Breast cancer has a significant heritable basis, of which ∼60% remains unexplained. Testing for BRCA1/BRCA2 offers useful discrimination of breast cancer risk within families, and identification of ...additional breast cancer susceptibility genes could offer clinical utility.
We included 2135 invasive breast cancer cases recruited via the Breast and Ovarian Cancer Susceptibility study, a retrospective UK study of familial breast cancer. Eligibility criteria: female, BRCA-negative, white European ethnicity, and one of: (i) breast cancer family history, (ii) bilateral disease, (iii) young age of onset (<30 years), and (iv) concomitant ovarian cancer.
We undertook exome sequencing of cases and carried out gene-level burden testing of rare damaging variants against those from 51 377 ethnicity-matched population controls from gnomAD.
159/2135 (7.4%) cases had a qualifying variant in an established breast cancer susceptibility gene, with minimal evidence of signal in other cancer susceptibility genes. Known breast cancer susceptibility genes PALB2, CHEK2, and ATM were the only genes to retain statistical significance after correcting for multiple testing. Due to the enrichment of hereditary cases in the series, we had good power (>80%) to detect a gene of BRCA1-like risk odds ratio (OR) = 10.6 down to a population minor allele frequency of 4.6 × 10−5 (1 in 10 799, less than one-tenth that of BRCA1)and of PALB2-like risk (OR = 5.0) down to a population minor allele frequency of 2.8 × 10−4 (1 in 1779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (OR = 2-3) like CHEK2 and ATM.
This is the largest case-control whole-exome analysis of enriched breast cancer published to date. Whilst additional breast cancer susceptibility genes likely exist, those of high penetrance are likely to be of very low mutational frequency. Contention exists regarding the clinical utility of such genes.
•We report the largest exome sequencing study of hereditary breast cancer to date, comparing 2135 cases to 51 377 controls.•We demonstrate that a novel breast cancer gene (OR ≥ 5) is unlikely to exist at any appreciable population frequency.•We had good power (> 80%) to detect any PALB2-like breast cancer gene (odds ratio = 5) at population frequency of 1 in 1779 (< half that of PALB2).•Our insights into the architecture of breast cancer susceptibility give context to the negative findings of the last decade.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The SoLid experiment, short for Search for Oscillations with a Lithium-6 detector, is a new generation neutrino experiment which tries to address the key challenges for high precision reactor ...neutrino measurements at very short distances from a reactor core and with little or no overburden. The primary goal of the SoLid experiment is to perform a precise measurement of the electron antineutrino energy spectrum and flux and to search for very short distance neutrino oscillations as a probe of eV-scale sterile neutrinos. This paper describes the SoLid detection principle, the mechanical design and the construction of the detector. It then reports on the installation and commissioning on site near the BR2 reactor, Belgium, and finally highlights its performance in terms of detector response and calibration.
Thin-film polyvinylidene fluoride piezoelectric sensors have long been recognized as a promising alternative to traditional metal foil strain gauges in applications where only dynamic or quasistatic ...signals are of interest. Compared to metal foil strain gauges, polyvinylidene fluoride sensors feature high sensitivity, high dynamic range, and broad frequency bandwidth. However, transverse sensitivity of the polyvinylidene fluoride sensor is higher than that of a metal foil strain gauge, making it more difficult to isolate a particular strain component or a deformation mode when the host structure is under complex loading. In addition, polyvinylidene fluoride films are sensitive to changes in ambient temperature due to the pyroelectric effect. In this article, three temperature-compensated polyvinylidene fluoride sensor rosette designs are proposed for isolating specific strain component(s) and deformation mode(s) of interest. First-principles based models are derived to relate the polyvinylidene fluoride sensor rosette output to the actual elastic strain component of interest. Experimental validation is conducted to verify the proposed models and to compare the performance of the polyvinylidene fluoride sensor rosettes with their metal foil strain gauge counterparts.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
