Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome

SPTBN1 mutations cause a neurodevelopmental syndrome characterized by intellectual disability, language and motor delays, autism, seizures and other features. The variants disrupt beta II-spectrin function and disturb cytoskeletal organization and dynamics. SPTBN1 encodes beta II-spectrin, the ubiquitously expressed beta-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal beta II-spectrin have defects in cortical organization, developmental delay and behavioral deficiencies. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous SPTBN1 variants may also show measurable compromise of neural development and function. Here we identify heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays;mild to severe intellectual disability;autistic features;seizures;behavioral and movement abnormalities;hypotonia;and variable dysmorphic facial features. We show that these SPTBN1 variants lead to effects that affect beta II-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics. Our studies define SPTBN1 variants as the genetic basis of a neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and underscore the critical role of beta II-spectrin in the central nervous system

Déplacement(s) comme méthode(s)

Displacement is a paradigm I use to describe the ways in which I organize myself and invite others to reposition themselves while being in constant movement in and between contexts that are also in perpetual motion. Move and be moved, displace and be displaced are principles that (i) imply constant readings of contexts, the creation of appropriate situations, or/and informed uses of existing situations; and (ii) call for attitudes of presence, distanciation, and (re-)positioning. Five methods and three practices came out of the time dedicated to search and research within my PhD project. My thesis, titled “Displacement(s) as Method(s)”, is a matrix of several formats (such as letter, catalogue, conversation) and media (text, film, etc.), which I used to filter my works, methods, practices, and tools. Within this matrix, one can choose one’s own journey and process, and the time one wants to dedicate to and invest in it – from a few minutes to several hours. The reader is invited to dive into a work that has its own reality, temporality, and space. Each notion, positioning, format, and work is a fragment of the research I have processed over the last four years. These diverging and overlapping elements and components are numerous and multiple; they nourish and densify my proposition of an articulation.Déplacement est un paradigme qui permet de décrire les procédés que j’utilise pour m’organiser en tant qu’individu, artiste et chercheur. Mon processus se fait en mouvement constant que ce soit dans un contexte particulier ou entre différents contextes, aussi en perpétuel mouvements. Bouger et être bougé, déplacer et être déplacé sont des procédés qui impliquent une lecture ininterrompue des contextes, la création de situations appropriées, et/ ou une utilisation réfléchie de situations existantes. Cela appelle des attitudes de présence, de distanciation et de (re-)positionnement. Cinq méthodes et trois pratiques sont nées du temps consacré à cette recherche développée dans le cadre d’un doctorat. Celles-ci sont proposées, partagées afin d’inviter le lecteur à un jeu de perception(s) et de positionnement(s) en vue d’un déplacement. Ma thèse intitulée “Displacement(s) as Method(s)”, est une matrice constituée de plusieurs formats (lettre, catalogue, conversation) et médias (texte, film, etc.) dont l’objectif est d’analyser mes œuvres, méthodes, pratiques et outils. Il est possible d’y circuler à son gré, de suivre le processus de son choix et de consacrer un temps qui peut aller de quelques minutes à plusieurs heures. Le lecteur est invité à plonger dans un travail qui a ses propres réalités, temporalités et espaces. Chaque notion, chaque positionnement, chaque format et chaque proposition artistique sont des fragments d’une recherche développée et mise en pratique pendant quatre années. Les multiples éléments de cette recherche entraînent des divergences et des superpositions qui densifient ma proposition d’articulation

Dansbaren : The Mob Without Flash

"Dansbaren — The Mob without Flash is a printed object consisting of two parts: a book dedicated to critical thinking in the field of dance and choreography and a tablecloth of topics. It is a tool for continuing dialogues, putting dance discourse, literally, on the table. In both a local and international context Dansbaren, a series of public talks and discussions initiated by Gothenburg artist-run platform Dansbyrån, has been uniting dance theory with practice for 15 years. This publication re-activates Dansbaren’s central topics: dialogue formats, power relations, aesthetics, self-organization, sharing knowledge, appropriating language, artistic practice, history making and feedback methods." -- Project's website

