Back to the family: a renewed approach to rare variant studies

A report on the 62nd Annual Meeting of the American Society of Human Genetics, San Francisco, California, USA, 6-10 November 2012

EZH1/2 function mostly within canonical PRC2 and exhibit proliferation-dependent redundancy that shapes mutational signatures in cancer

Contains fulltext : 202562.pdf (Publisher’s version ) (Open Access

OTX2 Duplication Is Implicated in Hemifacial Microsomia

Hemifacial microsomia (HFM) is the second most common facial anomaly after cleft lip and palate. The phenotype is highly variable and most cases are sporadic. We investigated the disorder in a large pedigree with five affected individuals spanning eight meioses. Whole-exome sequencing results indicated the absence of a pathogenic coding point mutation. A genome-wide survey of segmental variations identified a 1.3 Mb duplication of chromosome 14q22.3 in all affected individuals that was absent in more than 1000 chromosomes of ethnically matched controls. The duplication was absent in seven additional sporadic HFM cases, which is consistent with the known heterogeneity of the disorder. To find the critical gene in the duplicated region, we analyzed signatures of human craniofacial disease networks, mouse expression data, and predictions of dosage sensitivity. All of these approaches implicated OTX2 as the most likely causal gene. Moreover, OTX2 is a known oncogenic driver in medulloblastoma, a condition that was diagnosed in the proband during the course of the study. Our findings suggest a role for OTX2 dosage sensitivity in human craniofacial development and raise the possibility of a shared etiology between a subtype of hemifacial microsomia and medulloblastoma

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Analyse des variants rares dans les maladies neurodégénératives humaines orientée par les modèles cellulaires de protéotoxicité

Aggregation of specific proteins within neurons and glia comprise the hallmark pathologies of neurodegenerative diseases like Alzheimer’s (AD) and Parkinson’s disease (PD). It remains uncertain whether different clinical diseases linked to misfolding of the same protein share common genetic risk drivers and whether different protein-aggregation pathologies are mechanistically related or distinct. In previous studies, we established amyloid-beta and alpha-synuclein yeast models that recapitulate the molecular pathologies of AD and PD, respectively. To address these questions, we performed targeted exome sequencing in 500 patients with four distinct synucleinopathies: PD, PD with dementia (PDD), dementia with Lewy bodies (LBD) and multiple system atrophy (MSA). Together with known AD and PD genes, we sequenced human homologs of genetic modulators of alpha-synuclein and beta-amyloid toxicity identified in genome-wide screens in yeast, including a broad range of orthologs to identify genetic drivers in diverse patient, cellular and disease specific contexts. Despite the small number of samples, the relatively small set of 430 genes allowed us to concentrate the statistical power on more likely targets. As a control, we compared the burden of rare variants to a cohort of more than 2500 healthy aged individuals with no reported history of cancer, cardiovascular disease, or neurodegenerative disease. Variants in both beta-amyloid (ARGHEF1, MAP2K3, PKN2, TEAD2) and alpha-synuclein (PTPRR, PTPRS, HKR1) genetic networks were enriched across different synucleinopathies compared to healthy aged controls, as were variants in both known PD and AD genes. Associations were independent of concomitant AD pathology. Gene-level tests, including a trend test developed for rare variant analysis, confirmed and extended these findings in additional MSA and PD cohorts. Our data implicate shared genetic drivers across distinct synucleinopathies and demonstrate convergent genetic networks in beta-amyloid and alpha-synuclein proteinopathies in humans. We envision that our cross-species approaches will continue to yield important insights for complex diseases with evolutionarily conserved biological mechanisms, and perhaps help fulfill therapeutic promises in the post-genomics era.L'agrégation de protéines spécifiques dans les neurones et la glie constitue la pathologie caractéristique des maladies neurodégénératives comme la maladie d'Alzheimer et la maladie de Parkinson. Cependant, on ne sait toujours pas si les différentes maladies cliniques liées au mauvais repliement d'une même protéine ont des facteurs de risque génétiques communs et si les différentes pathologies liées à l'agrégation des protéines sont mécaniquement liées ou distinctes. Dans des études précédentes, nous avons établi des modèles de levure amyloïde-bêta et alpha-synucléine qui récapitulent les pathologies moléculaires de la MA et de la MP, respectivement. Pour répondre à ces questions, nous avons effectué un séquençage ciblé de l'exome chez 500 patients atteints de quatre synucléinopathies distinctes : MP, MP avec démence (PDD), démence à corps de Lewy (LBD) et atrophie de systèmes multiples (MSA). En plus des gènes connus de la MA et de la MP, nous avons séquencé les homologues humains des modulateurs génétiques de la toxicité de l'alpha-synucléine et de la bêta-amyloïde identifiés dans des cribles à l'échelle du génome dans la levure, y compris un large éventail d'orthologues afin d'identifier les moteurs génétiques dans divers contextes spécifiques aux patients, aux cellules et aux maladies. L’ensemble relativement restreint de 430 gènes nous a permis de concentrer la puissance statistique sur des cibles plus probables. À titre de contrôle, nous avons comparé le taux des variantes rares à une cohorte de plus de 2 500 personnes âgées en bonne santé, sans antécédents déclarés de cancer, de maladie cardiovasculaire ou de maladie neurodégénérative. Les variants des réseaux génétiques de la bêta-amyloïde et de l'alpha-synucléine étaient enrichis dans les différentes synucléinopathies par rapport aux témoins âgés sains, tout comme les variants des gènes connus de la MP et de la MA. Les associations étaient indépendantes de la pathologie concomitante de la MA. Des tests au niveau des gènes, y compris un test de tendance développé pour l'analyse des variants rares, ont confirmé et étendu ces résultats dans des cohortes supplémentaires de MSA et de PD. Nos données impliquent des facteurs génétiques communs à des synucléinopathies distinctes et démontrent des réseaux génétiques convergents dans les protéinopathies bêta-amyloïde et alpha-synucléine chez l'homme. Nous pensons que nos approches inter-espèces continueront à fournir des informations importantes sur des maladies complexes dont les mécanismes biologiques sont conservés au cours de l'évolution, et qu'elles permettront peut-être de répondre aux promesses thérapeutiques de l'ère post-génomique

