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Predicting Yield From Cardiac Genetic Testing–A Clinically Achievable Way to Achieve Equity and Triage Appropriately
Abstracts
609 Multiple Gene Variants in Hypertrophic Cardiomyopathy in the Era of Next Generation Sequencing C. Burns 1,2,3,∗ , R. Bagnall 1,2 , L. Lam 1,2,3 , C. Semsarian 1,2,3 , J. Ingles 1,2,3 1 Central Clinical School, Sydney Medical School, University of Sydney, Sydney, Australia 2 Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia 3 Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia
Introduction: Multiple likely pathogenic/pathogenic (LP/P) variants in hypertrophic cardiomyopathy (HCM) were described 10 years ago with a prevalence of 5%. We sought to re-examine the significance of multiple rare variants in the setting of comprehensive and targeted panels. Methods: Of 758 HCM probands, we included 382 seen in a specialised centre with ≥45 cardiomyopathy genes screened. There were 224 (59%) probands with ≥1 rare variant (allele frequency ≤0.02%). Variants were analysed using varying sized panels to represent comprehensive or targeted testing. Results: Based on a 45-gene panel, 127 (33%) had a LP/P variant, 139 (36%) had variants of uncertain significance (VUS) and 66 (17%) probands had multiple rare variants. A targeted 8-gene panel yielded 125 (32%) LP/P variants, 52 (14%) VUS and 14 (4%) probands had multiple rare variants. No proband had 2 LP/P variants. Including affected family members (total n = 412) cluster-adjusted analyses identified a phenotype effect, with younger age (OR 0.95, 95%CI 0.920.98, p = 0.004) and family history of sudden cardiac death (OR 3.5, 95%CI 1.3-9.9, p = 0.02) significantly more likely in multiple versus single variant patients when considering an 8-gene panel, but not larger panels. Further, those with multiple variants had worse event-free survival from all cause death, cardiac transplantation and cardiac arrest (log-rank p = 0.008). Conclusion: No proband had multiple LP/P variants, in contrast to previous reports quoting a 5% yield. However, multiple rare variants regardless of classification were seen in 4% and contributed to earlier disease onset and cardiac events. Our findings support a cumulative variant hypothesis in HCM. http://dx.doi.org/10.1016/j.hlc.2017.06.610 610 Predicting Yield From Cardiac Genetic Testing–A Clinically Achievable Way to Achieve Equity and Triage Appropriately D. Zentner ∗ , T. Thompson, J. Taylor, M. Bogwitz, A. Trainer, J. Vohra, I. Winship, P. James Royal Melbourne Hospital, Melbourne, Australia Background and Aims: Clinical guidelines for cardiac genetic testing predate routine use of massive parallel
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sequencing (MPS) technologies and have not been balanced by assessment of likely mutation detection estimation. We sought to ascertain whether routinely collected clinical information could assist in identifying patients with a higher pre-test probability of positive mutation detection. Methodology and Results: A clinical tool was developed in a consecutive population of 125 patients (discovery group) referred to a cardiac genetic clinic in which MPS testing was ordered. Results demonstrated utility of the clinical tool in predicting an increased chance of positive mutation detection outcome from genetic testing. The performance of the tool was optimised using the discovery group to establish the weighting of individual factors within the tool. Extra weighting was assigned to factors with a higher odds ratio (OR) for positive mutation detection. The modified tool was then validated in a subsequent cohort of 40 patients (validation cohort). A score of ≥ 3 gave an OR of 5.61 (1.6–19.9) for positive mutation detection. Discussion and Conclusion: An easily applicable clinical tool can estimate likely mutation detection from MPS testing. Within the reality of a Medicare unfunded test and limited available healthcare funding, this approach allows equitable use of new technology aimed at those with a predicted higher yield and can assist in pre-test counselling of patients. http://dx.doi.org/10.1016/j.hlc.2017.06.611 611 Significant Differences in Genetic Risk Profiles Between Maori and European Presenting with Myocardial Infarction A. Holley 1,2,∗ , H. Northcott 2,3 , P. Gladding 4 , S. Harding 2,5 , P. Larsen 1,2 1 University
of Otago, Wellington, New Zealand Cardiovascular Group, Wellington, New Zealand 3 Victoria University of Wellington, Wellington, New Zealand 4 Department of Cardiology, North Shore Hospital, Auckland, New Zealand 5 Department of Cardiology, Wellington Hospital, Wellington, New Zealand 2 Wellington
Background: Genome-wide association studies and population studies have identified single nucleotide polymorphisms (SNPs) associated with increased risk of development and progression of coronary artery disease, and with response to therapeutic intervention. An emerging way of managing the complexity of large numbers of SNPs that modestly predict outcome individually, is to combine them into a genetic risk score (GRS). However, before GRS tools developed in European and North American populations can be utilised in New Zealand, it is important to examine the SNP distribution involved in GRS in our own primary and secondary prevention populations. Methods: We examined the frequency of 27 SNPs from a previously validated GRS in a cohort of patients presenting with myocardial infarction (MI). The observed frequency of each SNP was compared between MI patients identifying as Maori or European.
