Neonatal diabetes, gallbladder agenesis, duodenal atresia, and intestinal malrotation caused by a novel homozygous mutation in RFX6

Recently, bi-allelic mutations in the transcription factor RFX6 were described as the cause of a rare condition characterized by neonatal diabetes with pancreatic and biliary hypoplasia and duodenal/jejunal atresia. A male infant developed severe hyperglycemia (446mg/dL) within 24h of birth. Acute abdominal concerns by day five necessitated exploratory surgery that revealed duodenal atresia, gallbladder agenesis, annular pancreas and intestinal malrotation. He also exhibited chronic diarrhea and feeding intolerance, cholestatic jaundice, and subsequent liver failure. He died of sepsis at four months old while awaiting liver transplantation. The phenotype of neonatal diabetes with intestinal atresia and biliary agenesis clearly pointed to RFX6 as the causative gene; indeed, whole exome sequencing revealed a novel homozygous RFX6 mutation c.779A>C; p.Lys260Thr (K260T). This missense mutation also changes the consensus 5′ splice donor site before intron 7 and is thus predicted to cause disruption in splicing. Both parents, who were not known to be related, were heterozygous carriers. Targeted genetic testing based on consideration of phenotypic features may reveal a cause among the many genes now associated with heterogeneous forms of monogenic neonatal diabetes. Our study demonstrates the feasibility of using modern sequencing technology to identify one such rare cause. Continued research is needed to determine the possible cost-effectiveness of this approach, especially when clear phenotypic clues are absent. Further study of patients with RFX6 mutations should clarify its role in pancreatic, intestinal and enteroendocrine cellular development and explain features such as the diarrhea exhibited in our case

Microcephaly, epilepsy, and neonatal diabetes due to compound heterozygous mutations in IER3IP1: Insights into the natural history of a rare disorder

Neonatal diabetes mellitus is known to have over 20 different monogenic causes. A syndrome of permanent neonatal diabetes along with primary microcephaly with simplified gyral pattern associated with severe infantile epileptic encephalopathy was recently described in two independent reports in which disease-causing homozygous mutations were identified in the immediate early response-3 interacting protein-1 (IER3IP1) gene. We report here an affected male born to a non-consanguineous couple who was noted to have insulin-requiring permanent neonatal diabetes, microcephaly, and generalized seizures. He was also found to have cortical blindness, severe developmental delay and numerous dysmorphic features. He experienced a slow improvement but not abrogation of seizure frequency and severity on numerous anti-epileptic agents. His clinical course was further complicated by recurrent respiratory tract infections and he died at 8years of age. Whole exome sequencing was performed on DNA from the proband and parents. He was found to be a compound heterozygote with two different mutations in IER3IP1: p.Val21Gly (V21G) and a novel frameshift mutation p.Phe27fsSer*25. IER3IP1 is a highly conserved protein with marked expression in the cerebral cortex and in beta cells. This is the first reported case of compound heterozygous mutations within IER3IP1 resulting in neonatal diabetes. The triad of microcephaly, generalized seizures, and permanent neonatal diabetes should prompt screening for mutations in IER3IP1. As mutations in genes such as NEUROD1 and PTF1A could cause a similar phenotype, next-generation sequencing approaches-such as exome sequencing reported here-may be an efficient means of uncovering a diagnosis in future cases

Operation and performance of the ATLAS semiconductor tracker

The semiconductor tracker is a silicon microstrip detector forming part of the inner tracking system of the ATLAS experiment at the LHC. The operation and performance of the semiconductor tracker during the first years of LHC running are described. More than 99% of the detector modules were operational during this period, with an average intrinsic hit efficiency of (99.74±0.04)%. The evolution of the noise occupancy is discussed, and measurements of the Lorentz angle, δ-ray production and energy loss presented. The alignment of the detector is found to be stable at the few-micron level over long periods of time. Radiation damage measurements, which include the evolution of detector leakage currents, are found to be consistent with predictions and are used in the verification of radiation background simulations

Search for H→γγ produced in association with top quarks and constraints on the Yukawa coupling between the top quark and the Higgs boson using data taken at 7 TeV and 8 TeV with the ATLAS detector

A search is performed for Higgs bosons produced in association with top quarks using the diphoton decay mode of the Higgs boson. Selection requirements are optimized separately for leptonic and fully hadronic final states from the top quark decays. The dataset used corresponds to an integrated luminosity of 4.5 fb−14.5 fb−1 of proton–proton collisions at a center-of-mass energy of 7 TeV and 20.3 fb−1 at 8 TeV recorded by the ATLAS detector at the CERN Large Hadron Collider. No significant excess over the background prediction is observed and upper limits are set on the tt¯H production cross section. The observed exclusion upper limit at 95% confidence level is 6.7 times the predicted Standard Model cross section value. In addition, limits are set on the strength of the Yukawa coupling between the top quark and the Higgs boson, taking into account the dependence of the tt¯H and tH cross sections as well as the H→γγ branching fraction on the Yukawa coupling. Lower and upper limits at 95% confidence level are set at −1.3 and +8.0 times the Yukawa coupling strength in the Standard Model