Analyse des variants rares dans les maladies neurodégénératives humaines orientée par les modèles cellulaires de protéotoxicité

Aggregation of specific proteins within neurons and glia comprise the hallmark pathologies of neurodegenerative diseases like Alzheimer’s (AD) and Parkinson’s disease (PD). It remains uncertain whether different clinical diseases linked to misfolding of the same protein share common genetic risk drivers and whether different protein-aggregation pathologies are mechanistically related or distinct. In previous studies, we established amyloid-beta and alpha-synuclein yeast models that recapitulate the molecular pathologies of AD and PD, respectively. To address these questions, we performed targeted exome sequencing in 500 patients with four distinct synucleinopathies: PD, PD with dementia (PDD), dementia with Lewy bodies (LBD) and multiple system atrophy (MSA). Together with known AD and PD genes, we sequenced human homologs of genetic modulators of alpha-synuclein and beta-amyloid toxicity identified in genome-wide screens in yeast, including a broad range of orthologs to identify genetic drivers in diverse patient, cellular and disease specific contexts. Despite the small number of samples, the relatively small set of 430 genes allowed us to concentrate the statistical power on more likely targets. As a control, we compared the burden of rare variants to a cohort of more than 2500 healthy aged individuals with no reported history of cancer, cardiovascular disease, or neurodegenerative disease. Variants in both beta-amyloid (ARGHEF1, MAP2K3, PKN2, TEAD2) and alpha-synuclein (PTPRR, PTPRS, HKR1) genetic networks were enriched across different synucleinopathies compared to healthy aged controls, as were variants in both known PD and AD genes. Associations were independent of concomitant AD pathology. Gene-level tests, including a trend test developed for rare variant analysis, confirmed and extended these findings in additional MSA and PD cohorts. Our data implicate shared genetic drivers across distinct synucleinopathies and demonstrate convergent genetic networks in beta-amyloid and alpha-synuclein proteinopathies in humans. We envision that our cross-species approaches will continue to yield important insights for complex diseases with evolutionarily conserved biological mechanisms, and perhaps help fulfill therapeutic promises in the post-genomics era.L'agrégation de protéines spécifiques dans les neurones et la glie constitue la pathologie caractéristique des maladies neurodégénératives comme la maladie d'Alzheimer (MA) et la maladie de Parkinson (MP). Cependant, on ne sait toujours pas si les différentes maladies cliniques liées au mauvais repliement d'une même protéine ont des facteurs de risque génétiques communs et si les différentes pathologies liées à l'agrégation des protéines sont mécaniquement liées ou distinctes. Dans des études précédentes, nous avons établi des modèles de levure amyloïde-bêta et alpha-synucléine qui récapitulent les pathologies moléculaires de la MA et de la MP, respectivement. Pour répondre à ces questions, nous avons effectué un séquençage ciblé de l'exome chez 500 patients atteints de quatre synucléinopathies distinctes : MP, MP avec démence (MPD), maladie à corps de Lewy (MCL) et atrophie de systèmes multiples (ASM). En plus des gènes connus de la MA et de la MP, nous avons séquencé les homologues humains des modulateurs génétiques de la toxicité de l'alpha-synucléine et de la bêta-amyloïde identifiés dans des cribles à l'échelle du génome dans la levure, y compris un large éventail d'orthologues afin d'identifier les moteurs génétiques dans divers contextes spécifiques aux patients, aux cellules et aux maladies. L’ensemble relativement restreint de 430 gènes nous a permis de concentrer la puissance statistique sur des cibles plus probables. À titre de contrôle, nous avons comparé le poids des variantes rares à une cohorte de plus de 2 500 personnes âgées en bonne santé, sans antécédents déclarés de cancer, de maladie cardiovasculaire ou de maladie neurodégénérative. Les variants des réseaux génétiques de la bêta-amyloïde et de l'alpha-synucléine étaient enrichis dans les différentes synucléinopathies par rapport aux témoins âgés sains, tout comme les variants des gènes connus de la MP et de la MA. Les associations étaient indépendantes de la pathologie concomitante de la MA. Des tests au niveau des gènes, y compris un test de tendance développé pour l'analyse des variants rares, ont confirmé et étendu ces résultats dans des cohortes supplémentaires d’ASM et de la MP. Nos données impliquent des facteurs génétiques communs à des synucléinopathies distinctes et démontrent des réseaux génétiques convergents dans les protéinopathies bêta-amyloïde et alpha-synucléine chez l'homme. Nous pensons que nos approches inter-espèces continueront à fournir des informations importantes sur des maladies complexes dont les mécanismes biologiques sont conservés au cours de l'évolution, et qu'elles permettront peut-être de répondre aux promesses thérapeutiques de l'ère post-génomique