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Although costly, genome-wide sequencing (GWS) detects an extensive range of variants, enhancing our ability to diagnose and assess risk for an increasing number of diseases. In addition to detecting variants related to the indication for testing, GWS can detect secondary variants in BRCA1, BRCA2, and other genes for which early intervention may improve health. As the list of secondary findings grows, there is increased demand for surveillance and management by multiple specialists, adding pressure to constrained health care budgets. Secondary finding testing is actively debated because some consider it opportunistic screening for future health risks that may not manifest. Given the economic implications of secondary finding testing and follow-up and its unproven clinical utility, the objective is to assess the incremental cost-effectiveness of secondary finding ascertainment per case detected and per unit of improved clinical utility in families of children with unexplained suspected genetic conditions undergoing clinical GWS. Those undergoing trio genome or exome sequencing are eligible for the study. Positive secondary finding index cases will be matched to negative controls (1:2) based on age group, primary result(s) type, and clinical indication. During the 2-year study, 71 cases and 142 matched controls are expected. Health service use will be collected in patients and 1 adult family member every 6 months. The per-child and per-dyad total cost will be determined by multiplying use of each resource by a corresponding unit price and summing all cost items. Costs will be estimated from the public and societal payer perspectives. The mean cost per child and per dyad for secondary finding–positive and secondary finding–negative groups will be compared statistically. If important demographic differences are observed between groups, ordinary least-squares regression, log transformation, or other nonparametric technique will be used to compare adjusted mean costs. The ratio of the difference in mean cost to the secondary finding yield will be used to estimate incremental cost-effectiveness. In secondary analyses, effectiveness will be estimated using the number of clinical management changes due to secondary findings or the Clinician-Reported Genetic Testing Utility Index (C-GUIDE) score, a validated measure of clinical utility. Sensitivity analysis will be undertaken to assess the robustness of the findings to variation in key parameters. This study generates key evidence to inform clinical practice and funding allocation related to secondary finding testing. The inclusion of family members and a new measure of clinical utility represent important advancements in economic evaluation in genomics.

Sotos syndrome (SS) represents an important human model system for the study of epigenetic regulation; it is an overgrowth/intellectual disability syndrome caused by mutations in a histone methyltransferase, NSD1 . As layered epigenetic modifications are often interdependent, we propose that pathogenic NSD1 mutations have a genome-wide impact on the most stable epigenetic mark, DNA methylation (DNAm). By interrogating DNAm in SS patients, we identify a genome-wide, highly significant NSD1 +/− -specific signature that differentiates pathogenic NSD1 mutations from controls, benign NSD1 variants and the clinically overlapping Weaver syndrome. Validation studies of independent cohorts of SS and controls assigned 100% of these samples correctly. This highly specific and sensitive NSD1 +/− signature encompasses genes that function in cellular morphogenesis and neuronal differentiation, reflecting cardinal features of the SS phenotype. The identification of SS-specific genome-wide DNAm alterations will facilitate both the elucidation of the molecular pathophysiology of SS and the development of improved diagnostic testing. Sotos syndrome is an growth syndrome characterized by advanced growth in childhood, characteristic facial appearance and intellectual disability. Here the authors identify a genome-wide DNA methylation signature that accurately diagnoses Sotos Syndrome and distinguishes it from similar conditions.

The next generation of water Cherenkov neutrino telescopes in the Mediterranean Sea are under construction offshore France (KM3NeT/ORCA) and Sicily (KM3NeT/ARCA). The KM3NeT/ORCA detector features an energy detection threshold which allows to collect atmospheric neutrinos to study flavour oscillation. This paper reports the KM3NeT/ORCA sensitivity to this phenomenon. The event reconstruction, selection and classification are described. The sensitivity to determine the neutrino mass ordering was evaluated and found to be 4.4σ if the true ordering is normal and 2.3σ if inverted, after 3 years of data taking. The precision to measure Δm322 and θ23 were also estimated and found to be 85.10-6eV2 and (-3.1+1.9)∘ for normal neutrino mass ordering and, 75.10-6eV2 and (-7.0+2.0)∘ for inverted ordering. Finally, a unitarity test of the leptonic mixing matrix by measuring the rate of tau neutrinos is described. Three years of data taking were found to be sufficient to exclude event rate variations larger than 20% at 3σ level.