Fiducial and differential cross sections of Higgs boson production measured in the four-lepton decay channel in pp collisions at √s = 8 TeV with the ATLAS detector

Measurements of fiducial and differential cross sections of Higgs boson production in the H→ZZ∗ → 4ℓ decay channel are presented. The cross sections are determined within a fiducial phase space and corrected for detection efficiency and resolution effects. They are based on 20.3 fb−¹ of pp collision data, produced at √s = 8 TeV centre-of-mass energy at the LHC and recorded by the ATLAS detector. The differential measurements are performed in bins of transverse momentum and rapidity of the four-lepton system, the invariant mass of the subleading lepton pair and the decay angle of the leading lepton pair with respect to the beam line in the four-lepton rest frame, as well as the number of jets and the transverse momentum of the leading jet. The measured cross sections are compared to selected theoretical calculations of the Standard Model expectations. No significant deviation from any of the tested predictions is found

Search for W′→tb→qqbb decays in pp collisions at √s=8 TeV with the ATLAS detector

A search for a massive W′ gauge boson decaying to a top quark and a bottom quark is performed with the ATLAS detector in pp collisions at the LHC. The dataset was taken at a centre-of-mass energy of √s=8 TeV and corresponds to 20.3 fb−1 of integrated luminosity. This analysis is done in the hadronic decay mode of the top quark, where novel jet substructure techniques are used to identify jets from high-momentum top quarks. This allows for a search for high-mass W′ bosons in the range 1.5–3.0 TeV. b-tagging is used to identify jets originating from b-quarks. The data are consistent with Standard Model background-only expectations, and upper limits at 95 % confidence level are set on the W′→tb cross section times branching ratio ranging from 0.16pb to 0.33pb for left-handed W′ bosons, and ranging from 0.10pb to 0.21pb for W′ bosons with purely right-handed couplings. Upper limits at 95 % confidence level are set on the W′-boson coupling to tb as a function of the W′ mass using an effective field theory approach, which is independent of details of particular models predicting a W′boson

Measurement of the cross section of high transverse momentum Z→bb̄ production in proton–proton collisions at √s = 8 TeV with the ATLAS detector

This Letter reports the observation of a high transverse momentum Z→bb̄ signal in proton–proton collisions at √s=8 TeV and the measurement of its production cross section. The data analysed were collected in 2012 with the ATLAS detector at the LHC and correspond to an integrated luminosity of 19.5 fb−¹. The Z→bb̄ decay is reconstructed from a pair of b -tagged jets, clustered with the anti-ktkt jet algorithm with R=0.4R=0.4, that have low angular separation and form a dijet with pT>200 GeVpT>200 GeV. The signal yield is extracted from a fit to the dijet invariant mass distribution, with the dominant, multi-jet background mass shape estimated by employing a fully data-driven technique that reduces the dependence of the analysis on simulation. The fiducial cross section is determined to be σZ→bb¯fid=2.02±0.20 (stat.) ±0.25 (syst.)±0.06 (lumi.) pb=2.02±0.33 pb, in good agreement with next-to-leading-order theoretical predictions

Measurement of the View the tt production cross-section using eμ events with b-tagged jets in pp collisions at √s = 13 TeV with the ATLAS detector

This paper describes a measurement of the inclusive top quark pair production cross-section (σtt¯) with a data sample of 3.2 fb−1 of proton–proton collisions at a centre-of-mass energy of √s = 13 TeV, collected in 2015 by the ATLAS detector at the LHC. This measurement uses events with an opposite-charge electron–muon pair in the final state. Jets containing b-quarks are tagged using an algorithm based on track impact parameters and reconstructed secondary vertices. The numbers of events with exactly one and exactly two b-tagged jets are counted and used to determine simultaneously σtt¯ and the efficiency to reconstruct and b-tag a jet from a top quark decay, thereby minimising the associated systematic uncertainties. The cross-section is measured to be: σtt¯ = 818 ± 8 (stat) ± 27 (syst) ± 19 (lumi) ± 12 (beam) pb, where the four uncertainties arise from data statistics, experimental and theoretical systematic effects, the integrated luminosity and the LHC beam energy, giving a total relative uncertainty of 4.4%. The result is consistent with theoretical QCD calculations at next-to-next-to-leading order. A fiducial measurement corresponding to the experimental acceptance of the leptons is also presented

Search for the Standard Model Higgs boson decay to μ+μ− with the ATLAS detector

A search is reported for Higgs boson decay to μ+μ−μ+μ− using data with an integrated luminosity of 24.8 fb−124.8 fb−¹ collected with the ATLAS detector in pp collisions at √s=7 and 8 TeV at the CERN Large Hadron Collider. The observed dimuon invariant mass distribution is consistent with the Standard Model background-only hypothesis in the 120–150 GeV search range. For a Higgs boson with a mass of 125.5 GeV, the observed (expected) upper limit at the 95% confidence level is 7.0 (7.2) times the Standard Model expectation. This corresponds to an upper limit on the branching ratio BR(H→μ+μ−)of 1.5×10−31.5×10−3