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Michael J Ackerman - One of the best experts on this subject based on the ideXlab platform.

  • yield of the ryr2 Genetic Test in suspected catecholaminergic polymorphic ventricular tachycardia and implications for Test interpretation
    Circulation: Genomic and Precision Medicine, 2018
    Co-Authors: Jamie D Kapplinger, Krishna Pundi, Nicholas B Larson, Thomas E Callis, David J Tester, Arthur A.m. Wilde, Hennie Bikker, Michael J Ackerman
    Abstract:

    Background: Pathogenic RYR2 variants account for ≈60% of clinically definite cases of catecholaminergic polymorphic ventricular tachycardia. However, the rate of rare benign RYR2 variants identified in the general population remains a challenge for Genetic Test interpretation. Therefore, we examined the results of the RYR2 Genetic Test among patients referred for commercial Genetic Testing and examined factors impacting variant interpretability. Methods: Frequency and location comparisons were made for RYR2 variants identified among 1355 total patients of varying clinical certainty and 60 706 Exome Aggregation Consortium controls. The impact of the clinical phenotype on the yield of RYR2 variants was examined. Six in silico tools were assessed using patient- and control-derived variants. Results: A total of 18.2% (218/1200) of patients referred for commercial Testing hosted rare RYR2 variants, statistically less than the 59% (46/78) yield among clinically definite cases, resulting in a much higher potential Genetic false discovery rate among referrals considering the 3.2% background rate of rare, benign RYR2 variants. Exclusion of clearly putative pathogenic variants further complicates the interpretation of the next novel RYR2 variant. Exonic/topologic analyses revealed overrepresentation of patient variants in exons covering only one third of the protein. In silico tools largely failed to show evidence toward enhancement of variant interpretation. Conclusions: Current expert recommendations have resulted in increased use of RYR2 Genetic Testing in patients with questionable clinical phenotypes. Using the largest to date catecholaminergic polymorphic ventricular tachycardia patient versus control comparison, this study highlights important variables in the interpretation of variants to overcome the 3.2% background rate that confounds RYR2 variant interpretation.

  • characterization of a phenotype based Genetic Test prediction score for unrelated patients with hypertrophic cardiomyopathy
    Mayo Clinic proceedings, 2014
    Co-Authors: Martijn J Bos, Melissa L Will, Bernard J Gersh, Teresa M Kruisselbrink, Steve R Ommen, Michael J Ackerman
    Abstract:

    Abstract Objectives To determine the prevalence and spectrum of mutations and genotype-phenotype relationships in the largest hypertrophic cardiomyopathy (HCM) cohort to date and to provide an easy, clinically applicable phenotype-derived score that provides a preTest probability for a positive HCM Genetic Test result. Patients and Methods Between April 1, 1997, and February 1, 2007, 1053 unrelated patients with the clinical diagnosis of HCM (60% male; mean ± SD age at diagnosis, 44.4±19 years) had HCM Genetic Testing for the 9 HCM-associated myofilament genes. Phenotyping was performed by review of electronic medical records. Results Overall, 359 patients (34%) were genotype positive for a putative HCM-associated mutation in 1 or more HCM-associated genes. Univariate and multivariate analyses identified the echocardiographic reverse curve morphological subtype, an age at diagnosis younger than 45 years, a maximum left ventricular wall thickness of 20 mm or greater, a family history of HCM, and a family history of sudden cardiac death as positive predictors of positive Genetic Test results, whereas hypertension was a negative predictor. A score, based on the number of predictors of a positive Genetic Test result, predicted a positive Genetic Test result ranging from 6% when only hypertension was present to 80% when all 5 positive predictor markers were present. Conclusion In this largest HCM cohort published to date, the overall yield of Genetic Testing was 34%. Although all the patients were diagnosed clinically as having HCM, the presence or absence of 6 simple clinical/echocardiographic markers predicted the likelihood of mutation-positive HCM. Phenotype-guided Genetic Testing using the Mayo HCM Genotype Predictor score provides an easy tool for an effective Genetic counseling session.

