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
BACKGROUND: In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP... Show moreBACKGROUND: In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking.METHODS: We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires.RESULTS: We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected.CONCLUSIONS: This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype. Show less
Windhorst, R.; Alpaslan, M.; Andrews, S.; Ashcraft, T.; Broadhurst, T.; Coe, D.; ... ; Zitrin, A. 2019
In this work, we analyze the mass distribution of MACSJ1206.2-0847, particularly focusing on the halo properties of its cluster members. The cluster appears relaxed in its X-ray emission, but has... Show moreIn this work, we analyze the mass distribution of MACSJ1206.2-0847, particularly focusing on the halo properties of its cluster members. The cluster appears relaxed in its X-ray emission, but has a significant amount of intracluster light that is not centrally concentrated, suggesting that galaxy-scale interactions are still ongoing despite the overall relaxed state. The cluster lenses 12 background galaxies into multiple images and one galaxy at z = 1.033 into a giant arc and its counterimage. The multiple image positions and the surface brightness (SFB) distribution of the arc, which is bent around several cluster members, are sensitive to the cluster galaxy halo properties. We model the cluster mass distribution with a Navarro-Frenk-White profile and the galaxy halos with two parameters for the mass normalization and the extent of a reference halo assuming scalings with their observed near-infrared light. We match the multiple image positions at an rms level of 0.''85 and can reconstruct the SFB distribution of the arc in several filters to a remarkable accuracy based on this cluster model. The length scale where the enclosed galaxy halo mass is best constrained is about 5 effective radii{mdash}a scale in between those accessible to dynamical and field strong-lensing mass estimates on the one hand and galaxy-galaxy weak-lensing results on the other hand. The velocity dispersion and halo size of a galaxy with m $_{160W, AB}$ = 19.2 and M $_{B, Vega}$ = -20.7 are {$σ$} = 150 km s$^{-1}$ and r {ap} 26 {plusmn} 6 kpc, respectively, indicating that the halos of the cluster galaxies are tidally stripped. We also reconstruct the unlensed source, which is smaller by a factor of ~{}5.8 in area, demonstrating the increase in morphological information due to lensing. We conclude that this galaxy likely has star-forming spiral arms with a red (older) central component. Show less
