Identification of chromosomal aneuploidies and copy number variants that are associated with fetal structural anomalies has substantial value. Although whole-exome sequencing (WES) has been applied ...to case series of a few selected prenatal cases, its value in routine clinical settings has not been prospectively assessed in a large unselected cohort of fetuses with structural anomalies. We therefore aimed to determine the incremental diagnostic yield (ie, the added value) of WES following uninformative results of standard investigations with karyotype testing and chromosomal microarray in an unselected cohort of sequential pregnancies showing fetal structural anomalies.
In this prospective cohort study, the parents of fetuses who were found to have a structural anomaly in a prenatal ultrasound were screened for possible participation in the study. These participants were predominantly identified in or were referred to the Columbia University Carmen and John Thain Center for Prenatal Pediatrics (New York, NY, USA). Fetuses with confirmed aneuploidy or a causal pathogenic copy number variant were excluded from WES analyses. By use of WES of the fetuses and parents (parent–fetus trios), we identified genetic variants that indicated an underlying cause (diagnostic genetic variants) and genetic variants that met the criteria of bioinformatic signatures that had previously been described to be significantly enriched among diagnostic genetic variants.
Between April 24, 2015, and April 19, 2017, 517 sequentially identified pregnant women found to have fetuses with a structural anomaly were screened for their eligibility for inclusion in our study. 71 (14%) couples declined testing, 87 (17%) trios were missing at least one DNA sample (from either parent or the fetus), 69 (13%) trios had a clinically relevant abnormal karyotype or chromosomal microarray finding, 51 (10%) couples did not consent to WES or withdrew consent, and five (1%) samples were not of good enough quality for analysis. DNA samples from 234 (45%) eligible trios were therefore used for analysis of the primary outcome. By use of trio sequence data, we identified diagnostic genetic variants in 24 (10%) families. Mutations with bioinformatic signatures that were indicative of pathogenicity but with insufficient evidence to be considered diagnostic were also evaluated; 46 (20%) of the 234 fetuses assessed were found to have such signatures.
Our analysis of WES data in a prospective cohort of unselected fetuses with structural anomalies shows the value added by WES following the use of routine genetic tests. Our findings suggest that, in cases of fetal anomalies in which assessment with karyotype testing and chromosomal microarray fail to determine the underlying cause of a structural anomaly, WES can add clinically relevant information that could assist current management of a pregnancy. The unique challenges of WES-based prenatal diagnostics require analysis by a multidisciplinary team of perinatal practitioners and laboratory specialists.
Institute for Genomic Medicine (Columbia University Irving Medical Center).
A central challenge in interpreting personal genomes is determining which mutations most likely influence disease. Although progress has been made in scoring the functional impact of individual ...mutations, the characteristics of the genes in which those mutations are found remain largely unexplored. For example, genes known to carry few common functional variants in healthy individuals may be judged more likely to cause certain kinds of disease than genes known to carry many such variants. Until now, however, it has not been possible to develop a quantitative assessment of how well genes tolerate functional genetic variation on a genome-wide scale. Here we describe an effort that uses sequence data from 6503 whole exome sequences made available by the NHLBI Exome Sequencing Project (ESP). Specifically, we develop an intolerance scoring system that assesses whether genes have relatively more or less functional genetic variation than expected based on the apparently neutral variation found in the gene. To illustrate the utility of this intolerance score, we show that genes responsible for Mendelian diseases are significantly more intolerant to functional genetic variation than genes that do not cause any known disease, but with striking variation in intolerance among genes causing different classes of genetic disease. We conclude by showing that use of an intolerance ranking system can aid in interpreting personal genomes and identifying pathogenic mutations.
