Genetic and phenotypic spectrum associated with IFIH1 gain-of-function

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi–Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate

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

The phenotypic spectrum of WWOX -related disorders: 20 additional cases of WOREE syndrome and review of the literature

Purpose: Germline WWOX pathogenic variants have been associated with disorder of sex differentiation (DSD), spinocerebellar ataxia (SCA), and WWOX-related epileptic encephalopathy (WOREE syndrome). We review clinical and molecular data on WWOX-related disorders, further describing WOREE syndrome and phenotype/genotype correlations. Methods: We report clinical and molecular findings in 20 additional patients from 18 unrelated families with WOREE syndrome and biallelic pathogenic variants in the WWOX gene. Different molecular screening approaches were used (quantitative polymerase chain reaction/multiplex ligation-dependent probe amplification [qPCR/MLPA], array comparative genomic hybridization [array-CGH], Sanger sequencing, epilepsy gene panel, exome sequencing). Results: Two copy-number variations (CNVs) or two single-nucleotide variations (SNVs) were found respectively in four and nine families, with compound heterozygosity for one SNV and one CNV in five families. Eight novel missense pathogenic variants have been described. By aggregating our patients with all cases reported in the literature, 37 patients from 27 families with WOREE syndrome are known. This review suggests WOREE syndrome is a very severe epileptic encephalopathy characterized by absence of language development and acquisition of walking, early-onset drug-resistant seizures, ophthalmological involvement, and a high likelihood of premature death. The most severe clinical presentation seems to be associated with null genotypes. Conclusion: Germline pathogenic variants in WWOX are clearly associated with a severe early-onset epileptic encephalopathy. We report here the largest cohort of individuals with WOREE syndrome

Effects of eight neuropsychiatric copy number variants on human brain structure

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions

The designation of humans - transparency and opacity

International audienceWe designate humans with nouns or pronouns. In this paper, I focus on nouns, both simple and complex, and will address the related issues of transparency and opacity, which, in the Saussurian terminology, correspond to ‘relative’ and ‘absolute’ arbitrariness (Saussure 1916: 180-184). (Opaque nouns, such as ‘man’ or ‘cousin’, are absolutely arbitrary in that there seems to be no reason for using those words rather than other ones. With transparent nouns, on the contrary, there seems to be a good reason to give a certain name to a certain entity). My first aim is to show that nouns which designate humans tend to be more opaque than those which name other entities, and that transparent constructions may take on specific shades of meaning when applied to humans. My hypothesis is that transparent designations do not readily designate people because reducing someone to one characteristic amounts to ignoring a human being’s essential complexity.I then compare nouns (in general) with other parts of speech, and, within the domain of word-formation, I also observe a higher degree of opacity for the first set. My hypothesis is that nouns, more than any other part of speech, must be opaque, because, perhaps better than any other part of speech, they categorize. How, indeed, can a category be named? One cannot name an item after the prototype of the category it belongs to (as the prototype does not represent all members), or with a characteristic shared by all members of the category (as in most cases there isn’t one). The only way is to resort to an arbitrary, and therefore opaque, sign.One may therefore draw a parallel between the grammatical category of nouns and the designation of humans, in that they are both characterized by opacity. In fact, humans encapsulate at least one ingredient of categorization, i.e. opacity (people have an identity: they are more than the sum of their acts). One may therefore tentatively see humans as the conceptual basis for categorisation, and for nouns – in as much nouns categorise

Le pronom personnel "one" dans "A Room of One's Own" de Virginia Woolf. Engagement ou désengagement ?

