Sara L Van Driest, Quinn S Wells, Sarah Stallings, William S Bush, Adam Gordon, Deborah A Nickerson, Jerry H Kim, David R Crosslin, Gail P Jarvik, David S Carrell, James D Ralston, Eric B Larson, Suzette J Bielinski, Janet E Olson, Zi Ye, Iftikhar J Kullo, Noura S Abul-Husn, Stuart A Scott, Erwin Bottinger, Berta Almoguera, John Connolly, Rosetta Chiavacci, Hakon Hakonarson, Laura J Rasmussen-Torvik, Vivian Pan, Stephen D Persell, Maureen Smith, Rex L Chisholm, Terrie E Kitchner, Max M He, Murray H Brilliant, John R Wallace, Kimberly F Doheny, M Benjamin Shoemaker, Rongling Li, Teri A Manolio, Thomas E Callis, Daniela Macaya, Marc S Williams, David Carey, Jamie D Kapplinger, Michael J Ackerman, Marylyn D Ritchie, Joshua C Denny, Dan M Roden
<p><strong>Importance: </strong>Large-scale DNA sequencing identifies incidental rare variants in established Mendelian disease genes, but the frequency of related clinical phenotypes in unselected patient populations is not well established. Phenotype data from electronic medical records (EMRs) may provide a resource to assess the clinical relevance of rare variants.</p><p><strong>Objective: </strong>To determine the clinical phenotypes from EMRs for individuals with variants designated as pathogenic by expert review in arrhythmia susceptibility genes.</p><p><strong>Design, setting, and participants: </strong>This prospective cohort study included 2022 individuals recruited for nonantiarrhythmic drug exposure phenotypes from October 5, 2012, to September 30, 2013, for the Electronic Medical Records and Genomics Network Pharmacogenomics project from 7 US academic medical centers. Variants in SCN5A and KCNH2, disease genes for long QT and Brugada syndromes, were assessed for potential pathogenicity by 3 laboratories with ion channel expertise and by comparison with the ClinVar database. Relevant phenotypes were determined from EMRs, with data available from 2002 (or earlier for some sites) through September 10, 2014.</p><p><strong>Exposures: </strong>One or more variants designated as pathogenic in SCN5A or KCNH2.</p><p><strong>Main outcomes and measures: </strong>Arrhythmia or electrocardiographic (ECG) phenotypes defined by International Classification of Diseases, Ninth Revision (ICD-9) codes, ECG data, and manual EMR review.</p><p><strong>Results: </strong>Among 2022 study participants (median age, 61 years [interquartile range, 56-65 years]; 1118 [55%] female; 1491 [74%] white), a total of 122 rare (minor allele frequency <0.5%) nonsynonymous and splice-site variants in 2 arrhythmia susceptibility genes were identified in 223 individuals (11% of the study cohort). Forty-two variants in 63 participants were designated potentially pathogenic by at least 1 laboratory or ClinVar, with low concordance across laboratories (Cohen κ = 0.26). An ICD-9 code for arrhythmia was found in 11 of 63 (17%) variant carriers vs 264 of 1959 (13%) of those without variants (difference, +4%; 95% CI, -5% to +13%; P = .35). In the 1270 (63%) with ECGs, corrected QT intervals were not different in variant carriers vs those without (median, 429 vs 439 milliseconds; difference, -10 milliseconds; 95% CI, -16 to +3 milliseconds; P = .17). After manual review, 22 of 63 participants (35%) with designated variants had any ECG or arrhythmia phenotype, and only 2 had corrected QT interval longer than 500 milliseconds.</p><p><strong>Conclusions and relevance: </strong>Among laboratories experienced in genetic testing for cardiac arrhythmia disorders, there was low concordance in designating SCN5A and KCNH2 variants as pathogenic. In an unselected population, the putatively pathogenic genetic variants were not associated with an abnormal phenotype. These findings raise question
