| 1. |
- Fresard, Laure, et al.
(författare)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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Ingår i: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Tidskriftsartikel (refereegranskat)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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| 2. |
- Downey, Harriet, et al.
(författare)
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Training future generations to deliver evidence-based conservation and ecosystem management
- 2021
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Ingår i: Ecological Solutions and Evidence. - : Wiley. - 2688-8319. ; 2:1
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Forskningsöversikt (refereegranskat)abstract
- 1. To be effective, the next generation of conservation practitioners and managers need to be critical thinkers with a deep understanding of how to make evidence-based decisions and of the value of evidence synthesis.2. If, as educators, we do not make these priorities a core part of what we teach, we are failing to prepare our students to make an effective contribution to conservation practice.3. To help overcome this problem we have created open access online teaching materials in multiple languages that are stored in Applied Ecology Resources. So far, 117 educators from 23 countries have acknowledged the importance of this and are already teaching or about to teach skills in appraising or using evidence in conservation decision-making. This includes 145 undergraduate, postgraduate or professional development courses.4. We call for wider teaching of the tools and skills that facilitate evidence-based conservation and also suggest that providing online teaching materials in multiple languages could be beneficial for improving global understanding of other subject areas.
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| 3. |
- Bouchard, Claude, et al.
(författare)
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Personalized Preventive Medicine : Genetics and the Response to Regular Exercise in Preventive Interventions
- 2015
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Ingår i: Progress in cardiovascular diseases. - : Elsevier BV. - 0033-0620 .- 1873-1740. ; 57:4, s. 337-346
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Tidskriftsartikel (refereegranskat)abstract
- Regular exercise and a physically active lifestyle have favorable effects on health. Several issues related to this theme are addressed in this report. A comment on the requirements of personalized exercise medicine and in-depth biological profiling along with the opportunities that they offer is presented. This is followed by a brief overview of the evidence for the contributions of genetic differences to the ability to benefit from regular exercise. Subsequently, studies showing that mutations in TP53 influence exercise capacity in mice and humans are succinctly described. The evidence for effects of exercise on endothelial function in health and disease also is covered. Finally, changes in cardiac and skeletal muscle in response to exercise and their implications for patients with cardiac disease are summarized. Innovative research strategies are needed to define the molecular mechanisms involved in adaptation to exercise and to translate them into useful clinical and public health applications.
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| 4. |
- Mínguez‐Viñas, Teresa, et al.
(författare)
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Two epilepsy‐associated variants in KCNA2 (KV1.2) at position H310 oppositely affect channel functional expression
- 2023
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Ingår i: Journal of Physiology. - : WILEY. - 0022-3751 .- 1469-7793. ; 601:23, s. 5367-5389
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Tidskriftsartikel (refereegranskat)abstract
- Two KCNA2 variants (p.H310Y and p.H310R) were discovered in paediatric patients with epilepsy and developmental delay. KCNA2 encodes KV1.2-channel subunits, which regulate neuronal excitability. Both gain and loss of KV1.2 function cause epilepsy, precluding the prediction of variant effects; and while H310 is conserved throughout the KV-channel superfamily, it is largely understudied. We investigated both variants in heterologously expressed, human KV1.2 channels by immunocytochemistry, electrophysiology and voltage-clamp fluorometry. Despite affecting the same channel, at the same position, and being associated with severe neurological disease, the two variants had diametrically opposite effects on KV1.2 functional expression. The p.H310Y variant produced ‘dual gain of function’, increasing both cell-surface trafficking and activity, delaying channel closure. We found that the latter is due to the formation of a hydrogen bond that stabilizes the active state of the voltage-sensor domain. Additionally, H310Y abolished ‘ball and chain’ inactivation of KV1.2 by KVβ1 subunits, enhancing gain of function. In contrast, p.H310R caused ‘dual loss of function’, diminishing surface levels by multiple impediments to trafficking and inhibiting voltage-dependent channel opening. We discuss the implications for KV-channel biogenesis and function, an emergent hotspot for disease-associated variants, and mechanisms of epileptogenesis.
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| 5. |
- Drezner, Jonathan A, et al.
(författare)
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Abnormal electrocardiographic findings in athletes : recognising changes suggestive of primary electrical disease.
- 2013
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Ingår i: British Journal of Sports Medicine. - : BMJ. - 0306-3674 .- 1473-0480. ; 47:3, s. 153-67
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Tidskriftsartikel (refereegranskat)abstract
- Cardiac channelopathies are potentially lethal inherited arrhythmia syndromes and an important cause of sudden cardiac death (SCD) in young athletes. Other cardiac rhythm and conduction disturbances also may indicate the presence of an underlying cardiac disorder. The 12-lead ECG is utilised as both a screening and a diagnostic tool for detecting conditions associated with SCD. Fundamental to the appropriate evaluation of athletes undergoing ECG is an understanding of the ECG findings that may indicate the presence of a pathological cardiac disease. This article describes ECG findings present in primary electrical diseases afflicting young athletes and outlines appropriate steps for further evaluation of these ECG abnormalities. The ECG findings defined as abnormal in athletes were established by an international consensus panel of experts in sports cardiology and sports medicine.
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| 6. |
- Drezner, Jonathan A, et al.
(författare)
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Abnormal electrocardiographic findings in athletes : recognising changes suggestive of cardiomyopathy.