In this report a method for the affinity purification and radiolabeling of recombinant mouse interleukin (IL)-4 is described. It is shown on the basis of several criteria that IL-4 retains full ...biologic activity after radioiodination and can therefore be used as a valid model for measuring the binding characteristics of native IL-4. By using Scatchard plot analysis of equilibrium binding data, it is demonstrated that 125I-IL-4 binds to a high affinity cell surface receptor which is expressed by both hemopoietic and nonhemopoietic cells. The dissociation constant for 125I-IL-4 (Kd = 20 to 60 pM) corresponds to the concentration of IL-4 which gives 50% biologic activity (i.e., 10 to 30 pM). Binding of 125I-IL-4 is rapid (t1/2 of 2 min), whereas dissociation occurs at a slow rate (t1/2 approximately 4 hr). The IL-4 receptor shows a high degree of specificity. Whereas unlabeled mouse IL-4 competed with mouse 125I-IL-4 in an equimolar fashion for binding to IL-4 receptors, several other lymphokines, including mouse IL-2, IL-3, interferon-gamma, granulocyte-macrophage colony-stimulating factor, and human IL-1, IL-2, and IL-4 were unable to inhibit, even at molar excesses of 400 to 800-fold. At 37 degrees C, 125I-IL-4 is rapidly internalized (approximately 200 molecules/cell/min) by HT-2 cells, with at least 85% of cell surface receptors being functional in this respect. Receptors for IL-4 were found to be expressed by subclasses of T and B cells, mast cells, macrophages, and by cells of the myeloid and erythroid lineages. This wide distribution of receptor expression closely matches the known spectrum of biologic activities of IL-4, including proliferation and/or differentiation of T and B cells, mast cells and granulocytes, and induction of macrophage antigen-presenting capacity. IL-4 receptors were also found on a variety of nonhemopoietic cells such as cloned stromal cell lines from the bone marrow, spleen, thymus, and brain, and on muscle, brain, melanoma, fibroblast, and liver cells. Indeed, only 5 of more than 90 cell types tested have undetectable numbers of IL-4 receptors. The biologic effects of IL-4 on nonhemopoietic cells have not yet been reported and await elucidation.
A physical map of the mouse genome is an essential tool for both positional cloning and genomic sequencing in this key model system for biomedical research. Indeed, the construction of a mouse ...physical map with markers spaced at an average interval of 300 kb is one of the stated goals of the Human Genome Project. Here we report the results of a project at the Whitehead Institute/MIT Center for Genome Research to construct such a physical map of the mouse. We built the map by screening sequenced-tagged sites (STSs) against a large-insert yeast artificial chromosome (YAC) library and then integrating the STS-content information with a dense genetic map. The integrated map shows the location of 9,787 loci, providing landmarks with an average spacing of approximately 300 kb and affording YAC coverage of approximately 92% of the mouse genome. We also report the results of a project at the MRC UK Mouse Genome Centre targeted at chromosome X. The project produced a YAC-based map containing 619 loci (with 121 loci in common with the Whitehead map and 498 additional loci), providing especially dense coverage of this sex chromosome. The YAC-based physical map directly facilitates positional cloning of mouse mutations by providing ready access to most of the genome. More generally, use of this map in addition to a newly constructed radiation hybrid (RH) map provides a comprehensive framework for mouse genomic studies.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
BackgroundWe present a case characteristic of Laurin-Sandrow syndrome in a term male infant. The infant is the third son of Caucasian parents born following uncomplicated pregnancy. There is no ...family history of limb abnormalities or genetic conditions.The infant was noted to have a wide nasal bridge, bilateral erythematous linear prominences on his columella with polydactyly and syndactyly of both hands and feet. There was wrist flexion and cupped hands, each with 7 normal length digits but no opposable thumbs. The feet were of 'mirrored' appearance with a further 17 digits.MethodsMRI imaging of the brain revealed overall structural brain asymmetry, with agenesis of the corpus callosum and ventricular dilatation. Metacarpals and metatarsals were present for each digit, with an additional extra-axial digit noted on the left foot. Initial suggestion of autosomal dominant Grieg Cephalopolysyndactly (GCP) was revised by the Clinical Geneticist to Laurin-Sandrow Syndrome, with genetic PCR negative for GCP.ResultsLaurin-Sandrow Syndrome represents an extremely rare genetic condition of polysyndactyly associated with 14 q13 gene translocation, with fewer than 30 cases described in the literature.FigureFigureConclusionIn cases of extreme duplication of digits with nasal anomalies, cranial imaging and early review by a geneticist may be key in revealing the underlying diagnosis.