{"title":"Association of Arrhythmia-Related Genetic Variants With Phenotypes Documented in Electronic Medical Records.","authors":"Sara L Van Driest, Quinn S Wells, Sarah Stallings, William S Bush, Adam Gordon, Deborah A Nickerson, Jerry H Kim, David R Crosslin, Gail P Jarvik, David S Carrell, James D Ralston, Eric B Larson, Suzette J Bielinski, Janet E Olson, Zi Ye, Iftikhar J Kullo, Noura S Abul-Husn, Stuart A Scott, Erwin Bottinger, Berta Almoguera, John Connolly, Rosetta Chiavacci, Hakon Hakonarson, Laura J Rasmussen-Torvik, Vivian Pan, Stephen D Persell, Maureen Smith, Rex L Chisholm, Terrie E Kitchner, Max M He, Murray H Brilliant, John R Wallace, Kimberly F Doheny, M Benjamin Shoemaker, Rongling Li, Teri A Manolio, Thomas E Callis, Daniela Macaya, Marc S Williams, David Carey, Jamie D Kapplinger, Michael J Ackerman, Marylyn D Ritchie, Joshua C Denny, Dan M Roden","doi":"10.1001/jama.2015.17701","DOIUrl":"10.1001/jama.2015.17701","url":null,"abstract":"<p><strong>Importance: </strong>Large-scale DNA sequencing identifies incidental rare variants in established Mendelian disease genes, but the frequency of related clinical phenotypes in unselected patient populations is not well established. Phenotype data from electronic medical records (EMRs) may provide a resource to assess the clinical relevance of rare variants.</p><p><strong>Objective: </strong>To determine the clinical phenotypes from EMRs for individuals with variants designated as pathogenic by expert review in arrhythmia susceptibility genes.</p><p><strong>Design, setting, and participants: </strong>This prospective cohort study included 2022 individuals recruited for nonantiarrhythmic drug exposure phenotypes from October 5, 2012, to September 30, 2013, for the Electronic Medical Records and Genomics Network Pharmacogenomics project from 7 US academic medical centers. Variants in SCN5A and KCNH2, disease genes for long QT and Brugada syndromes, were assessed for potential pathogenicity by 3 laboratories with ion channel expertise and by comparison with the ClinVar database. Relevant phenotypes were determined from EMRs, with data available from 2002 (or earlier for some sites) through September 10, 2014.</p><p><strong>Exposures: </strong>One or more variants designated as pathogenic in SCN5A or KCNH2.</p><p><strong>Main outcomes and measures: </strong>Arrhythmia or electrocardiographic (ECG) phenotypes defined by International Classification of Diseases, Ninth Revision (ICD-9) codes, ECG data, and manual EMR review.</p><p><strong>Results: </strong>Among 2022 study participants (median age, 61 years [interquartile range, 56-65 years]; 1118 [55%] female; 1491 [74%] white), a total of 122 rare (minor allele frequency <0.5%) nonsynonymous and splice-site variants in 2 arrhythmia susceptibility genes were identified in 223 individuals (11% of the study cohort). Forty-two variants in 63 participants were designated potentially pathogenic by at least 1 laboratory or ClinVar, with low concordance across laboratories (Cohen κ = 0.26). An ICD-9 code for arrhythmia was found in 11 of 63 (17%) variant carriers vs 264 of 1959 (13%) of those without variants (difference, +4%; 95% CI, -5% to +13%; P = .35). In the 1270 (63%) with ECGs, corrected QT intervals were not different in variant carriers vs those without (median, 429 vs 439 milliseconds; difference, -10 milliseconds; 95% CI, -16 to +3 milliseconds; P = .17). After manual review, 22 of 63 participants (35%) with designated variants had any ECG or arrhythmia phenotype, and only 2 had corrected QT interval longer than 500 milliseconds.</p><p><strong>Conclusions and relevance: </strong>Among laboratories experienced in genetic testing for cardiac arrhythmia disorders, there was low concordance in designating SCN5A and KCNH2 variants as pathogenic. In an unselected population, the putatively pathogenic genetic variants were not associated with an abnormal phenotype. These findings raise question","PeriodicalId":94181,"journal":{"name":"Psychology of sport and exercise","volume":"1 1","pages":"47-57"},"PeriodicalIF":29.0,"publicationDate":"2016-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76845906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2002-01-01Epub Date: 2001-09-28DOI: 10.1186/ar379
Thomas Kamradt
Lyme disease is a tick-borne multisystem disease that affects primarily the skin, nervous system, heart and joints. At least three species of Borrelia burgdorferi sensu lato, namely Borrelia burgdorferi sensu stricto, Borrelia garinii, and Borrelia afzelii, can cause the disease. This review will focus mainly on the pathophysiology of Lyme arthritis, the long-term outcome of Lyme disease, and the recently licensed vaccine against Lyme disease.
