, post-crâne et dents) a été analysée. L’échantillon utilisé a été sélectionné parmi les individus les mieux représentés et conservés de la collection ostéo-archéologique Notre-Dame-du-Bourg (Digne-les-Bains, périodes médiévale et moderne). Les analyses ont été réalisées, suite à quatre séries de cotations (trois observatrices), et lorsque plus de 20 observations sur des variables polymorphiques ont été obtenues. La qualité de l’accord a été établie selon l’échelle de Fleiss et al. (2003). Bien que les données manquantes aient été un frein dans cette étude, plusieurs propositions sont faites afin de palier ce phénomène. De plus, nous mettons en avant et discutons le fait que l’expérience a un impact sur l’observation des variables qualitatives. Au final, un protocole basé sur la sélection de VA répétables et reproductibles est proposé pour normaliser les comparaisons entre études dans un contexte aussi bien bioarchéologique que médico-légal

Mini-Exome Coupled to Read-Depth Based Copy Number Variation Analysis in Patients with Inherited Ataxias

International audienceNext-generation sequencing (NGS) has an established diagnostic value for inherited ataxia. However, the need of a rigorous process of analysis and validation remains challenging. Moreover, copy number variations (CNV) or dynamic expansions of repeated sequence are classically considered not adequately detected by exome sequencing technique. We applied a strategy of mini-exome coupled to read-depth based CNV analysis to a series of 33 patients with probable inherited ataxia and onset <50 years. The mini-exome consisted of the capture of 4,813 genes having associated clinical phenotypes. Pathogenic variants were found in 42% and variants of uncertain significance in 24% of the patients. These results are comparable to those from whole exome sequencing and better than previous targeted NGS studies. CNV and dynamic expansions of repeated CAG sequence were identified in three patients. We identified both atypical presentation of known ataxia genes (ATM, NPC1) and mutations in genes very rarely associated with ataxia (ERCC4, HSD17B4). We show that mini-exome bioinformatics data analysis allows the identification of CNV and dynamic expansions of repeated sequence. Our study confirms the diagnostic value of the proposed genetic analysis strategy. We also provide an algorithm for the multidisciplinary process of analysis, interpretation, and validation of NGS data

GnRH replacement rescues cognition in Down syndrome

At the present time, no viable treatment exists for cognitive and olfactory deficits in Down syndrome (DS). We show in a DS model (Ts65Dn mice) that these progressive nonreproductive neurological symptoms closely parallel a postpubertal decrease in hypothalamic as well as extrahypothalamic expression of a master molecule that controls reproduction—gonadotropin-releasing hormone (GnRH)—and appear related to an imbalance in a microRNA-gene network known to regulate GnRH neuron maturation together with altered hippocampal synaptic transmission. Epigenetic, cellular, chemogenetic, and pharmacological interventions that restore physiological GnRH levels abolish olfactory and cognitive defects in Ts65Dn mice, whereas pulsatile GnRH therapy improves cognition and brain connectivity in adult DS patients. GnRH thus plays a crucial role in olfaction and cognition, and pulsatile GnRH therapy holds promise to improve cognitive deficits in DS.</p

Episignatures in practice: independent evaluation of published episignatures for the molecular diagnostics of ten neurodevelopmental disorders

Variants of uncertain significance (VUS) are a significant issue for the molecular diagnosis of rare diseases. The publication of episignatures as effective biomarkers of certain Mendelian neurodevelopmental disorders has raised hopes to help classify VUS. However, prediction abilities of most published episignatures have not been independently investigated yet, which is a prerequisite for an informed and rigorous use in a diagnostic setting. We generated DNA methylation data from 101 carriers of (likely) pathogenic variants in ten different genes, 57 VUS carriers, and 25 healthy controls. Combining published episignature information and new validation data with a k-nearest-neighbour classifier within a leave-one-out scheme, we provide unbiased specificity and sensitivity estimates for each of the signatures. Our procedure reached 100% specificity, but the sensitivities unexpectedly spanned a very large spectrum. While ATRX, DNMT3A, KMT2D , and NSD1 signatures displayed a 100% sensitivity, CREBBP-RSTS and one of the CHD8 signatures reached <40% sensitivity on our dataset. Remaining Cornelia de Lange syndrome, KMT2A , KDM5C and CHD7 signatures reached 70–100% sensitivity at best with unstable performances, suffering from heterogeneous methylation profiles among cases and rare discordant samples. Our results call for cautiousness and demonstrate that episignatures do not perform equally well. Some signatures are ready for confident use in a diagnostic setting. Yet, it is imperative to characterise the actual validity perimeter and interpretation of each episignature with the help of larger validation sample sizes and in a broader set of episignatures