Gene panel and exome sequencing have revealed a high rate of molecular diagnoses among diseases where the genetic architecture has proven suitable for sequencing approaches, with a large number of ...distinct and highly penetrant causal variants identified among a growing list of disease genes. The challenge is, given the DNA sequence of a new patient, to distinguish disease-causing from benign variants. Large samples of human standing variation data highlight regional variation in the tolerance to missense variation within the protein-coding sequence of genes. This information is not well captured by existing bioinformatic tools, but is effective in improving variant interpretation. To address this limitation in existing tools, we introduce the missense tolerance ratio (MTR), which summarizes available human standing variation data within genes to encapsulate population level genetic variation. We find that patient-ascertained pathogenic variants preferentially cluster in low MTR regions (
< 0.005) of well-informed genes. By evaluating 20 publicly available predictive tools across genes linked to epilepsy, we also highlight the importance of understanding the empirical null distribution of existing prediction tools, as these vary across genes. Subsequently integrating the MTR with the empirically selected bioinformatic tools in a gene-specific approach demonstrates a clear improvement in the ability to predict pathogenic missense variants from background missense variation in disease genes. Among an independent test sample of case and control missense variants, case variants (0.83 median score) consistently achieve higher pathogenicity prediction probabilities than control variants (0.02 median score; Mann-Whitney
test,
< 1 × 10
). We focus on the application to epilepsy genes; however, the framework is applicable to disease genes beyond epilepsy.
Ranking human genes based on their tolerance to functional genetic variation can greatly facilitate patient genome interpretation. It is well established, however, that different parts of proteins ...can have different functions, suggesting that it will ultimately be more informative to focus attention on functionally distinct portions of genes. Here we evaluate the intolerance of genic sub-regions using two biological sub-region classifications. We show that the intolerance scores of these sub-regions significantly correlate with reported pathogenic mutations. This observation extends the utility of intolerance scores to indicating where pathogenic mutations are mostly likely to fall within genes.
The quality and production technology of grain-oriented electrical steel have been improved over the past 70 years. Firstly, through the improvement of {1
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1〉 alignment, development of ...thinner-gauge material, and establishment of magnetic domain refining techniques, magnetic properties of the material have been improved dramatically. Secondly, many mechanisms have been proposed for the reason why Goss texture develops selectively during the final annealing stage. Thirdly, to reduce manufacturing costs, many new techniques have been developed. The most advanced in commercial realization is the application of low-temperature slab-reheating techniques. Despite these achievements, the mechanisms of texture selection are not yet clear in all their details. Further improvement of magnetic properties and the application of compact production process for grain-oriented electrical steels in commercial production are needed to be realized.
Identifying the underlying causes of disease requires accurate interpretation of genetic variants. Current methods ineffectively capture pathogenic non-coding variants in genic regions, resulting in ...overlooking synonymous and intronic variants when searching for disease risk. Here we present the Transcript-inferred Pathogenicity (TraP) score, which uses sequence context alterations to reliably identify non-coding variation that causes disease. High TraP scores single out extremely rare variants with lower minor allele frequencies than missense variants. TraP accurately distinguishes known pathogenic and benign variants in synonymous (AUC = 0.88) and intronic (AUC = 0.83) public datasets, dismissing benign variants with exceptionally high specificity. TraP analysis of 843 exomes from epilepsy family trios identifies synonymous variants in known epilepsy genes, thus pinpointing risk factors of disease from non-coding sequence data. TraP outperforms leading methods in identifying non-coding variants that are pathogenic and is therefore a valuable tool for use in gene discovery and the interpretation of personal genomes.While non-coding synonymous and intronic variants are often not under strong selective constraint, they can be pathogenic through affecting splicing or transcription. Here, the authors develop a score that uses sequence context alterations to predict pathogenicity of synonymous and non-coding genetic variants, and provide a web server of pre-computed scores.
Idiopathic pulmonary fibrosis (IPF) is an increasingly recognized, often fatal lung disease of unknown etiology.
The aim of this study was to use whole-exome sequencing to improve understanding of ...the genetic architecture of pulmonary fibrosis.
We performed a case-control exome-wide collapsing analysis including 262 unrelated individuals with pulmonary fibrosis clinically classified as IPF according to American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines (81.3%), usual interstitial pneumonia secondary to autoimmune conditions (11.5%), or fibrosing nonspecific interstitial pneumonia (7.2%). The majority (87%) of case subjects reported no family history of pulmonary fibrosis.
We searched 18,668 protein-coding genes for an excess of rare deleterious genetic variation using whole-exome sequence data from 262 case subjects with pulmonary fibrosis and 4,141 control subjects drawn from among a set of individuals of European ancestry. Comparing genetic variation across 18,668 protein-coding genes, we found a study-wide significant (P < 4.5 × 10
) case enrichment of qualifying variants in TERT, RTEL1, and PARN. A model qualifying ultrarare, deleterious, nonsynonymous variants implicated TERT and RTEL1, and a model specifically qualifying loss-of-function variants implicated RTEL1 and PARN. A subanalysis of 186 case subjects with sporadic IPF confirmed TERT, RTEL1, and PARN as study-wide significant contributors to sporadic IPF. Collectively, 11.3% of case subjects with sporadic IPF carried a qualifying variant in one of these three genes compared with the 0.3% carrier rate observed among control subjects (odds ratio, 47.7; 95% confidence interval, 21.5-111.6; P = 5.5 × 10
).