  • hrs ehra expert consensus statement on the state of Genetic Testing for the channelopathies and cardiomyopathies
    Europace, 2011
    Co-Authors: Michael J Ackerman, Silvia G Priori, Stephan Willems, Charles I Berul, Ramon Brugada, Hugh Calkins, John A Camm, Patrick T Ellinor, Michael H Gollob, Robert J Hamilton
    Abstract:

    This international consensus statement provides the state of Genetic Testing for the channelopathies and cardiomyopathies. It summarizes the opinion of the international writing group members based on their own experience and on a general review of the literature with respect to the use and role of Genetic Testing for these potentially heritable cardiac conditions. This document focuses primarily on the state of Genetic Testing for the 13 distinct entities detailed and the relative diagnostic, prognostic, and therapeutic impact of the Genetic Test result for each entity. It does not focus on the therapeutic management of the various channelopathies and cardiomyopathies. Treatment/management issues are only discussed for those diseases (i.e., LQTS, HCM, DCM + CCD, RCM) in which the Genetic Test result could potentially influence treatment considerations. Writing recommendations for Genetic diseases require adaptation of the methodology normally adopted to prepare guidelines for clinical practice. Documents produced by other scientific societies have acknowledged the need to define the criteria used to rank the strength of recommendation for Genetic diseases.1 The most obvious difference is that randomized and/or blinded studies do not exist. Instead, most of the available data are derived from registries that have followed patients and recorded outcome information. The authors of this statement have therefore defined specific criteria for Class I, Class IIa or b, and Class III recommendations and have used the conventional language adopted by AHA/ACC/ESC Guidelines to express each class. All recommendations are level of evidence (LOE) C (i.e., based on experts' opinions). A Class I recommendation ( “is recommended” ) was applied for Genetic Testing in index cases with a sound clinical suspicion for the presence of a channelopathy or a cardiomyopathy when the positive predictive value of a Genetic Test is high (likelihood of positive result >40% and signal/noise ratio >10; Table 3), AND/OR when …

  • spectrum and prevalence of mutations from the first 2 500 consecutive unrelated patients referred for the familion long qt syndrome Genetic Test
    Heart Rhythm, 2009
    Co-Authors: Jamie D Kapplinger, David J Tester, Arthur A.m. Wilde, Benjamin A Salisbury, Janet L Carr, Carole Harriskerr, Guido D Pollevick, Michael J Ackerman
    Abstract:

    Background Long QT syndrome (LQTS) is a potentially lethal, highly treatable cardiac channelopathy for which Genetic Testing has matured from discovery to translation and now clinical implementation. Objectives Here we examine the spectrum and prevalence of mutations found in the first 2,500 unrelated cases referred for the FAMILION ® LQTS clinical Genetic Test. Methods Retrospective analysis of the first 2,500 cases (1,515 female patients, average age at Testing 23 ± 17 years, range 0 to 90 years) scanned for mutations in 5 of the LQTS-susceptibility genes: KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6). Results Overall, 903 referral cases (36%) hosted a possible LQTS-causing mutation that was absent in >2,600 reference alleles; 821 (91%) of the mutation-positive cases had single genotypes, whereas the remaining 82 patients (9%) had >1 mutation in ≥1 gene, including 52 cases that were compound heterozygous with mutations in >1 gene. Of the 562 distinct mutations, 394 (70%) were missense, 428 (76%) were seen once, and 336 (60%) are novel, including 92 of 199 in KCNQ1 , 159 of 226 in KCNH2 , and 70 of 110 in SCN5A . Conclusion This cohort increases the publicly available compendium of putative LQTS-associated mutations by >50%, and approximately one-third of the most recently detected mutations continue to be novel. Although control population data suggest that the great majority of these mutations are pathogenic, expert interpretation of Genetic Test results will remain critical for effective clinical use of LQTS Genetic Test results.

Sean V Tavtigian - One of the best experts on this subject based on the ideXlab platform.

  • sequence variant classification and reporting recommendations for improving the interpretation of cancer susceptibility Genetic Test results
    Human Mutation, 2008
    Co-Authors: Sharon E Plon, Diana Eccles, Douglas F Easton, William D Foulkes, Maurizio Genuardi, Marc S Greenblatt, Frans B L Hogervorst, Nicoline Hoogerbrugge, Amanda B Spurdle, Sean V Tavtigian
    Abstract:

    Genetic Testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based Testing of germline DNA is used to determine whether an individual carries a change that is clearly likely to disrupt normal gene function. Genetic Testing may detect changes that are clearly pathogenic, clearly neutral, or variants of unclear clinical significance. Such variants present a considerable challenge to the diagnostic laboratory and the receiving clinician in terms of interpretation and clear presentation of the implications of the result to the patient. There does not appear to be a consistent approach to interpreting and reporting the clinical significance of variants either among genes or among laboratories. The potential for confusion among clinicians and patients is considerable and misinterpretation may lead to inappropriate clinical consequences. In this article we review the current state of sequence-based Genetic Testing, describe other standardized reporting systems used in oncology, and propose a standardized classification system for application to sequence-based results for cancer predisposition genes. We suggest a system of five classes of variants based on the degree of likelihood of pathogenicity. Each class is associated with specific recommendations for clinical management of at-risk relatives that will depend on the syndrome. We propose that panels of experts on each cancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and cancer management guidelines. The international adoption of a standardized reporting system should improve the clinical utility of sequence-based Genetic Tests to predict cancer risk.

