Whole genome sequencing of one complex pedigree illustrates challenges with genomic medicine

BACKGROUND: Human Phenotype Ontology (HPO) has risen as a useful tool for precision medicine by providing a standardized vocabulary of phenotypic abnormalities to describe presentations of human pathologies; however, there have been relatively few reports combining whole genome sequencing (WGS) and HPO, especially in the context of structural variants. METHODS: We illustrate an integrative analysis of WGS and HPO using an extended pedigree, which involves Prader-Willi Syndrome (PWS), hereditary hemochromatosis (HH), and dysautonomia-like symptoms. A comprehensive WGS pipeline was used to ensure reliable detection of genomic variants. Beyond variant filtering, we pursued phenotypic prioritization of candidate genes using Phenolyzer. RESULTS: Regarding PWS, WGS confirmed a 5.5 Mb de novo deletion of the parental allele at 15q11.2 to 15q13.1. Phenolyzer successfully returned the diagnosis of PWS, and pinpointed clinically relevant genes in the deletion. Further, Phenolyzer revealed how each of the genes is linked with the phenotypes represented by HPO terms. For HH, WGS identified a known disease variant (p.C282Y) in HFE of an affected female. Analysis of HPO terms alone fails to provide a correct diagnosis, but Phenolyzer successfully revealed the phenotype-genotype relationship using a disease-centric approach. Finally, Phenolyzer also revealed the complexity behind dysautonomia-like symptoms, and seven variants that might be associated with the phenotypes were identified by manual filtering based on a dominant inheritance model. CONCLUSIONS: The integration of WGS and HPO can inform comprehensive molecular diagnosis for patients, eliminate false positives and reveal novel insights into undiagnosed diseases. Due to extreme heterogeneity and insufficient knowledge of human diseases, it is also important that phenotypic and genomic data are standardized and shared simultaneously

Rate and duration of hospitalisation for acute pulmonary embolism in the real-world clinical practice of different countries : Analysis from the RIETE registry

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Relative sea-level rise around East Antarctica during Oligocene glaciation

During the middle and late Eocene (∼48-34 Myr ago), the Earth's climate cooled and an ice sheet built up on Antarctica. The stepwise expansion of ice on Antarcticainduced crustal deformation and gravitational perturbations around the continent. Close to the ice sheet, sea level rosedespite an overall reduction in the mass of the ocean caused by the transfer of water to the ice sheet. Here we identify the crustal response to ice-sheet growth by forcing a glacial-hydro isostatic adjustment model with an Antarctic ice-sheet model. We find that the shelf areas around East Antarctica first shoaled as upper mantle material upwelled and a peripheral forebulge developed. The inner shelf subsequently subsided as lithosphere flexure extended outwards from the ice-sheet margins. Consequently the coasts experienced a progressive relative sea-level rise. Our analysis of sediment cores from the vicinity of the Antarctic ice sheet are in agreement with the spatial patterns of relative sea-level change indicated by our simulations. Our results are consistent with the suggestion that near-field processes such as local sea-level change influence the equilibrium state obtained by an icesheet grounding line

Combination of the W boson polarization measurements in top quark decays using ATLAS and CMS data at root s=8 TeV

The combination of measurements of the W boson polarization in top quark decays performed by the ATLAS and CMS collaborations is presented. The measurements are based on proton-proton collision data produced at the LHC at a centre-of-mass energy of 8 TeV, and corresponding to an integrated luminosity of about 20 fb(-1)for each experiment. The measurements used events containing one lepton and having different jet multiplicities in the final state. The results are quoted as fractions of W bosons with longitudinal (F-0), left-handed (F-L), or right-handed (F-R) polarizations. The resulting combined measurements of the polarization fractions are F-0= 0.693 +/- 0.014 and F-L= 0.315 +/- 0.011. The fractionF(R)is calculated from the unitarity constraint to be F-R=-0.008 +/- 0.007. These results are in agreement with the standard model predictions at next-to-next-to-leading order in perturbative quantum chromodynamics and represent an improvement in precision of 25 (29)% for F-0(F-L) with respect to the most precise single measurement. A limit on anomalous right-handed vector (V-R), and left- and right-handed tensor (g(L), g(R)) tWb couplings is set while fixing all others to their standard model values. The allowed regions are [-0.11,0.16] for V-R, [-0.08,0.05] for g(L), and [-0.04,0.02] for g(R), at 95% confidence level. Limits on the corresponding Wilson coefficients are also derived.Peer reviewe

Measurement of hadronic event shapes in high-p T multijet final states at √s = 13 TeV with the ATLAS detector

A measurement of event-shape variables in proton-proton collisions at large momentum transfer is presented using data collected at s = 13 TeV with the ATLAS detector at the Large Hadron Collider. Six event-shape variables calculated using hadronic jets are studied in inclusive multijet events using data corresponding to an integrated luminosity of 139 fb−1. Measurements are performed in bins of jet multiplicity and in different ranges of the scalar sum of the transverse momenta of the two leading jets, reaching scales beyond 2 TeV. These measurements are compared with predictions from Monte Carlo event generators containing leading-order or next-to-leading order matrix elements matched to parton showers simulated to leading-logarithm accuracy. At low jet multiplicities, shape discrepancies between the measurements and the Monte Carlo predictions are observed. At high jet multiplicities, the shapes are better described but discrepancies in the normalisation are observed. [Figure not available: see fulltext.