The Genetics of Pneumothorax.

A genetic influence on spontaneous pneumothoraces-those occurring without a traumatic or iatrogenic cause-is supported by several lines of evidence: 1) pneumothorax can cluster in families (i.e., familial spontaneous pneumothorax), 2) mutations in the FLCN gene have been found in both familial and sporadic cases, and 3) pneumothorax is a known complication of several genetic syndromes. Herein, we review known genetic contributions to both sporadic and familial pneumothorax. We summarize the pneumothorax-associated genetic syndromes, including Birt-Hogg-Dubé syndrome, Marfan syndrome, vascular (type IV) Ehlers-Danlos syndrome, alpha-1 antitrypsin deficiency, tuberous sclerosis complex/lymphangioleiomyomatosis, Loeys-Dietz syndrome, cystic fibrosis, homocystinuria, and cutis laxa, among others. At times, pneumothorax is their herald manifestation. These syndromes have serious potential extrapulmonary complications (e.g., malignant renal tumors in Birt-Hogg-Dubé syndrome), and surveillance and/or treatment is available for most disorders; thus, establishing a diagnosis is critical. To facilitate this, we provide an algorithm to guide the clinician in discerning which cases of spontaneous pneumothorax may have a genetic or familial contribution, which cases warrant genetic testing, and which cases should prompt an evaluation by a geneticist

Bringing order to protein disorder through comparative genomics and genetic interactions

Abstract Background Intrinsically disordered regions are widespread, especially in proteomes of higher eukaryotes. Recently, protein disorder has been associated with a wide variety of cellular processes and has been implicated in several human diseases. Despite its apparent functional importance, the sheer range of different roles played by protein disorder often makes its exact contribution difficult to interpret. Results We attempt to better understand the different roles of disorder using a novel analysis that leverages both comparative genomics and genetic interactions. Strikingly, we find that disorder can be partitioned into three biologically distinct phenomena: regions where disorder is conserved but with quickly evolving amino acid sequences (flexible disorder); regions of conserved disorder with also highly conserved amino acid sequences (constrained disorder); and, lastly, non-conserved disorder. Flexible disorder bears many of the characteristics commonly attributed to disorder and is associated with signaling pathways and multi-functionality. Conversely, constrained disorder has markedly different functional attributes and is involved in RNA binding and protein chaperones. Finally, non-conserved disorder lacks clear functional hallmarks based on our analysis. Conclusions Our new perspective on protein disorder clarifies a variety of previous results by putting them into a systematic framework. Moreover, the clear and distinct functional association of flexible and constrained disorder will allow for new approaches and more specific algorithms for disorder detection in a functional context. Finally, in flexible disordered regions, we demonstrate clear evolutionary selection of protein disorder with little selection on primary structure, which has important implications for sequence-based studies of protein structure and evolution

Familial pneumothorax: towards precision medicine.

One in 10 patients suffering from primary spontaneous pneumothoraces has a family history of the disorder. Such familial pneumothoraces can occur in isolation, but can also be the presentation of serious genetic disorders with life-threatening vascular or cancerous complications. As the pneumothorax frequently precedes the more dangerous complications by many years, it provides an opportunity to intervene in a focused manner, permitting the practice of precision medicine. In this review, we will discuss the clinical manifestations and underlying biology of the genetic causes of familial pneumothorax

Molecular Gas in NUclei of GAlaxies (NUGA): VI. Detection of a molecular gas disk/torus via HCN in the Seyfert2 galaxy NGC6951?

