The clinical and molecular spectrum of the KDM6B-related neurodevelopmental disorder

International audienceDe novo variants are a leading cause of neurodevelopmental disorders (NDDs), but because every monogenic NDD is different and usually extremely rare, it remains a major challenge to understand the complete phenotype and genotype spectrum of any morbid gene. According to OMIM, heterozygous variants in KDM6B cause "neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities." Here, by examining the molecular and clinical spectrum of 85 reported individuals with mostly de novo (likely) pathogenic KDM6B variants, we demonstrate that this description is inaccurate and potentially misleading. Cognitive deficits are seen consistently in all individuals, but the overall phenotype is highly variable. Notably, coarse facies and distal skeletal anomalies, as defined by OMIM, are rare in this expanded cohort while other features are unexpectedly common (e.g., hypotonia, psychosis, etc.). Using 3D protein structure analysis and an innovative dual Drosophila gain-of-function assay, we demonstrated a disruptive effect of 11 missense/in-frame indels located in or near the enzymatic JmJC or Zn-containing domain of KDM6B. Consistent with the role of KDM6B in human cognition, we demonstrated a role for the Drosophila KDM6B ortholog in memory and behavior. Taken together, we accurately define the broad clinical spectrum of the KDM6B-related NDD, introduce an innovative functional testing paradigm for the assessment of KDM6B variants, and demonstrate a conserved role for KDM6B in cognition and behavior. Our study demonstrates the critical importance of international collaboration, sharing of clinical data, and rigorous functional analysis of genetic variants to ensure correct disease diagnosis for rare disorders

The Transformation of Social Institutions in the North American Southeast

Corporate institutions, which transformed in the American Southeast over some 14,000 years, include social heterarchies and hierarchies that arose within the institutional contexts of descent groups, ritual sodalities, and social houses. The strategic and tactical actions of competitive and cooperative agents contributed to differing expressions of organizational changes through a variety of forms, including feasting, feuding/warfare, inalienable goods circulation, indebtedness, monumental constructions, mortuary events, processions/rogations, strategic marriages, and additional ritual and social practices. The nexus of social institutions that evolved along these pathways served as a catalyst for social changes, including the ways through which social institutions became transformed. Such social processes inform archaeologists of the agency, organization, and practice of people who not only invented and manipulated cosmologies, ideologies, institutions, and resources to achieve varying degrees of inequality, power, and wealth, but also those who resisted the efforts of aggrandizers. The author’s arguments focus on aristocratic social actions and actors, and the practices that enabled them to gain power and wealth through exclusive and restrictive corporate institutions