  • sequence variant classification and reporting recommendations for improving the interpretation of cancer susceptibility Genetic Test results
    Human Mutation, 2008
    Co-Authors: Sharon E Plon, Diana Eccles, Douglas F Easton, William D Foulkes, Maurizio Genuardi, Marc S Greenblatt, Frans B L Hogervorst, Nicoline Hoogerbrugge, Amanda B Spurdle, Sean V Tavtigian
    Abstract:

    Genetic Testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based Testing of germline DNA is used to determine whether an individual carries a change that is clearly likely to disrupt normal gene function. Genetic Testing may detect changes that are clearly pathogenic, clearly neutral, or variants of unclear clinical significance. Such variants present a considerable challenge to the diagnostic laboratory and the receiving clinician in terms of interpretation and clear presentation of the implications of the result to the patient. There does not appear to be a consistent approach to interpreting and reporting the clinical significance of variants either among genes or among laboratories. The potential for confusion among clinicians and patients is considerable and misinterpretation may lead to inappropriate clinical consequences. In this article we review the current state of sequence-based Genetic Testing, describe other standardized reporting systems used in oncology, and propose a standardized classification system for application to sequence-based results for cancer predisposition genes. We suggest a system of five classes of variants based on the degree of likelihood of pathogenicity. Each class is associated with specific recommendations for clinical management of at-risk relatives that will depend on the syndrome. We propose that panels of experts on each cancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and cancer management guidelines. The international adoption of a standardized reporting system should improve the clinical utility of sequence-based Genetic Tests to predict cancer risk.

Sharon E Plon - One of the best experts on this subject based on the ideXlab platform.

  • experiences and attitudes of genome investigators regarding return of individual Genetic Test results
    Genetics in Medicine, 2013
    Co-Authors: Rachel B Ramoni, Amy L Mcguire, Jill O Robinson, Debra S Morley, Sharon E Plon, Steven Joffe
    Abstract:

    Experiences and attitudes of genome investigators regarding return of individual Genetic Test results

  • sequence variant classification and reporting recommendations for improving the interpretation of cancer susceptibility Genetic Test results
    Human Mutation, 2008
    Co-Authors: Sharon E Plon, Diana Eccles, Douglas F Easton, William D Foulkes, Maurizio Genuardi, Marc S Greenblatt, Frans B L Hogervorst, Nicoline Hoogerbrugge, Amanda B Spurdle, Sean V Tavtigian
    Abstract:

    Genetic Testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based Testing of germline DNA is used to determine whether an individual carries a change that is clearly likely to disrupt normal gene function. Genetic Testing may detect changes that are clearly pathogenic, clearly neutral, or variants of unclear clinical significance. Such variants present a considerable challenge to the diagnostic laboratory and the receiving clinician in terms of interpretation and clear presentation of the implications of the result to the patient. There does not appear to be a consistent approach to interpreting and reporting the clinical significance of variants either among genes or among laboratories. The potential for confusion among clinicians and patients is considerable and misinterpretation may lead to inappropriate clinical consequences. In this article we review the current state of sequence-based Genetic Testing, describe other standardized reporting systems used in oncology, and propose a standardized classification system for application to sequence-based results for cancer predisposition genes. We suggest a system of five classes of variants based on the degree of likelihood of pathogenicity. Each class is associated with specific recommendations for clinical management of at-risk relatives that will depend on the syndrome. We propose that panels of experts on each cancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and cancer management guidelines. The international adoption of a standardized reporting system should improve the clinical utility of sequence-based Genetic Tests to predict cancer risk.