Several studies of nearby active galaxies indicate significantly higher HCN-to-CO intensity ratios in AGN than in starburst (SB) environments. HCN enhancement can be caused by many different effects, such as higher gas densities/temperatures, UV/X-ray radiation, and non-collisional excitation. As active galaxies often exhibit intense circumnuclear SB, high angular resolution/sensitivity observations are of paramount importance to disentangling the influence of SB from that of nuclear activity on the chemistry of the surrounding molecular gas. The tight relation of HCN enhancement and nuclear activity may qualify HCN as an ideal tracer of molecular gas close to the AGN, providing complementary and additional information to that gained via CO. NGC6951 houses nuclear and SB activity, making it an ideal testbed in which to study the effects of different excitation conditions on the molecular gas. We used the new ABCD configurations of the IRAM PdBI to observe HCN(1-0) in NGC6951 at high angular resolution (1''). We detect very compact (<50pc) HCN emission in its nucleus, supporting previous hints of nuclear gas structure. Our observations also reveal HCN emission in the SB ring and resolve it into several peaks, leading to a higher coincidence between the HCN and CO distributions than previously reported. We find a significantly higher HCN-to-CO intensity ratio (>0.4) in the nucleus than in the SB ring (0.02-0.05). As for NGC1068, this might result from a higher HCN abundance in the centre due to an X-ray dominated gas chemistry, but a higher gas density/temperature or additional non-collisional excitation of HCN cannot be entirely ruled out, based on these observations. The compact HCN emission is associated with rotating gas in a circumnuclear disk/torus.Comment: Letter accepted for publication in a special issue of A&A presenting results of the new extended configuration at the IRAM PdBI, to appear most likely around June 2007. Letter has 4 pages and 2 figures. Abstract has been shortened to meet the line limits of astrop-p

Guidance for management of free-roaming community cats: a bioeconomic analysis

Objectives This study used computer simulation modeling to estimate and compare costs of different free-roaming cat (FRC) management options (lethal and non-lethal removal, trap–neuter–return, combinations of these options and no action) and their ability to reduce FRC population abundance in open demographic settings. The findings provide a resource for selecting management approaches that are well matched for specific communities, goals and timelines, and they represent use of best available science to address FRC issues. Methods Multiple FRC management approaches were simulated at varying intensities using a stochastic individual- based model in the software package Vortex. Itemized costs were obtained from published literature and expert feedback. Metrics generated to evaluate and compare management scenarios included final population size, total cost and a cost efficiency index, which was the ratio between total cost and population size reduction. Results Simulations suggested that cost-effective reduction of FRC numbers required sufficient management intensity, regardless of management approach, and greatly improved when cat abandonment was minimized. Removal yielded the fastest initial reduction in cat abundance, but trap–neuter–return was a viable and potentially more cost-effective approach if performed at higher intensities over a sufficient duration. Of five management scenarios that reduced the final population size by approximately 45%, the three scenarios that relied exclusively on removal were considerably more expensive than the two scenarios that relied exclusively or primarily on sterilization. Conclusions and relevance FRCs present a challenge in many municipalities, and stakeholders representing different perspectives may promote varying and sometimes incompatible population management policies and strategies. Although scientific research is often used to identify FRC impacts, its use to identify viable, cost-effective management solutions has been inadequate. The data provided by simulating different interventions, combined with community- specific goals, priorities and ethics, provide a framework for better-informed FRC policy and management outcomes

Beyond the Exome: What’s Next in Diagnostic Testing for Mendelian Conditions

Despite advances in clinical genetic testing, including the introduction of exome sequencing (ES), more than 50% of individuals with a suspected Mendelian condition lack a precise molecular diagnosis. Clinical evaluation is increasingly undertaken by specialists outside of clinical genetics, often occurring in a tiered fashion and typically ending after ES. The current diagnostic rate reflects multiple factors, including technical limitations, incomplete understanding of variant pathogenicity, missing genotype-phenotype associations, complex gene-environment interactions, and reporting differences between clinical labs. Maintaining a clear understanding of the rapidly evolving landscape of diagnostic tests beyond ES, and their limitations, presents a challenge for non-genetics professionals. Newer tests, such as short-read genome or RNA sequencing, can be challenging to order, and emerging technologies, such as optical genome mapping and long-read DNA sequencing, are not available clinically. Furthermore, there is no clear guidance on the next best steps after inconclusive evaluation. Here, we review why a clinical genetic evaluation may be negative, discuss questions to be asked in this setting, and provide a framework for further investigation, including the advantages and disadvantages of new approaches that are nascent in the clinical sphere. We present a guide for the next best steps after inconclusive molecular testing based upon phenotype and prior evaluation, including when to consider referral to research consortia focused on elucidating the underlying cause of rare unsolved genetic disorders