Background Autism spectrum disorder (ASD) is a common and etiologically heterogeneous neurodevelopmental disorder. Although many genetic causes have been identified (> 200 ASD-risk genes), no single gene variant accounts for > 1% of all ASD cases. A role for epigenetic mechanisms in ASD etiology is supported by the fact that many ASD-risk genes function as epigenetic regulators and evidence that epigenetic dysregulation can interrupt normal brain development. Gene-specific DNAm profiles have been shown to assist in the interpretation of variants of unknown significance. Therefore, we investigated the epigenome in patients with ASD or two of the most common genomic variants conferring increased risk for ASD. Genome-wide DNA methylation (DNAm) was assessed using the Illumina Infinium HumanMethylation450 and MethylationEPIC arrays in blood from individuals with ASD of heterogeneous, undefined etiology ( n = 52), and individuals with 16p11.2 deletions (16p11.2del, n = 9) or pathogenic variants in the chromatin modifier CHD8 ( CHD8 +/− , n = 7). Results DNAm patterns did not clearly distinguish heterogeneous ASD cases from controls. However, the homogeneous genetically-defined 16p11.2del and CHD8 +/− subgroups each exhibited unique DNAm signatures that distinguished 16p11.2del or CHD8 +/− individuals from each other and from heterogeneous ASD and control groups with high sensitivity and specificity. These signatures also classified additional 16p11.2del ( n = 9) and CHD8 ( n = 13) variants as pathogenic or benign. Our findings that DNAm alterations in each signature target unique genes in relevant biological pathways including neural development support their functional relevance. Furthermore, genes identified in our CHD8 +/− DNAm signature in blood overlapped differentially expressed genes in CHD8 +/− human-induced pluripotent cell-derived neurons and cerebral organoids from independent studies. Conclusions DNAm signatures can provide clinical utility complementary to next-generation sequencing in the interpretation of variants of unknown significance. Our study constitutes a novel approach for ASD risk-associated molecular classification that elucidates the vital cross-talk between genetics and epigenetics in the etiology of ASD.

The KM3NeT/ARCA neutrino detector is currently under construction at 3500 m depth offshore Capo Passero, Sicily, in the Mediterranean Sea. The main science objectives are the detection of high-energy cosmic neutrinos and the discovery of their sources. Simulations were conducted for the full KM3NeT/ARCA detector, instrumenting a volume of 1 km 3 , to estimate the sensitivity and discovery potential to point-like neutrino sources. This paper covers the reconstruction of track- and shower-like signatures, as well as the criteria employed for neutrino event selection. With an angular resolution below 0.1 ∘ for tracks and under 2 ∘ for showers, the sensitivity to point-like neutrino sources surpasses existing observed limits across the entire sky.

In children undergoing genetic testing for physical health concerns, we examined how often the results also revealed information about their risk for neurodevelopmental disorders. The study sample consisted of 3056 genetic tests (1686 chromosomal microarrays––CMAs, and 1378 next-generation sequencing––NGS panels) ordered at a tertiary pediatric hospital because of a physical/congenital health problem. Tests ordered to investigate developmental concerns were excluded. Pathogenic, or likely pathogenic variants were manually reviewed for diagnostic likelihood, and for evidence of an association with a neurodevelopmental disorder (e.g., autism or intellectual disability). A total of 169 CMAs (10%) and 232 NGS panels (17%) had likely diagnostic results. More than half (52%) of all diagnostic results had established evidence of a neurodevelopmental disorder association. In summary, there is a high prevalence of neurodevelopmental implications from genetic tests ordered for physical/congenital indications. This broad clinical utility suggests a growing need for genetics-first developmental care pathways.

The measurement of the flux of muons produced in cosmic ray air showers is essential for the study of primary cosmic rays. Such measurements are important in extensive air shower detectors to assess the energy spectrum and the chemical composition of the cosmic ray flux, complementary to the information provided by fluorescence detectors. Detailed simulations of the cosmic ray air showers are carried out, using codes such as CORSIKA, to estimate the muon flux at sea level. These simulations are based on the choice of hadronic interaction models, for which improvements have been implemented in the post-LHC era. In this work, a deficit in simulations that use state-of-the-art QCD models with respect to the measurement deep underwater with the KM3NeT neutrino detectors is reported. The KM3NeT/ARCA and KM3NeT/ORCA neutrino telescopes are sensitive to TeV muons originating mostly from primary cosmic rays with energies around 10 TeV. The predictions of state-of-the-art QCD models show that the deficit with respect to the data is constant in zenith angle; no dependency on the water overburden is observed. The observed deficit at a depth of several kilometres is compatible with the deficit seen in the comparison of the simulations and measurements at sea level.

A bstract Oscillations of atmospheric muon and electron neutrinos produce tau neutrinos with energies in the GeV range, which can be observed by the ORCA detector of the KM3NeT neutrino telescope in the Mediterranean Sea. First measurements with ORCA6, an early subarray corresponding to about 5% of the final detector, are presented. A sample of 5828 neutrino candidates has been selected from the analysed exposure of 433 kton-years. The ν τ normalisation, defined as the ratio between the number of observed and expected tau neutrino events, is measured to be S τ = 0.48 − 0.33 + 0.5 . This translates into a ν τ charged-current cross section measurement of σ τ meas = 2.5 − 1.8 + 2.6 × 10 − 38 cm 2 nucleon − 1 at the median ν τ energy of 20.3 GeV. The result is consistent with the measurements of other experiments. In addition, the current limit on the non-unitarity parameter affecting the τ -row of the neutrino mixing matrix was improved, with α 33 > 0.95 at the 95% confidence level.