We identified TERT, RTEL1, and PARN-three telomere-related genes previously implicated in familial pulmonary fibrosis-as significant contributors to sporadic IPF. These results support the idea that telomere dysfunction is involved in IPF pathogenesis.
We describe studies in molecular profiling and biological pathway analysis that use sparse latent factor and regression models for microarray gene expression data. We discuss breast cancer ...applications and key aspects of the modeling and computational methodology. Our case studies aim to investigate and characterize heterogeneity of structure related to specific oncogenic pathways, as well as links between aggregate patterns in gene expression profiles and clinical biomarkers. Based on the metaphor of statistically derived "factors" as representing biological "subpathway" structure, we explore the decomposition of fitted sparse factor models into pathway subcomponents and investigate how these components overlay multiple aspects of known biological activity. Our methodology is based on sparsity modeling of multivariate regression, ANOVA, and latent factor models, as well as a class of models that combines all components. Hierarchical sparsity priors address questions of dimension reduction and multiple comparisons, as well as scalability of the methodology. The models include practically relevant non-Gaussian/nonparametric components for latent structure, underlying often quite complex non-Gaussianity in multivariate expression patterns. Model search and fitting are addressed through stochastic simulation and evolutionary stochastic search methods that are exemplified in the oncogenic pathway studies. Supplementary supporting material provides more details of the applications, as well as examples of the use of freely available software tools for implementing the methodology.
Traditional approaches to coastal defence often struggle to reduce the risks of accelerated climate change. Incorporating nature-based components into coastal defences may enhance adaptation to ...climate change with added benefits, but we need to compare their performance against conventional hard measures. We conduct a meta-analysis that compares the performances of hard, hybrid, soft and natural measures for coastal defence across different functions of risk reduction, climate change mitigation, and cost-effectiveness. Hybrid and soft measures offer higher risk reduction and climate change mitigation benefits than unvegetated natural systems, while performing on par with natural measures. Soft and hybrid measures are more cost-effective than hard measures, while hybrid measures provide the highest hazard reduction among all measures. All coastal defence measures have a positive economic return over a 20-year period. Mindful of risk context, our results provide strong an evidence-base for integrating and upscaling nature-based components into coastal defences in lower risk areas.
Abstract
Small-scale aquaculture systems can contribute significantly to food and nutritional security, poverty alleviation, and rural development, especially in developing countries. However, the ...intensification of aquaculture systems often has negative environmental outcomes. The adoption of diversification practices (e.g. polyculture, pond-dike cropping (PDC)) and better management practices (BMPs) has been identified as a possible approach to intensify sustainably small-scale aquaculture production. This study assesses the sustainability outcomes of the adoption of diversification practices and BMPs in small-scale production models. We focus on Myanmar, a developing country characterized by a rapidly expanding small-scale aquaculture sector. We analyze 624 household surveys with small-scale aquaculture producers in central and northern Myanmar. We estimate the effects of diversification practices and BMPs on different sustainability outcomes, namely economic outcomes (i.e. aquaculture yield and benefit-cost ratio), environmental outcomes (i.e. nitrogen and phosphorus use efficiency), and food security outcomes (i.e. fish self-consumption and household dietary diversity) through linear mixed-effects models. Our results reveal that diversified production models (whether integrating or not integrating BMPs) could have significant positive effects on economic and food security outcomes, as well as phosphorus use efficiency, compared to ‘unimproved monoculture’. However, such production models do not seem to have any major effect on nitrogen use efficiency. The adoption of BMPs on diversified production models seems to have little (if any) added effect on any of the studied sustainability outcomes, which suggests the need to improve existing BMPs or even develop new BMPs fit for Myanmar’s context. These findings have implications about the possible contribution of diversification practices and BMPs for enabling sustainable intensification in small-scale aquaculture settings in Myanmar, and other rural developing contexts.
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