- 2013
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Ingår i: British Journal of Sports Medicine. - : BMJ. - 0306-3674 .- 1473-0480. ; 47:3, s. 137-52
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Tidskriftsartikel (refereegranskat)abstract
- Cardiomyopathies are a heterogeneous group of heart muscle diseases and collectively are the leading cause of sudden cardiac death (SCD) in young athletes. The 12-lead ECG is utilised as both a screening and diagnostic tool for detecting conditions associated with SCD. Fundamental to the appropriate evaluation of athletes undergoing ECG is an understanding of the ECG findings that may indicate the presence of an underlying pathological cardiac disorder. This article describes ECG findings present in cardiomyopathies afflicting young athletes and outlines appropriate steps for further evaluation of these ECG abnormalities. The ECG findings defined as abnormal in athletes were established by an international consensus panel of experts in sports cardiology and sports medicine.
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| 7. |
- Drezner, Jonathan A, et al.
(författare)
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Electrocardiographic interpretation in athletes : the 'Seattle criteria'.
- 2013
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Ingår i: British Journal of Sports Medicine. - : BMJ. - 0306-3674 .- 1473-0480. ; 47:3, s. 122-4
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Tidskriftsartikel (refereegranskat)abstract
- Sudden cardiac death (SCD) is the leading cause of death in athletes during sport. Whether obtained for screening or diagnostic purposes, an ECG increases the ability to detect underlying cardiovascular conditions that may increase the risk for SCD. In most countries, there is a shortage of physician expertise in the interpretation of an athlete's ECG. A critical need exists for physician education in modern ECG interpretation that distinguishes normal physiological adaptations in athletes from abnormal findings suggestive of pathology. On 13-14 February 2012, an international group of experts in sports cardiology and sports medicine convened in Seattle, Washington, to define contemporary standards for ECG interpretation in athletes. The objective of the meeting was to develop a comprehensive training resource to help physicians distinguish normal ECG alterations in athletes from abnormal ECG findings that require additional evaluation for conditions associated with SCD.
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| 8. |
- Drezner, Jonathan A, et al.
(författare)
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Normal electrocardiographic findings : recognising physiological adaptations in athletes.
- 2013
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Ingår i: British Journal of Sports Medicine. - : BMJ. - 0306-3674 .- 1473-0480. ; 47:3, s. 125-36
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Tidskriftsartikel (refereegranskat)abstract
- Electrocardiographic changes in athletes are common and usually reflect benign structural and electrical remodelling of the heart as a physiological adaptation to regular and sustained physical training (athlete's heart). The ability to identify an abnormality on the 12-lead ECG, suggestive of underlying cardiac disease associated with sudden cardiac death (SCD), is based on a sound working knowledge of the normal ECG characteristics within the athletic population. This document will assist physicians in identifying normal ECG patterns commonly found in athletes. The ECG findings presented as normal in athletes were established by an international consensus panel of experts in sports cardiology and sports medicine.
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| 9. |
- Mattsson, C. Mikael, et al.
(författare)
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Informing women’s cardiovascular health through genomic analysis of extreme endurance athletes
- 2015
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Konferensbidrag (refereegranskat)abstract
- Cardiovascular health exists as a spectrum of wellness and disease states. We hypothesize that interrogating the tail ends of the distribution for individuals with extreme phenotypes, such as high VO2max in endurance athletes, will inform prevention, cause and treatment of pathogenic conditions. Mounting literature suggests that the physiological path to athletic performance is different among males and females. Traits with published sexual dichotomy include lactate threshold, efficiency, heat management, and fat metabolism. To define the genetic roots of this dichotomy, we propose to investigate sex-specific genetic determinants of VO2max among elite endurance athletes. We have recruited 36 female (VO2max>63 ml/kg; >99.99th percentile) and 129 male (>75 ml/kg) elite athletes (n=167) who have been consented and undergone enhanced whole exome sequencing. Even with differential eligibility, skewed recruitment (1:3.5) is a challenge. We will recruit a total of 100 female and 156 male elite athletes, and analyze these 256 exomes for burden of rare genetic variation that may impact sex-specific determinants of VO2max. We will combine these data with an additional 1850 samples of elite athletes to evaluate for common variants that have sex-specific effects on VO2max. Lastly, we will do a sex specific genetic cohort comparison of endurance athletes with existing collections of cardiovascular disease patients. Our preliminary results show tantalizing evidence for several highly plausible sex specific genes, including androgen receptor (AR) and FTO. The AR is the target of several known performance enhancing drugs, such as testosterone. FTO is associated with numerous aspects of body composition, energy management and even some evidence for age of menarche. While already promising, rigorous analysis, increased sample size and orthogonal replication is required as our next step.
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| 10. |
- Mattsson, C. Mikael, et al.
(författare)
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Sports genetics moving forward - lessons learned from medical research
- 2016
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Ingår i: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 48:3, s. 175-182
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Tidskriftsartikel (refereegranskat)abstract
- Sports genetics can take advantage of lessons learned from human disease genetics. By righting past mistakes and increasing scientific rigor, the breadth and depth of knowledge in the field can be magnified. We present an outline of challenges facing sports genetics in the light of experiences from medical research.Sports performance is complex, resulting from a combination of a wide variety of different traits and attributes. Improving sports genetics will foremost require analyses based on detailed phenotyping. In order to find widely valid, reproducible common variants associated with athletic phenotypes, study sample sizes must be dramatically increased. One paradox is that in order to confirm relevance, replications in specific populations must be undertaken. Family studies of athletes may facilitate the discovery of rare variants with large effects on athletic phenotypes. The complexity of the human genome, combined with the complexity of athletic phenotypes, will require additional metadata and biological validation to identify a comprehensive set of genes involved.Analysis of personal genetic and multiomic profiles contribute to our conceptualization of precision medicine; the same will be the case in precision sports science. In the refinement of sports genetics it is essential to evaluate similarities and differences between genders and among ethnicities. Sports genetics to date have been hampered by small sample sizes and biased methodology which can lead to erroneous associations and overestimation of effect sizes. Consequently, currently available genetic tests based on these inherently limited data cannot predict athletic performance with any accuracy.
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