Feature-expression heat maps – A new visual method to explore complex associations between two variable sets

AbstractIntroductionExisting methods such as correlation plots and cluster heat maps are insufficient in the visual exploration of multiple associations between genetics and phenotype, which is of importance to achieve a better understanding of the pathophysiology of psychiatric and other illnesses. The implementation of a combined presentation of effect size and statistical significance in a graphical method, added to the ordering of the variables based on the effect-ordered data display principle was deemed useful by the authors to facilitate in the process of recognizing meaningful patterns in these associations.Materials and methodsThe requirements, analyses and graphical presentation of the feature-expression heat map are described. The graphs display associations of two sets of ordered variables where a one-way direction is assumed. The associations are depicted as circles representing a combination of effect size (color) and statistical significance (radius).ResultsAn example dataset is presented and relation to other methods, limitations, areas of application and possible future enhancements are discussed.ConclusionThe feature-expression heat map is a useful graphical instrument to explore associations in complex biological systems where one-way direction is assumed, such as genotype-phenotype pathophysiological models

Distillation: Revisiting some rules of thumb

Chemical Engineering111950-55CHEE

Suppression of nitridation-induced interface traps and hole mobility degradation by nitrogen plasma nitridation

10.1149/1.1459682Electrochemical and Solid-State Letters54G26-G28ESLE

Impact of decoupled plasma nitridation of ultra-thin gate oxide on the performance of p-channel MOSFETs

10.1088/0268-1242/17/6/101Semiconductor Science and Technology176L25-L28SSTE

Expanding the phenotype of GMPPB mutations

Dystroglycanopathies are a heterogeneous group of diseases with a broad phenotypic spectrum ranging from severe disorders with congenital muscle weakness, eye and brain structural abnormalities and intellectual delay to adult-onset limb-girdle muscular dystrophies without mental retardation. Most frequently the disease onset is congenital or during childhood. The exception is FKRP mutations, in which adult onset is a common presentation. Here we report eight patients from five non-consanguineous families where next generation sequencing identified mutations in the GMPPB gene. Six patients presented as an adult or adolescent-onset limb-girdle muscular dystrophy, one presented with isolated episodes of rhabdomyolysis, and one as a congenital muscular dystrophy. This report expands the phenotypic spectrum of GMPPB mutations to include limb-girdle muscular dystrophies with adult onset with or without intellectual disability, or isolated rhabdomyolysis

G.P.219: Diagnosing the limb-girdle muscular dystrophies using whole exome sequencing: An Australian cohort

Limb-girdle muscular dystrophies (LGMDs) are a heterogeneous group of genetic disorders associated with proximal muscle weakness that begins after 2 years of age and dystrophic changes on muscle biopsy. The genetic cause of LGMD in Australia remains uncertain in approximately 40% of patients resulting in uncertainty about reproductive risks for patients and long term prognosis. We reviewed the clinical information in a large cohort of patients with LGMD who lacked a genetic diagnosis, usually after extensive previous investigations (n = 50). We first screened patients for myotonic dystrophy type 2 and then performed whole exome sequencing (WES), analysing data using the ‘xBrowse’ web interface (Broad Institute). Testing for myotonic dystrophy type 2 (DM2) identified 2 families in our LGMD cohort. Using WES we identified likely pathogenic mutations in known myopathy genes in 20 families, often in genes not typically associated with LGMD. Two families were diagnosed with dominant LGMD, 9 families with recessive LGMD, 3 with mutations congenital muscular dystrophy genes, 3 with collagen myopathies, 2 with metabolic myopathies and 1 in ACTA1. In addition one family had a mutation CHD7, a gene usually associated with CHARGE syndrome. Our overall diagnostic success rate was 46% in our LGMD cohort of patients most of whom had been extensively investigated previously and who remained without a genetic diagnosis. The diversity of genetic causes that we identified supports the clinical observation of that LGMD is highly heterogeneous and shares clinical features with many other forms of myopathy. Our study emphasises the challenges that clinicians face making a genetic diagnosis in all families. Whole exome sequencing and similar next-generation sequencing are likely to be efficient and cost-effective methods for identifying the genetic basis of LGMD but clinicians must remember that some disorders in the differential diagnosis, such as DM2, are routinely missed by WES

Neuroinflammation in bipolar disorder:A [C-11]-(R)-PK11195 positron emission tomography study

Background: The "monocyte-T-cell theory of mood disorders" regards neuroinflammation, i.e. marked activation of microglia, as a driving force in bipolar disorder. Microglia activation can be visualized in vivo using [C-11]-(R)-PK11195 PET. Indirect evidence suggests the hippocampus as a potential focus of neuroinflammation in bipolar disorder. We aim to determine if there is increased [C-11]-(R)-PK11195binding to activated microglia in the hippocampus of patients with bipolar I disorder when compared to healthy controls. Material and methods: Fourteen patients with bipolar I disorder and eleven healthy controls were included in the analyses. Dynamic 60-min PET scans were acquired after the injection of [C-11]-(R)-PK11195. All subjects underwent psychiatric interviews as well as an MRI scan, which was used for anatomic co-registration in the data analysis. The data from the PET scans was analyzed with a twotissue-compartment model to calculate the binding potential, using the metabolite-corrected plasma and blood curve as input. : A significantly increased [C-11]-(R)-PK11195 binding potential, which is indicative of neuroinflammation, was found in the right hippocampus of the patients when compared to the healthy controls (1.66 (CI 1.45-1.91) versus 1.33 (Cl 1.16-1.53); p = 0.033, respectively). Although the same trend was observed in the left hippocampus, this difference was not statistically significant. Conclusion: This study is the first to demonstrate the presence of focal neuroinflammation in the right hippocampus in bipolar I disorder. (C) 2014 Elsevier Inc. All rights reserved

