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

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities

Metal organic vapor phase epitaxy of hexagonal Ge–Sb–Te (GST)

Epitaxial, hexagonal Ge–Sb–Te was grown on Si(111)Si(111) substrates by Metal Organic Vapor Phase Epitaxy (MOVPE) using the precursor digermane. The effect of reactor pressure, growth temperature and in situ pre-treatment on morphology and Ge–Sb–Te composition was studied. The composition is sensitive to reactor pressure and growth temperature. Compositional control is achieved at a reactor pressure of View the MathML source50hPa. Substrate pre-treatment affects film coalescence. The use of hydrogen and a suitable precursor pre-treatment leads to enhanced surface coverage. X-ray diffraction reveals a trigonal structure with lattice parameters close to that reported for Ge1Sb2Te4Ge1Sb2Te4 crystallizing in the View the MathML sourceR3¯m phase. The composition was confirmed by energy-dispersive X-ray spectroscopy

Modern chemical synthesis methods towards low-dimensional phase change structures in the Ge–Sb–Te material system

This report centers on different modern chemical synthesis methods suitable for production with which low-dimensional crystalline structures are attainable in the Ge–Sb–Te material system. The general characteristics of the methods are described first. The special challenges are discussed for the Ge–Sb–Te material system. Growth optimization is studied, and the resulting nanostructures are presented. At last a comparison of the methods is given with respect to research scale vapor transport approach on the one hand and the potential described for future application in technology on the other hand

Evaluation of Internal Slab Quality by an Advanced Ultrasonic Testing System

Thyssenkrupp Steel Europe AG at Duisburg, Germany performs comprehensive efforts to improve slab quality. According to the current state of the art, the internal quality of slabs could only be determined by extensive destructive and time-consuming slab sampling. ln collaboration with the Fraunhofer Institute for NondestructiveTesting IZFP, Saarbrücken, a new tomographic ultrasonic system was developed and set in service for evaluating the internal slab quality in situ in the process chain. The new ultrasonic slab testing system is able to inspect the complete slab by providing cross-section images, which allow quantifying the internal homogeneity. To perform an inspection a mobile unit is placed on the slab surface at the slab yards. The system automatically scans the slab over its whole length, acquires ultrasonic data, performs reconstruction and presents images. For an intuitive evaluation directly after measurement, cracks and segregation porosity can be visualized in situ without destroying the examined slab or taking samples. For comparison of testing results and quality management, a new classification standard for scoring the slab quality was developed. With the new device, real time testing of internal slab quality can be performed, which enables adjusting the casting machine and slab handling parameters quickly after production

Chemical vapour deposition of chalcogenide phase change materials using digermane

The use of digermane (Ge2H6) as a Ge-source was investigated for the low temperature metal organic chemical vapour deposition (MOCVD) of GexSbyTez (GST) films. Strong influence of the reactor pressure and growth temperature on the film morphology was observed by SEM and AFM imaging. The incorporation of Ge into the GST crystalline structure was proven using Raman scattering and XPS measurements

Metal organic chemical vapor deposition of GexSbyTez layers grown by using digermane

GexSbyTez (GST) films grown on Si(111) substrates by epitaxy tend to be polycrystalline and therefore rough. Especially the incorporation of Germanium in the films is problematic. Thin and smooth film surfaces are however a prerequisite for memory applications. In the past we demonstrated that the metal organic chemical vapor deposition (MOCVD) growth of highly mismatched III/V materials such as InAs/GaAs can be accomplished conformally, if a low temperature growth process is used. This knowledge is transferred to MOCVD growth of GST. To this end as a Ge precursor digermane was employed which is expected to decompose at low temperatures. Commercial sources for Sb (triethylanthimony) and Te (diethyltellur) were chosen, which are suitable for low temperature deposition. At first the growth of Sb2Te3 layers was optimized. Than digermane was added to the growth process. Growth was evaluated by SEM, XRD and Raman measurements. It was found that GST can be deposited at the same conditions as Sb2Te3. SEM pictures show well coalesced, trigonal crystalline structures and XRD measurements verify the integration of Ge. The influence of growth parameters on layer growth will be presented