De 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... Show moreDe 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. Show less
Rural household travel patterns have been largely ignored in African transport studies. Over the past ten years, however, village-level surveys have been undertaken which reveal the preeminence of... Show moreRural household travel patterns have been largely ignored in African transport studies. Over the past ten years, however, village-level surveys have been undertaken which reveal the preeminence of female porterage in rural transport activities. Donor agencies are now focussing efforts on "appropriate" transport technology interventions to directly enhance rural mobility and to indirectly improve agricultural productivity. Preliminary evidence, however, suggests that men rather than women are the main benficiaries of appropriate transport technology. This paper asks why and suggests a number of methodological refinements to future rural transport studies to generate the necessary information for devising programmes with a higher likelihood of effective assistance to rural women transporters. The paper reviews the findings on rural household transport demand emanating from surveys and literature reviews in East and West Africa. Show less