  • sequence variant classification and reporting recommendations for improving the interpretation of cancer susceptibility Genetic Test results
    Human Mutation, 2008
    Co-Authors: Sharon E Plon, Diana Eccles, Douglas F Easton, William D Foulkes, Maurizio Genuardi, Marc S Greenblatt, Frans B L Hogervorst, Nicoline Hoogerbrugge, Amanda B Spurdle, Sean V Tavtigian
    Abstract:

    Genetic Testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based Testing of germline DNA is used to determine whether an individual carries a change that is clearly likely to disrupt normal gene function. Genetic Testing may detect changes that are clearly pathogenic, clearly neutral, or variants of unclear clinical significance. Such variants present a considerable challenge to the diagnostic laboratory and the receiving clinician in terms of interpretation and clear presentation of the implications of the result to the patient. There does not appear to be a consistent approach to interpreting and reporting the clinical significance of variants either among genes or among laboratories. The potential for confusion among clinicians and patients is considerable and misinterpretation may lead to inappropriate clinical consequences. In this article we review the current state of sequence-based Genetic Testing, describe other standardized reporting systems used in oncology, and propose a standardized classification system for application to sequence-based results for cancer predisposition genes. We suggest a system of five classes of variants based on the degree of likelihood of pathogenicity. Each class is associated with specific recommendations for clinical management of at-risk relatives that will depend on the syndrome. We propose that panels of experts on each cancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and cancer management guidelines. The international adoption of a standardized reporting system should improve the clinical utility of sequence-based Genetic Tests to predict cancer risk.

Michael D Grosz - One of the best experts on this subject based on the ideXlab platform.

Ilan R Kirsch - One of the best experts on this subject based on the ideXlab platform.

  • randomized comparison of phone versus in person brca1 2 predisposition Genetic Test result disclosure counseling
    Genetics in Medicine, 2007
    Co-Authors: Jean Jenkins, Kathleen A Calzone, Eileen Dimond, David J Liewehr, Seth M Steinberg, Oxana Jourkiv, Pam Klein, Peter W Soballe, Sheila A Prindiville, Ilan R Kirsch
    Abstract:

    week and 3 months after disclosure of Test results. Baseline measures were administered after the following had occurred: counseling/education session had been conducted, informed consent had been obtained, and decision to be Tested had been made. Satisfaction and cost assessments were administered after the result session. At 1 week, participants were asked their preferred method of result disclosure. Results: There were no differences in anxiety and general well-being measures between 50 phone and 52 in-person results disclosure. Both groups reported similar rates of satisfaction with services. Among those with a preference, 77% preferred the notification method assigned. There was a statistically significant preference for phone results among the 23% who did not prefer the method assigned. Greater costs were associated with in-person result disclosure. Conclusions: These data suggest that phone results are a reasonable alternative to traditional in-person BRCA1/2 Genetic Test disclosure without any negative psychologic outcomes or compromise in knowledge. However, further study is

  • Randomized comparison of phone versus in-person BRCA1/2 predisposition Genetic Test result disclosure counseling
    Genetics in Medicine, 2007
    Co-Authors: Jean Jenkins, Kathleen A Calzone, Eileen Dimond, David J Liewehr, Seth M Steinberg, Oxana Jourkiv, Pam Klein, Peter W Soballe, Sheila A Prindiville, Ilan R Kirsch
    Abstract:

    Purpose: This study evaluated whether phone results were equivalent to in-person result disclosure for individuals undergoing BRCA1/2 predisposition Genetic Testing. Methods: A total of 111 of 136 subjects undergoing education and counseling for BRCA1/2 predisposition Genetic Testing agreed to randomization to phone or in-person result disclosure. Content and format for both sessions were standardized. Data from the State-Trait Anxiety Inventory and the Psychological General Well-Being index were collected at baseline and then again at 1 week and 3 months after disclosure of Test results. Baseline measures were administered after the following had occurred: counseling/education session had been conducted, informed consent had been obtained, and decision to be Tested had been made. Satisfaction and cost assessments were administered after the result session. At 1 week, participants were asked their preferred method of result disclosure. Results: There were no differences in anxiety and general well-being measures between 50 phone and 52 in-person results disclosure. Both groups reported similar rates of satisfaction with services. Among those with a preference, 77% preferred the notification method assigned. There was a statistically significant preference for phone results among the 23% who did not prefer the method assigned. Greater costs were associated with in-person result disclosure. Conclusions: These data suggest that phone results are a reasonable alternative to traditional in-person BRCA1/2 Genetic Test disclosure without any negative psychologic outcomes or compromise in knowledge. However, further study is needed in a more clinically representative population to confirm these findings.