Use of whole-exome sequencing for diagnosis of Limb-Girdle muscular dystrophy

Importance To our knowledge, the efficacy of transferring next-generation sequencing from a research setting to neuromuscular clinics has never been evaluated. Objective To translate whole-exome sequencing (WES) to clinical practice for the genetic diagnosis of a large cohort of patients with limb-girdle muscular dystrophy (LGMD) for whom protein-based analyses and targeted Sanger sequencing failed to identify the genetic cause of their disorder. Design, Setting, and Participants We performed WES on 60 families with LGMDs (100 exomes). Data analysis was performed between January 6 and December 19, 2014, using the xBrowse bioinformatics interface (Broad Institute). Patients with LGMD were ascertained retrospectively through the Institute for Neuroscience and Muscle Research Biospecimen Bank between 2006 and 2014. Enrolled patients had been extensively investigated via protein studies and candidate gene sequencing and remained undiagnosed. Patients presented with more than 2 years of muscle weakness and with dystrophic or myopathic changes present in muscle biopsy specimens. Main Outcomes and Measures The diagnostic rate of LGMD in Australia and the relative frequencies of the different LGMD subtypes. Our central goals were to improve the genetic diagnosis of LGMD, investigate whether the WES platform provides adequate coverage of known LGMD-related genes, and identify new LGMD-related genes. Results With WES, we identified likely pathogenic mutations in known myopathy genes for 27 of 60 families. Twelve families had mutations in known LGMD-related genes. However, 15 families had variants in disease-related genes not typically associated with LGMD, highlighting the clinical overlap between LGMD and other myopathies. Common causes of phenotypic overlap were due to mutations in congenital muscular dystrophy–related genes (4 families) and collagen myopathy–related genes (4 families). Less common myopathies included metabolic myopathy (2 families), congenital myasthenic syndrome (DOK7), congenital myopathy (ACTA1), tubular aggregate myopathy (STIM1), myofibrillar myopathy (FLNC), and mutation of CHD7, usually associated with the CHARGE syndrome. Inclusion of family members increased the diagnostic efficacy of WES, with a diagnostic rate of 60% for “trios” (an affected proband with both parents) vs 40% for single probands. A follow-up screening of patients whose conditions were undiagnosed on a targeted neuromuscular disease–related gene panel did not improve our diagnostic yield. Conclusions and Relevance With WES, we achieved a diagnostic success rate of 45.0% in our difficult-to-diagnose cohort of patients with LGMD. We expand the clinical phenotypes associated with known myopathy genes, and we stress the importance of accurate clinical examination and histopathological results for interpretation of WES, with many diagnoses requiring follow-up review and ancillary investigations of biopsy specimens or serum samples

Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy

OBJECTIVE: To report novel disease and pathology due to HSPB8 mutations in 2 families with autosomal dominant distal neuromuscular disease showing both myofibrillar and rimmed vacuolar myopathy together with neurogenic changes. METHODS: We performed whole-exome sequencing (WES) in tandem with linkage analysis and candidate gene approach as well as targeted next-generation sequencing (tNGS) to identify causative mutations in 2 families with dominant rimmed vacuolar myopathy and a motor neuropathy. Pathogenic variants and familial segregation were confirmed using Sanger sequencing. RESULTS: WES and tNGS identified a heterozygous change in HSPB8 in both families: c.421A > G p.K141E in family 1 and c.151insC p.P173SfsX43 in family 2. Affected patients had a distal myopathy that showed myofibrillar aggregates and rimmed vacuoles combined with a clear neurogenic component both on biopsy and neurophysiologic studies. MRI of lower limb muscles demonstrated diffuse tissue changes early in the disease stage progressing later to fatty replacement typical of a myopathy. CONCLUSION: We expand the understanding of disease mechanisms, tissue involvement, and phenotypic outcome of HSPB8 mutations. HSPB8 is part of the chaperone-assisted selective autophagy (CASA) complex previously only associated with Charcot-Marie-Tooth type 2L (OMIM 60673) and distal hereditary motor neuronopathy type IIa. However, we now demonstrate that patients can develop a myopathy with histologic features of myofibrillar myopathy with aggregates and rimmed vacuoles, similar to the pathology in myopathies due to gene defects in other compounds of the CASA complex such as BAG3 and DNAJB6 after developing the early neurogenic effects

Anthropometric measures and HbA1c to detect dysglycemia in young Asian women planning conception: The S-PRESTO cohort

10.1038/s41598-020-66147-xScientific Reports10