pinecone/core-2020-05-10-deduplication huggingface dataset:
Haplotype reference consortium panel: Practical implications of imputations with large reference panels

Recently, the Haplotype Reference Consortium (HRC) released a large imputation panel that allows more accurate imputation of genetic variants. In this study, we compared a set of directly assayed common and rare variants from an exome array to imputed genotypes, that is, 1000 genomes project (1000GP) and HRC. We showed that imputation using the HRC panel improved the concordance between assayed and imputed genotypes at common, and especially, low-frequency variants. Furthermore, we performed a genome-wide association meta-analysis of vertical cup-disc ratio, a highly heritable endophenotype of glaucoma, in four cohorts using 1000GP and HRC imputations. We compared the results of the meta-analysis using 1000GP to the meta-analysis results using HRC. Overall, we found that using HRC imputation significantly improved P values (P = 3.07 × 10-61), particularly for suggestive variants. Both meta-analyses were performed in the same sample size, yet we found eight genome-wide significant loci in the HRC-based meta-analysis versus seven genome-wide significant loci in the 1000GP-based meta-analysis. This study provides supporting evidence of the new avenues for gene discovery and fine mapping that the HRC imputation panel offers
VariantValidator: Accurate validation, mapping and formatting of sequence variation descriptions.

The Human Genome Variation Society (HGVS) variant nomenclature is widely used to describe sequence variants in scientific publications, clinical reports and databases. However, the HGVS recommendations are complex and this often results in inaccurate variant descriptions being reported. The open-source hgvs Python package (https://github.com/biocommons/hgvs) provides a programmatic interface for parsing, manipulating, formatting and validating of variants according to the HGVS recommendations, but does not provide a user-friendly web interface. We have developed a web-based variant validation tool, VariantValidator (https://variantvalidator.org/), which utilizes the hgvs Python package and provides additional functionality to assist users who wish to accurately describe and report sequence-level variations that are compliant with the HGVS recommendations. VariantValidator was designed to ensure that users are guided through the intricacies of the HGVS nomenclature, e.g. if the user makes a mistake, VariantValidator automatically corrects the mistake if it can, or provides helpful guidance if it cannot. In addition, VariantValidator has the facility to interconvert genomic variant descriptions in HGVS and Variant Call Format (VCF) with a degree of accuracy which surpasses most competing solutions.Wellcome Trust. Grant Number: 097828/Z/11/BPeer-reviewedPublisher Versio
MYO5B, STX3, and STXBP2 mutations reveal a common disease mechanism that unifies a subset of congenital diarrheal disorders: A mutation update

Microvillus inclusion disease (MVID) is a rare but fatal autosomal recessive congenital diarrheal disorder caused by MYO5B mutations. In 2013, we launched an open-access registry for MVID patients and their MYO5B mutations (www.mvid-central.org). Since then, additional unique MYO5B mutations have been identified in MVID patients, but also in non-MVID patients. Animal models have been generated that formally prove the causality between MYO5B and MVID. Importantly, mutations in two other genes, STXBP2 and STX3, have since been associated with variants of MVID, shedding new light on the pathogenesis of this congenital diarrheal disorder. Here, we review these additional genes and their mutations. Furthermore, we discuss recent data from cell studies that indicate that the three genes are functionally linked and, therefore, may constitute a common disease mechanism that unifies a subset of phenotypically linked congenital diarrheal disorders. We present new data based on patient material to support this. To congregate existing and future information on MVID geno-/phenotypes, we have updated and expanded the MVID registry to include all currently known MVID-associated gene mutations, their demonstrated or predicted functional consequences, and associated clinical information
Thorough in silico and in vitro cDNA analysis of 21 putative BRCA1 and BRCA2 splice variants and a complex tandem duplication in BRCA2 allowing the identification of activated cryptic splice donor sites in BRCA2 exon 11

For 21 putative BRCA1 and BRCA2 splice site variants, the concordance between mRNA analysis and predictions by in silico programs was evaluated. Aberrant splicing was confirmed for 12 alterations. In silico prediction tools were helpful to determine for which variants cDNA analysis is warranted, however, predictions for variants in the Cartegni consensus region but outside the canonical sites, were less reliable. Learning algorithms like Adaboost and Random Forest outperformed the classical tools. Further validations are warranted prior to implementation of these novel tools in clinical settings. Additionally, we report here for the first time activated cryptic donor sites in the large exon 11 of BRCA2 by evaluating the effect at the cDNA level of a novel tandem duplication (5 breakpoint in intron 4; 3 breakpoint in exon 11) and of a variant disrupting the splice donor site of exon 11 (c.6841+1G>C). Additional sites were predicted, but not activated. These sites warrant further research to increase our knowledge on cis and trans acting factors involved in the conservation of correct transcription of this large exon. This may contribute to adequate design of ASOs (antisense oligonucleotides), an emerging therapy to render cancer cells sensitive to PARP inhibitor and platinum therapies
A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3