Genetic architecture of laterality defects revealed by whole exome sequencing

Aberrant left-right patterning in the developing human embryo can lead to a broad spectrum of congenital malformations. The causes of most laterality defects are not known, with variants in established genes accounting for <20% of cases. We sought to characterize the genetic spectrum of these conditions by performing whole-exome sequencing of 323 unrelated laterality cases. We investigated the role of rare, predicted-damaging variation in 1726 putative laterality candidate genes derived from model organisms, pathway analyses, and human phenotypes. We also evaluated the contribution of homo/hemizygous exon deletions and gene-based burden of rare variation. A total of 28 candidate variants (26 rare predicted-damaging variants and 2 hemizygous deletions) were identified, including variants in genes known to cause heterotaxy and primary ciliary dyskinesia (ACVR2B, NODAL, ZIC3, DNAI1, DNAH5, HYDIN, MMP21), and genes without a human phenotype association, but with prior evidence for a role in embryonic laterality or cardiac development. Sanger validation of the latter variants in probands and their parents revealed no de novo variants, but apparent transmitted heterozygous (ROCK2, ISL1, SMAD2), and hemizygous (RAI2, RIPPLY1) variant patterns. Collectively, these variants account for 7.1% of our study subjects. We also observe evidence for an excess burden of rare, predicted loss-of-function variation in PXDNL and BMS1- two genes relevant to the broader laterality phenotype. These findings highlight potential new genes in the development of laterality defects, and suggest extensive locus heterogeneity and complex genetic models in this class of birth defects

A visual and curatorial approach to clinical variant prioritization and disease gene discovery in genome-wide diagnostics

Background: Genome-wide data are increasingly important in the clinical evaluation of human disease. However, the large number of variants observed in individual patients challenges the efficiency and accuracy of diagnostic review. Recent work has shown that systematic integration of clinical phenotype data with genotype information can improve diagnostic workflows and prioritization of filtered rare variants. We have developed visually interactive, analytically transparent analysis software that leverages existing disease catalogs, such as the Online Mendelian Inheritance in Man database (OMIM) and the Human Phenotype Ontology (HPO), to integrate patient phenotype and variant data into ranked diagnostic alternatives. Methods: Our tool, “OMIM Explorer” (http://www.omimexplorer.com), extends the biomedical application of semantic similarity methods beyond those reported in previous studies. The tool also provides a simple interface for translating free-text clinical notes into HPO terms, enabling clinical providers and geneticists to contribute phenotypes to the diagnostic process. The visual approach uses semantic similarity with multidimensional scaling to collapse high-dimensional phenotype and genotype data from an individual into a graphical format that contextualizes the patient within a low-dimensional disease map. The map proposes a differential diagnosis and algorithmically suggests potential alternatives for phenotype queries—in essence, generating a computationally assisted differential diagnosis informed by the individual’s personal genome. Visual interactivity allows the user to filter and update variant rankings by interacting with intermediate results. The tool also implements an adaptive approach for disease gene discovery based on patient phenotypes. Results: We retrospectively analyzed pilot cohort data from the Baylor Miraca Genetics Laboratory, demonstrating performance of the tool and workflow in the re-analysis of clinical exomes. Our tool assigned to clinically reported variants a median rank of 2, placing causal variants in the top 1 % of filtered candidates across the 47 cohort cases with reported molecular diagnoses of exome variants in OMIM Morbidmap genes. Our tool outperformed Phen-Gen, eXtasy, PhenIX, PHIVE, and hiPHIVE in the prioritization of these clinically reported variants. Conclusions: Our integrative paradigm can improve efficiency and, potentially, the quality of genomic medicine by more effectively utilizing available phenotype information, catalog data, and genomic knowledge

Understanding Sectoral Differences in Downward Real Wage Rigidity: Workforce Composition, Institutions, Technology and Competition

This paper examines whether differences in wage rigidity across sectors can be explained by differences in workforce composition, competition, technology and wage-bargaining institutions. We adopt the measure of downward real wage rigidity (DRWR) developed by Dickens and Goette (2006) and rely on a large administrative matched employer-employee dataset for Belgium over the period 1990-2002. Firstly, our results indicate that DRWR is significantly higher for white-collar workers and lower for older workers and for workers with higher earnings and bonuses. Secondly, beyond labour force composition effects, sectoral differences in DRWR are related to competition, firm size, technology and wage bargaining institutions. We find that wages are more rigid in more competitive sectors, in labour-intensive sectors, and in sectors with predominant centralised wage setting at the sector level as opposed to firm-level wage agreements