International audienceIn this paper we look at the uses of personal pronoun one in A Room of One’s Own by Virginia Woolf. We first describe the grammatical features of the pronoun as illustrated in the text, showing that one is sometimes difficult to classify when using traditional criteria such as generic vs. specific reference, definiteness vs. indefiniteness, deixis vs. anaphora, third person vs. first person. We then show that these characteristics are used in order to represent shifts from particular situations or individuals to more general ones. We conclude that the frequent use of this pronoun contributes to Virginia Woolf’s aesthetic project. The writer treats thoughts as phenomena, i.e. observable entities. More than that, thoughts are viewed as disconnected from their experiential basis and as autonomous, potentially belonging to anyone.Dans cet article nous examinons les emplois du pronom personnel one dans A Room of One’s Own de Virginia Woolf. Nous commençons par décrire les caractéristiques grammaticales de ce pronom telles qu’elles sont illustrées dans le texte, et montrons que one est difficile à classer selon les critères traditionnels (générique-spécifique, défini-indéfini, déixis-anaphore, troisième-première personnes). Nous montrons ensuite que ces caractéristiques sont exploitées par l’auteur afin de représenter des glissements, de situations particulières à des situations plus générales. Nous concluons que l’usage fréquent de ce pronom sert le projet esthétique de Virginia Woolf. L’auteur traite les pensées comme des phénomènes, c’est-à-dire des entités observables. Plus que cela, les pensées sont vues comme (fictivement) déconnectées de leur ancrage expérientiel, autonomes, et appartenant potentiellement à tout le monde

Integrated relative clauses with indefinite antecedents : sub-categorization or joint categorization

Version publiable disponible pour téléchargementhttps://www.cairn.info/revue-etudes-anglaises-2015-3-page-316.htmInternational audienceNous nous penchons sur les propositions relatives restrictives (ou « intégrées ») à antécédent indéfini. Parmi celles-ci nous faisons une différence entre relatives serrées et lâches, et montrons qu'elles reflètent toutes deux un processus cognitif de catégorisation ad hoc. Les deux types diffèrent cependant, ce qui révèle finalement que la catégorisation n'est pas un processus unique mais peut au contraire se réaliser de plusieurs façons.We look at integrated relative clauses with indefinite antecedents. Amongst them we make a distinction between tight and loose relatives, and show that they both signal a cognitive process of ad hoc categorization. However there are differences between the two types, which ultimately reveal that categorization is not one but may be achieved through different means

Noms d’animés humains et opacité : le cas des conversions verbe - nom en anglais

International audienceThis paper is part of a broader investigation into how we designate humans. We suggest that nouns that designate humans tend to be more opaque than those which designate other entities. We hypothesise that this is linked to the way we conceptualise humans, i.e. as being more than the sum of their acts. In this paper we look more specifically into verb to noun conversions in English. First, we note that these are, within the domain of word-formation, very transparent, insofar as the base is not modified in any way. Then we observe that few designate humans; it seems that denoting a human on the ground of his or her participation in a process would amount to ignoring that person’s essential complexity. Lastly, we look at the few cases of conversion which do designate humans, in order to try and understand what makes this possible; we show that they tend to be derogatory or to reflect a personal relationship with the referent. Transparency then appears as a means to convey this personal relationship: the designations appear to be individual, rather than conventional

Pragmatic and stylistic uses of personal pronoun "one"

International audienceIn this paper we investigate the uses of personal pronoun one. Our study is based on 604 occurrences of personal pronoun one; 263 of those were extracted from the British National Corpus and the rest from other sources.First of all we discuss the inclusion of one in the category of personal pronouns, and describe its characteristics, i.e. its various meanings and the theoretical issues raised by its description. We then try to identify the factors that trigger the occurrence of one rather than another pronoun. We observe that one appears in hypothetical contexts, that it regularly co-occurs with modal auxiliaries and “thinking” verbs, and that generally speaking it involves a typical scenario (a ‘script’) where change is involved (most often, but not exclusively, a change in someone’s belief, or opinion). We propose that this is linked to the origin of the personal pronoun, which is related to the numeral one. We hypothesize that at some abstract level the notion of ‘unity’ is retained; the more a person undergoes change, the more we need to denote, somehow, his or her unity (the person is the same, despite the changes)

Anglais et langue inclusive – multiplication des marques ou neutralisation ?

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