The Loeys-Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal, and ocular system. Most typically, LDS patients present with aortic aneurysms and arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate. Initially, mutations in transforming growth factor-β (TGF-β) receptors (TGFBR1 and TGFBR2) were described to cause LDS, hereby leading to impaired TGF-β signaling. More recently, TGF-β ligands, TGFB2 and TGFB3, as well as intracellular downstream effectors of the TGF-β pathway, SMAD2 and SMAD3, were shown to be involved in LDS. This emphasizes the role of disturbed TGF-β signaling in LDS pathogenesis. Since most literature so far has focused on TGFBR1/2, we provide a comprehensive review on the known and some novel TGFB2/3 and SMAD2/3 mutations. For TGFB2 and SMAD3, the clinical manifestations, both of the patients previously described in the literature and our newly reported patients, are summarized in detail. This clearly indicates that LDS concerns a disorder with a broad phenotypical spectrum that is still emerging as more patients will be identified. All mutations described here are present in the corresponding Leiden Open Variant Database
The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity

Although the spliceogenic nature of the BRCA2 c.68-7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real-time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10-115. There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24) nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68-7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants
Results of next-generation sequencing gene panel diagnostics including copy-number variation analysis in 810 patients suspected of heritable thoracic aortic disorders

Simultaneous analysis of multiple genes using next-generation sequencing (NGS) technology has become widely available. Copy-number variations (CNVs) in disease-associated genes have emerged as a cause for several hereditary disorders. CNVs are, however, not routinely detected using NGS analysis. The aim of this study was to assess the diagnostic yield and the prevalence of CNVs using our panel of Hereditary Thoracic Aortic Disease (H-TAD)-associated genes. Eight hundred ten patients suspected of H-TAD were analyzed by targeted NGS analysis of 21 H-TAD associated genes. In addition, the eXome hidden Markov model (XHMM; an algorithm to identify CNVs in targeted NGS data) was used to detect CNVs in these genes. A pathogenic or likely pathogenic variant was found in 66 of 810 patients (8.1%). Of these 66 pathogenic or likely pathogenic variants, six (9.1%) were CNVs not detectable by routine NGS analysis. These CNVs were four intragenic (multi-)exon deletions in MYLK, TGFB2, SMAD3, and PRKG1, respectively. In addition, a large duplication including NOTCH1 and a large deletion encompassing SCARF2 were detected. As confirmed by additional analyses, both CNVs indicated larger chromosomal abnormalities, which could explain the phenotype in both patients. Given the clinical relevance of the identification of a genetic cause, CNV analysis using a method such as XHMM should be incorporated into the clinical diagnostic care for H-TAD patients
The mutation‐dependent pathogenicity of NPHS2 p.R229Q: A guide for clinical assessment

NPHS2, encoding podocin, is the major gene implicated in steroid‐resistant nephrotic syndrome. Its c.686G>A, p.R229Q variant is the first human variant with a mutation‐dependent pathogenicity; it is only pathogenic when trans‐associated to specific mutations. Secondary to its high allele frequency in the European, South Asian, African, and Latino populations, its benign trans‐associations can be accidentally identified in affected patients. Distinguishing pathogenic and benign p.R229Q associations can be challenging. In this paper, we present the currently known pathogenic and benign associations, and show that a rare p.R229Q association can be considered pathogenic if the variant in trans meets the following criteria; it affects the 270–351 residues and alters but does not disrupt the oligomerization, its p.R229Q association is found in a family with slowly progressing focal segmental glomerulosclerosis, but is expected to be rare in the general population (<1:106). We show that >15% of the p.R229Q associations identified so far in patients are benign
A rare missense mutation in a type 2 diabetes patient decreases the transcriptional activity of human sterol regulatory element binding protein-1