{"title":"Lyme disease and current aspects of immunization.","authors":"Thomas Kamradt","doi":"10.1186/ar379","DOIUrl":"10.1186/ar379","url":null,"abstract":"<p><p>Lyme disease is a tick-borne multisystem disease that affects primarily the skin, nervous system, heart and joints. At least three species of Borrelia burgdorferi sensu lato, namely Borrelia burgdorferi sensu stricto, Borrelia garinii, and Borrelia afzelii, can cause the disease. This review will focus mainly on the pathophysiology of Lyme arthritis, the long-term outcome of Lyme disease, and the recently licensed vaccine against Lyme disease.</p>","PeriodicalId":94181,"journal":{"name":"Psychology of sport and exercise","volume":"13 1","pages":"20-9"},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC128914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76951826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Y Terajima, H Nukui, A Kobayashi, S Fujimoto, S Hase, T Yoshioka, T Hashiba, S Satoh
The cDNA encoding a novel member (NT-ERS1) of ethylene receptor family of tobacco (Nicotiana tabacum L.) was obtained by a combination of RT-PCR and 5'-/3'-RACE cloning. The cDNA was 2,092 nucleotides long and had an open reading frame of 1,911 bp encoding 637 amino acids. The deduced polypeptide lacked a response regulator domain, indicating that the ethylene receptor belongs to an ERS-group. The amino acid sequence was similar to respective members of the tobacco ethylene receptor family: 67.8% to NT-ETR1, 39.1% to NTHK1 and 31.1% to NTHK2. Comparison of amino acid sequence suggested that NT-ERS1 is the counterpart of Nr in the ethylene receptor family of tomato, which belongs to Solanaceae as does tobacco. Northern blot analysis showed that mRNA of NT-ERS1 was present in leaf, shoot and root tissues, and accumulated in leaves treated with exogenous ethylene. A mutated NT-ERS1 cDNA transgene, obtained by introducing one nucleotide substitution into NT-ETR1 cDNA, conferred ethylene insensitivity in tobacco plants, indicating that the translation product of the cDNA actually functioned in the plants.
{"title":"Molecular cloning and characterization of a cDNA for a novel ethylene receptor, NT-ERS1, of tobacco (Nicotiana tabacum L.).","authors":"Y Terajima, H Nukui, A Kobayashi, S Fujimoto, S Hase, T Yoshioka, T Hashiba, S Satoh","doi":"10.1093/pcp/pce038","DOIUrl":"10.1093/pcp/pce038","url":null,"abstract":"<p><p>The cDNA encoding a novel member (NT-ERS1) of ethylene receptor family of tobacco (Nicotiana tabacum L.) was obtained by a combination of RT-PCR and 5'-/3'-RACE cloning. The cDNA was 2,092 nucleotides long and had an open reading frame of 1,911 bp encoding 637 amino acids. The deduced polypeptide lacked a response regulator domain, indicating that the ethylene receptor belongs to an ERS-group. The amino acid sequence was similar to respective members of the tobacco ethylene receptor family: 67.8% to NT-ETR1, 39.1% to NTHK1 and 31.1% to NTHK2. Comparison of amino acid sequence suggested that NT-ERS1 is the counterpart of Nr in the ethylene receptor family of tomato, which belongs to Solanaceae as does tobacco. Northern blot analysis showed that mRNA of NT-ERS1 was present in leaf, shoot and root tissues, and accumulated in leaves treated with exogenous ethylene. A mutated NT-ERS1 cDNA transgene, obtained by introducing one nucleotide substitution into NT-ETR1 cDNA, conferred ethylene insensitivity in tobacco plants, indicating that the translation product of the cDNA actually functioned in the plants.</p>","PeriodicalId":94181,"journal":{"name":"Psychology of sport and exercise","volume":"30 1","pages":"308-13"},"PeriodicalIF":4.9,"publicationDate":"2001-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/pcp/pce038","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84567324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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