In Search of New Imaging For Historical Earthquakes: A New Geophysical Survey Offshore Western Calabria (Southern Tyrrhenian Sea, Italy)

During the summer of 2010 we carried out a survey to acquire a multidisciplinary dataset within the Gulf of Sant'Eufemia (SE Tyrrhenian sea, Italy), with the aim of studying the active tectonics affecting the region, including that potentially responsible for key, elusive earthquakes such as the to-date unexplained 8 September 1905 (Mw 7 - 7.5) earthquake. The data here analysed highlight the presence of several tectonic and morphologic features characterizing the investigated area. We have recognized the Angitola Channel, a deep and wide canyon showing a straight trend in its coastward segment, and a meandering trend in the seaward segment. Based on morpho-structural elements, we maintain that the Angitola Channel could be tectonically controlled. Moreover, several gravitational instabilities as slumps and collapses affect the flanks of the morpho-structural high, detected offshore Capo Vaticano. Very high resolution seismic data have unveiled the presence of numerous fluid escape features and several mud volcanoes straddling the sector from the coastline to seaward.INOGS (RIMA Department) supported the acquisition of the entire dataset.Published385-4013.2. Tettonica attivaJCR Journalrestricte

A Normative Basis for EU External Relations? Protecting Internal Values Beyond the Single Market

This chapter analyses the EU’s obligation to uphold and promote its values and interests in its external polies, in particular as regards some of the values generally underpinning the EU’s internal market, and the rules and principles concerning services of general interest in particular. The first part of the chapter offers a mapping exercise of the relevant Treaty provisions—seeking to establish connections and ways of reading them so that they may “inform” each other. The second part puts them in the context of the debate about Normative Power Europe (NPE) —a much used, but not undisputed international relations concept coined to express the nature of the EU’s external policies and projection. The third inquires further into the “normative” nature and effect of the EU’s constitutional values and objectives. It will be argued that the Treaty normative basis for the EU’s external relations is meaningful and is to be taken seriously

DYNC2H1 hypomorphic or retina-predominant variants cause nonsyndromic retinal degeneration

Purpose: Determining the role of DYNC2H1 variants in nonsyndromic inherited retinal disease (IRD). Methods: Genome and exome sequencing were performed for five unrelated cases of IRD with no identified variant. In vitro assays were developed to validate the variants identified (fibroblast assay, induced pluripotent stem cell [iPSC] derived retinal organoids, and a dynein motility assay). Results: Four novel DYNC2H1 variants (V1, g.103327020_103327021dup; V2, g.103055779A>T; V3, g.103112272C>G; V4, g.103070104A>C) and one previously reported variant (V5, g.103339363T>G) were identified. In proband 1 (V1/V2), V1 was predicted to introduce a premature termination codon (PTC), whereas V2 disrupted the exon 41 splice donor site causing incomplete skipping of exon 41. V1 and V2 impaired dynein-2 motility in vitro and perturbed IFT88 distribution within cilia. V3, homozygous in probands 2–4, is predicted to cause a PTC in a retina-predominant transcript. Analysis of retinal organoids showed that this new transcript expression increased with organoid differentiation. V4, a novel missense variant, was in trans with V5, previously associated with Jeune asphyxiating thoracic dystrophy (JATD). Conclusion: The DYNC2H1 variants discussed herein were either hypomorphic or affecting a retina-predominant transcript and caused nonsyndromic IRD. Dynein variants, specifically DYNC2H1 variants are reported as a cause of non syndromic IRD

Assessing the digenic model in rare disorders using population sequencing data

An important fraction of patients with rare disorders remains with no clear genetic diagnostic, even after whole-exome or whole-genome sequencing, posing a difficulty in giving adequate treatment and genetic counseling. The analysis of genomic data in rare disorders mostly considers the presence of single gene variants in coding regions that follow a concrete monogenic mode of inheritance. A digenic inheritance, with variants in two functionally-related genes in the same individual, is a plausible alternative that might explain the genetic basis of the disease in some cases. In this case, digenic disease combinations should be absent or underrepresented in healthy individuals. We develop a framework to evaluate the significance of digenic combinations and test its statistical power in different scenarios. We suggest that this approach will be relevant with the advent of new sequencing efforts including hundreds of thousands of samples

Author Correction: Nuclear-mitochondrial DNA segments resemble paternally inherited mitochondrial DNA in humans

An amendment to this paper has been published and can be accessed via a link at the top of the paper

100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care — Preliminary Report

BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection. METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis. RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives. CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.)