11 pages, 3figures, 1 table.-PMID: 16429400 [PubMed]Sterol regulatory element binding protein 1 (SREBP-1) transcription factors play a key role in energy homeostasis by regulating genes involved in both carbohydrate and lipid metabolism, and in adipocyte differentiation. The 5' end of the mRNA-encoding SREBP-1 exists in two forms, designated 1a and 1c. The divergence results from the use of two transcription start sites that produce two separate 5' exons, each of which is spliced to a common exon 2. Mutations in the sterol regulatory element binding protein gene (SREBF)-1 may contribute to insulin resistance states. However, the variants described to date do not affect the SREBP function. In this study, we investigated the functional consequences of a novel missense mutation common to both SREBP-1 isoforms identified in a Spanish Type 2 diabetic patient (c.677C>T, SREBP-1a p.T226M; c.605C>T, SREBP-1c p.T202M). Using reporter gene analysis and electrophoretic mobility shift assays, we found that this variant impaires the transcriptional activity and reduces DNA binding ability despite its comparable protein stability to the wild-type SREBP-1. This decreased activity impaires the expression of known downstream targets, such as the LDL receptor and fatty acid synthase genes. Our findings suggest that the threonine residue and/or surrounding region play an important role in the SREBP-1 functionThis study was supported by grants from Instituto de Salud Carlos III, Red de Centros (RCMN) C03/08, and from Ministerio de Educación y Ciencia (SAF2003-01262). S.V. is supported by a fellowship from Consejo Superior de Investigaciones Científicas I3P-BPD2001-1.Peer reviewe
Peer-review for the peer-review system

The process of peer-review of papers submitted for publication and of grant proposals is widely accepted in modern science as a crucial guarantee of high-quality work. Foremost in restricted research areas, anonymous reviewers and editors may use their power to slow down or even reject competitive yet worthwhile work that does not fit or is questioning their own dogmas. This potential peers conflict of interest of may be particularly expressed in areas where empirical proofs of findings are de facto impossible, e.g. in physical anthropology. An example, two-way anonymous (double-blind) peer-review process improves the overall quality of evaluation but it is hard to implement in a highly specialized research field. Yet, the introduction of a completely open peer-review policy would most likely be supported by the overwhelming majority of reviewers. Furthermore, it may increase the overall quality of peer-review with reviewers to have their name acknowledged. Science should be about the possibility of advertising fresh concepts on evidence-based results in a non-biased, egalitarian, and open way with transparency the prime goal of editing such scientific discourse. By raising our foremost concerns and, hopefully, by the implementation of the proposed policy, we believe that these stated goals can be achieved, thus enhancing the true purpose of peer review particularly in the complex situation of scientific niches
Promoting innovation and excellence to face the rapid diffusion of Novel Psychoactive Substances (NPS) in the EU :
                    the outcomes of the ReDNet project

Objectives: The recent emergence of new psychoactive compounds (NPS) has raised prominent challenges in the fields of drug policy, substance use research, public health and service provision. The Recreational Drugs European Network (ReDNet) project, funded by the European Commission, was implemented to improve the information stream to young people and professionals about effects/risks of NPS identifying online products and disseminating relevant information through technological tools. Methods: Regular multilingual qualitative assessments of websites, drugs fora and other online resources were carried out using the Google search engine in 8 languages from collaborating countries. These included: the UK, Norway, Belgium, Germany, Hungary, Poland, Italy and Spain. Products were tested and prevention messages were developed and disseminated via technological tools such as interactive websites, SMS alert, social networking (Facebook, Twitter), Multimedia (You Tube), Smartphone applications (iPhone), and virtual learning environments (Second Life). Results: The ReDNet project established itself as the first Europe-wide prevention programme designed for NPS based on the efficacy of novel ICT-based forms of intervention. More than 650 NPS products and combinations were identified; relevant information was disseminated to target population and advice was given to both EU/ international agencies and national policy makers. Conclusions: Web monitoring activities are essential for mapping the diffusion of NPS and the use of technological tools can be successfully incorporated in specific prevention programmes. Furthermore, the involvement of multi-disciplinary international partnerships was and continues to be fundamental for responding to such a prominent challenge
Inferring about individual drug and schizotypy effects on cognitive functioning in polydrug using mephedrone users before and after clubbing

