Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP

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 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.This work was supported by grants from the European Research Area Networks Network of European Funding for Neuroscience Research through the Research Foundation–Flanders and the Chief Scientist Office–Ministry of Health (to RFK, GV, IG). This research was supported, in part, by grants from the Simons Foundation Autism Research Initiative (Grant No. SFARI 303241 to EEE) and National Institutes of Health (Grant No. R01MH101221 to EEE). This work was also supported by the Italian Ministry of Health and ‘5 per mille’ funding (to CR). For many individuals, sequencing was provided by research initiatives like the Care4Rare Research Consortium in Canada or the Deciphering Developmental Disorders (DDD) study in the UK. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (Grant No. HICF-1009–003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (Grant No. WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South Research Ethics Committee, and GEN/284/12 granted by the Republic of Ireland Research Ethics Committee). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network

Subsurface Sediment Mobilization in the southern Chryse Planitia on Mars

Ever since the presence of methane in the Martian atmosphere was reported from ground‐based, orbital, and in situ observations, mud volcanism was hypothesized to be a possible release mechanism, and various mud volcano fields have been tentatively identified. Although morphological similarities with Earth sedimentary volcanism have been proposed (e.g., Skinner & Mazzini, 2009, https://doi.org/10.1016/j.marpetgeo.2009.02.006), it is difficult, however, to prove unambiguously the presence of mud volcanism in remote sensing data, and some of the reported mud volcanoes have alternatively been interpreted as igneous volcanoes. A definitive identification of sedimentary volcanoes on Mars is therefore still problematic. A useful candidate area to test the hypothesis of sedimentary volcanism on Mars is a field of kilometer‐sized cone‐ and pie‐like landforms in the southern part of the large ancient Chryse impact basin, part of which was previously studied by Komatsu et al. (2016, https://doi.org/10.1016/j.icarus.2015.12.032). In this study, we searched for those landforms inside Chryse Planitia and determined their full spatial extent. We found that they can be divided into five morphologically different groups and that they occur exclusively on the level sedimentary plains. These findings enable us providing additional evidence to support the hypothesis of subsurface sediment mobilization as a possible mechanism for their formation