BackgroundWe present a case characteristic of Laurin-Sandrow syndrome in a term male infant. The infant is the third son of Caucasian parents born following uncomplicated pregnancy. There is no ...family history of limb abnormalities or genetic conditions.The infant was noted to have a wide nasal bridge, bilateral erythematous linear prominences on his columella with polydactyly and syndactyly of both hands and feet. There was wrist flexion and cupped hands, each with 7 normal length digits but no opposable thumbs. The feet were of ‘mirrored’ appearance with a further 17 digits.MethodsMRI imaging of the brain revealed overall structural brain asymmetry, with agenesis of the corpus callosum and ventricular dilatation. Metacarpals and metatarsals were present for each digit, with an additional extra-axial digit noted on the left foot. Initial suggestion of autosomal dominant Grieg Cephalopolysyndactly (GCP) was revised by the Clinical Geneticist to Laurin-Sandrow Syndrome, with genetic PCR negative for GCP.ResultsLaurin-Sandrow Syndrome represents an extremely rare genetic condition of polysyndactyly associated with 14 q13 gene translocation, with fewer than 30 cases described in the literature.Abstract PO-0612 Figure 1Abstract PO-0612 Figure 2ConclusionIn cases of extreme duplication of digits with nasal anomalies, cranial imaging and early review by a geneticist may be key in revealing the underlying diagnosis.
The next generation of very-short-baseline reactor experiments will require compact detectors operating at surface level and close to a nuclear reactor. This paper presents a new detector concept ...based on a composite solid scintillator technology. The detector target uses cubes of polyvinyltoluene interleaved with 6LiF:ZnS(Ag) phosphor screens to detect the products of the inverse beta decay reaction. A multi-tonne detector system built from these individual cells can provide precise localisation of scintillation signals, making efficient use of the detector volume. Monte Carlo simulations indicate that a neutron capture efficiency of over 70 % is achievable with a sufficient number of 6LiF:ZnS(Ag) screens per cube and that an appropriate segmentation enables a measurement of the positron energy which is not limited by γ-ray leakage. First measurements of a single cell indicate that a very good neutron-gamma discrimination and high neutron detection efficiency can be obtained with adequate triggering techniques. The light yield from positron signals has been measured, showing that an energy resolution of 14%/√E(MeV) is achievable with high uniformity. A preliminary neutrino signal analysis has been developed, using selection criteria for pulse shape, energy, time structure and energy spatial distribution and showing that an antineutrino efficiency of 40% can be achieved. It also shows that the fine segmentation of the detector can be used to significantly decrease both correlated and accidental backgrounds.
Trio-based whole-exome sequence (WES) data have established confident genetic diagnoses in ∼40% of previously undiagnosed individuals recruited to the Deciphering Developmental Disorders (DDD) study. ...Here we aim to use the breadth of phenotypic information recorded in DDD to augment diagnosis and disease variant discovery in probands. Median Euclidean distances (mEuD) were employed as a simple measure of similarity of quantitative phenotypic data within sets of ≥10 individuals with plausibly causative de novo mutations (DNM) in 28 different developmental disorder genes. 13/28 (46.4%) showed significant similarity for growth or developmental milestone metrics, 10/28 (35.7%) showed similarity in HPO term usage, and 12/28 (43%) showed no phenotypic similarity. Pairwise comparisons of individuals with high-impact inherited variants to the 32 individuals with causative DNM in ANKRD11 using only growth z-scores highlighted 5 likely causative inherited variants and two unrecognized DNM resulting in an 18% diagnostic uplift for this gene. Using an independent approach, naive Bayes classification of growth and developmental data produced reasonably discriminative models for the 24 DNM genes with sufficiently complete data. An unsupervised naive Bayes classification of 6,993 probands with WES data and sufficient phenotypic information defined 23 in silico syndromes (ISSs) and was used to test a “phenotype first” approach to the discovery of causative genotypes using WES variants strictly filtered on allele frequency, mutation consequence, and evidence of constraint in humans. This highlighted heterozygous de novo nonsynonymous variants in SPTBN2 as causative in three DDD probands.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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