Objective: Mephedrone has been recently made illegal in Europe, but little empirical evidence is available on its impact on human cognitive functions. We investigated acute and chronic effects of mephedrone consumption on drug-sensitive cognitive measures, while also accounting for the influence of associated additional drug use and personality features. Method: Twenty-six volunteers from the general population performed tasks measuring verbal learning, verbal fluency and cognitive flexibility before and after a potential drug-taking situation (pre- and post-clubbing at dance clubs, respectively). Participants also provided information on chronic and recent drug use, schizotypal (O-LIFE) and depressive symptoms (Beck depression inventory), sleep pattern and premorbid IQ. Results: We found that i) mephedrone users performed worse than non-users pre-clubbing, and deteriorated from the pre-clubbing to the post-clubbing assessment, ii) pre-clubbing cannabis and amphetamine (not mephedrone) use predicted relative cognitive attenuations, iii) post-clubbing, depression scores predicted relative cognitive attenuations, and iv) schizotypy was largely unrelated to cognitive functioning, apart from a negative relationship between cognitive disorganisation and verbal fluency. Conclusion: Results suggest that polydrug use and depressive symptoms in the general
population negatively affect cognition. For schizotypy, only elevated cognitive disorganisation showed potential links to a pathological cognitive profile previously reported along the psychosis dimension
Methoxetamine-related deaths in the UK :
                    an overview

Objective: The goal of this study is to provide an update on the data given on methoxetamine (MXE)-related fatalities that occurred in 2011???2013, presented at the Second International Conference on Novel Psychoactive Substances. Methods: Fatalities involving MXE were extracted from the database of the National Programme on Substance Abuse Deaths, which receives information on drug-related deaths from Coroners in the UK and Islands (Isle of Man, Jersey, Guernsey) and other data suppliers. Results: Eight cases, received by 3 September 2013, in which MXE was found at post-mortem and/or directly implicated in the death and/or mentioned in the Coroner's verdict are described. The median age at death was 27???years, with the majority of White ethnicity (6/8) and male (7/8). MXE was used together with other substances in 7/8 cases. MXE was found at post-mortem in all cases, directly implicated in the deaths of four and likely to have had an influence in two. Conclusions: More research needs to be conducted into its health effects and toxicity potential. Health care professionals should be made aware of the potential health harms of MXE, in order to develop early intervention measures and minimise the number of MXE-related poisonings and fatalities
Deaths of individuals aged 16-24 years in the UK after using mephedrone

Objective: Mephedrone is a stimulant drug chemically related to amphetamine, with effects similar to those of amphetamine and cocaine. This study aims to analyse fatalities following ingestion of mephedrone in the UK amongst 16-24 year olds in 2009-13, providing an update on data presented at the 2nd International Conference on Novel Psychoactive Substances. Methods: A literature search was undertaken to identify published information on pharmacology, toxicity, and fatalities associated with mephedrone. Fatalities involving mephedrone were extracted from the National Programme on Substance Abuse Deaths database, which receives information on drug-related deaths from Coroners in the UK and Islands and other data suppliers. Selection criteria: deceased aged 16-24 at time of death; mephedrone directly implicated in the cause of death and/or mentioned in the Coroner???s verdict. Results: Thirty cases met the study criteria and, when known, all were of White ethnicity, most (85%) had a history of drug use and 73% were male. Two-thirds (63%) were accidental poisonings. Mephedrone was used with other substances in most cases (87%); other substances were implicated in 60% of deaths. Conclusions: Mephedrone use can have potentially fatal consequences, especially in combination with other substances. Deaths in the 16-24 years age-group continue to occur from its use in the UK, despite it being a controlled drug. Health professionals and potential consumers should be alert to this risk
Human Rho guanine nucleotide exchange factor 11 gene is associated with schizophrenia in a Japanese population

ObjectiveThe human Rho guanine nucleotide exchange factor 11 (ARHGEF11) gene is one of the candidate genes for type 2 diabetes mellitus (T2DM). ARHGEF11 is mapped to chromosome 1q21, which has susceptible risk loci for T2DM and schizophrenia. We hypothesized that ARHGEF11 contributes to the pathogenesis of schizophrenia. 

MethodWe selected eight single nucleotide polymorphisms of ARHGEF11 that had significant associations with T2DM for a case-control association study of 490 patients with schizophrenia and 500 age-matched and sex-matched controls. 

ResultsWe did not find any differences in allelic, genotypic associations, or minor allele frequencies with schizophrenia. Analysis of the rs6427340-rs6427339 haplotype and the rs822585-rs6427340-rs6427339 haplotype combination provided significant evidence of an association with schizophrenia (global permutations p=0.00047 and 0.0032, respectively). C-C of the rs6427340-rs6427339 haplotype and A-C-C of the rs822585-rs6427340-rs6427339 haplotype carried higher risk factors for schizophrenia (permutation p=0.0010 and 0.0018, respectively). A-C-T of the rs822585-rs6427340-rs6427339 haplotype had a possible protective effect (permutation p=0.031). 

ConclusionThese results provide new evidence that ARHGEF11 may constitute a risk factor for schizophrenia