Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

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

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Finite-size scaling of complex magnetic materials near the phase transition

Nano-technologies such as heat-assisted magnetic recording, magnetic particle hyperthermia and skyrmion racetrack memory have been developing rapidly in recent years. However, there have been a number of issues relating to the finite-size of materials relevant to prospective nano-technologies. FePt is the leading candidate material in the development of heat-assisted magnetic recording. In recent years, there have been conflicting reports of the phase transition behaviour and critical exponents of FePt which have been attributed to its complex, long-ranged internal interactions. This thesis identifies anisotropy as the cause of the inconsistent measurements of the critical exponents, and introduces a two-dimensional finite-size scaling framework which is capable of overcoming the anisotropic interactions of FePt. Using this new technique, the critical exponents of FePt are shown to be those of the Heisenberg model. Granular technologies, such as heat-assisted magnetic recording and magnetic particle hyperthermia, have been shown to have a distribution of Curie temperatures. Identifying the Curie temperature distribution is an important step in accelerating the development of granular technologies which operate across the magnetic phase transition. This thesis presents a new characterisation technique which can be used to identify the parameters of the Curie temperature distribution. This technique only requires measurements of the temperature dependent magnetisation, realisable from standard magnetometry. Other materials, such as MnSi and FeGe, are being targeted towards applications such as skyrmion racetrack memory. The internal magnetisation of these helimagnetic materials has a tendency to twist, forming complex topological structures known as skyrmions. The finite-size effects of such materials is little understood and work is needed to quantify them. This thesis presents a qualitative exploration of the finite-size effects of helimagnetic materials. We demonstrate that both finite-size and choice of experimental protocol can significantly impact on the extent of the skyrmion phase. This thesis also identifies the critical exponents of the Dzyaloshinskii-Moriya interaction by using finitesize scaling. This is a key step towards proper finite-size scaling of general helimagnetic materials in the future

2D Ising Model MC Data

Dataset supporting: Waters, J. M. et al (2017). Identification of Curie temperature distributions in magnetic particulate systems. Journal Of Physics D. Results of Monte Carlo simulations of the 2D Ising model using disordered grains. Subfolders are labelled according to the size or distribution of sizes that are modelled, within those folders are the samples at different temperatures. The first column is magnetisation, the second is energy, the third is number of total spins.</span

Skyrmion MC Data

Magnetisation, energy, skyrmion number and spin alignment measurements from Monte Carlo simulations of a disctetised skyrmion model. Files are in HDF5 format with tables containing the raw data. This dataset supports the thesis &quot;Finite-Size Scaling of Complex Materials Near the Phase Transition&quot; by Jonathon Waters This dataset can be requested via http://library.soton.ac.uk/datarequest&rsquo; </span

FePt MC Data

Dataset supporting: Waters, J. M. et. al. (2019). Resolving Anomalies in the Critical Exponents of FePt Using Finite-Size Scaling in Magnetic Fields. Physical Review Applied. Results of Monte Carlo simulations of FePt grains. Files are in HDF5 format with tables containing the raw data. Zero field and field data is included, with grain radii at 2.1nm, 3nm and 3.9nm.</span