Not Now! Now! : Chronopolitics, Art & Research

"Not Now! Now! engages with the politics of time in art: historical narratives and memory, the unforeseen rhythms of time, and the challenge of visualizing time. The book connects the postcolonial and queer debate around chronopolitics with artistic strategies that introduce breaks, stutter time, use citations and anachronisms, and introduce deferrals and collapses between time and meaning. [...]" -- Publisher's website

Stankiewicz-Isidor syndrome: expanding the clinical and molecular phenotype

Purpose: Haploinsufficiency of PSMD12 has been reported in individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), facial dysmorphism, and congenital malformations, defined as Stankiewicz-Isidor syndrome (STISS). Investigations showed that pathogenic variants in PSMD12 perturb intracellular protein homeostasis. Our objective was to further explore the clinical and molecular phenotypic spectrum of STISS. Methods: We report 24 additional unrelated patients with STISS with various truncating single nucleotide variants or copy-number variant deletions involving PSMD12. We explore disease etiology by assessing patient cells and CRISPR/Cas9-engineered cell clones for various cellular pathways and inflammatory status. Results: The expressivity of most clinical features in STISS is highly variable. In addition to previously reported DD/ID, speech delay, cardiac and renal anomalies, we also confirmed preaxial hand abnormalities as a feature of this syndrome. Of note, 2 patients also showed chilblains resembling signs observed in interferonopathy. Remarkably, our data show that STISS patient cells exhibit a profound remodeling of the mTORC1 and mitophagy pathways with an induction of type I interferon-stimulated genes. Conclusion: We refine the phenotype of STISS and show that it can be clinically recognizable and biochemically diagnosed by a type I interferon gene signature

KAT6A Syndrome:genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants

Purpose Pathogenic variants in KAT6A have recently been identified as a cause of syndromic developmental delay. Within 2 years, the number of patients identified with pathogenic KAT6A variants has rapidly expanded and the full extent and variability of the clinical phenotype has not been reported. Methods We obtained data for patients with KAT6A pathogenic variants through three sources: treating clinicians, an online family survey distributed through social media, and a literature review. Results We identified 52 unreported cases, bringing the total number of published cases to 76. Our results expand the genotypic spectrum of pathogenic variants to include missense and splicing mutations. We functionally validated a pathogenic splice-site variant and identified a likely hotspot location for de novo missense variants. The majority of clinical features in KAT6A syndrome have highly variable penetrance. For core features such as intellectual disability, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications, genotype– phenotype correlations show that late-truncating pathogenic variants (exons 16–17) are significantly more prevalent. We highlight novel associations, including an increased risk of gastrointestinal obstruction. Conclusion Our data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management

KAT6A Syndrome: genotype–phenotype correlation in 76 patients with pathogenic KAT6A variants

PurposePathogenic variants in KAT6A have recently been identified as a cause of syndromic developmental delay. Within 2 years, the number of patients identified with pathogenic KAT6A variants has rapidly expanded and the full extent and variability of the clinical phenotype has not been reported.MethodsWe obtained data for patients with KAT6A pathogenic variants through three sources: treating clinicians, an online family survey distributed through social media, and a literature review.ResultsWe identified 52 unreported cases, bringing the total number of published cases to 76. Our results expand the genotypic spectrum of pathogenic variants to include missense and splicing mutations. We functionally validated a pathogenic splice-site variant and identified a likely hotspot location for de novo missense variants. The majority of clinical features in KAT6A syndrome have highly variable penetrance. For core features such as intellectual disability, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications, genotype- phenotype correlations show that late-truncating pathogenic variants (exons 16-17) are significantly more prevalent. We highlight novel associations, including an increased risk of gastrointestinal obstruction.ConclusionOur data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management

Correction:KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants

An amendment to this paper has been published and can be accessed via a link at the top of the paper