609 Multiple Gene Variants in Hypertrophic Cardiomyopathy in the Era of Next Generation Sequencing C. Burns 1,2,3,∗ , R. Bagnall 1,2 , L. Lam 1,2,3 , C. Semsarian 1,2,3 , J. Ingles 1,2,3 1 Central Clinical School, Sydney Medical School, University of Sydney, Sydney, Australia 2 Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia 3 Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia
Introduction: Multiple likely pathogenic/pathogenic (LP/P) variants in hypertrophic cardiomyopathy (HCM) were described 10 years ago with a prevalence of 5%. We sought to re-examine the significance of multiple rare variants in the setting of comprehensive and targeted panels. Methods: Of 758 HCM probands, we included 382 seen in a specialised centre with ≥45 cardiomyopathy genes screened. There were 224 (59%) probands with ≥1 rare variant (allele frequency ≤0.02%). Variants were analysed using varying sized panels to represent comprehensive or targeted testing. Results: Based on a 45-gene panel, 127 (33%) had a LP/P variant, 139 (36%) had variants of uncertain significance (VUS) and 66 (17%) probands had multiple rare variants. A targeted 8-gene panel yielded 125 (32%) LP/P variants, 52 (14%) VUS and 14 (4%) probands had multiple rare variants. No proband had 2 LP/P variants. Including affected family members (total n = 412) cluster-adjusted analyses identified a phenotype effect, with younger age (OR 0.95, 95%CI 0.920.98, p = 0.004) and family history of sudden cardiac death (OR 3.5, 95%CI 1.3-9.9, p = 0.02) significantly more likely in multiple versus single variant patients when considering an 8-gene panel, but not larger panels. Further, those with multiple variants had worse event-free survival from all cause death, cardiac transplantation and cardiac arrest (log-rank p = 0.008). Conclusion: No proband had multiple LP/P variants, in contrast to previous reports quoting a 5% yield. However, multiple rare variants regardless of classification were seen in 4% and contributed to earlier disease onset and cardiac events. Our findings support a cumulative variant hypothesis in HCM. http://dx.doi.org/10.1016/j.hlc.2017.06.610 610 Predicting Yield From Cardiac Genetic Testing–A Clinically Achievable Way to Achieve Equity and Triage Appropriately D. Zentner ∗ , T. Thompson, J. Taylor, M. Bogwitz, A. Trainer, J. Vohra, I. Winship, P. James Royal Melbourne Hospital, Melbourne, Australia Background and Aims: Clinical guidelines for cardiac genetic testing predate routine use of massive parallel
S307
.. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. ..
sequencing (MPS) technologies and have not been balanced by assessment of likely mutation detection estimation. We sought to ascertain whether routinely collected clinical information could assist in identifying patients with a higher pre-test probability of positive mutation detection. Methodology and Results: A clinical tool was developed in a consecutive population of 125 patients (discovery group) referred to a cardiac genetic clinic in which MPS testing was ordered. Results demonstrated utility of the clinical tool in predicting an increased chance of positive mutation detection outcome from genetic testing. The performance of the tool was optimised using the discovery group to establish the weighting of individual factors within the tool. Extra weighting was assigned to factors with a higher odds ratio (OR) for positive mutation detection. The modified tool was then validated in a subsequent cohort of 40 patients (validation cohort). A score of ≥ 3 gave an OR of 5.61 (1.6–19.9) for positive mutation detection. Discussion and Conclusion: An easily applicable clinical tool can estimate likely mutation detection from MPS testing. Within the reality of a Medicare unfunded test and limited available healthcare funding, this approach allows equitable use of new technology aimed at those with a predicted higher yield and can assist in pre-test counselling of patients. http://dx.doi.org/10.1016/j.hlc.2017.06.611 611 Significant Differences in Genetic Risk Profiles Between Maori and European Presenting with Myocardial Infarction A. Holley 1,2,∗ , H. Northcott 2,3 , P. Gladding 4 , S. Harding 2,5 , P. Larsen 1,2 1 University
of Otago, Wellington, New Zealand Cardiovascular Group, Wellington, New Zealand 3 Victoria University of Wellington, Wellington, New Zealand 4 Department of Cardiology, North Shore Hospital, Auckland, New Zealand 5 Department of Cardiology, Wellington Hospital, Wellington, New Zealand 2 Wellington
Background: Genome-wide association studies and population studies have identified single nucleotide polymorphisms (SNPs) associated with increased risk of development and progression of coronary artery disease, and with response to therapeutic intervention. An emerging way of managing the complexity of large numbers of SNPs that modestly predict outcome individually, is to combine them into a genetic risk score (GRS). However, before GRS tools developed in European and North American populations can be utilised in New Zealand, it is important to examine the SNP distribution involved in GRS in our own primary and secondary prevention populations. Methods: We examined the frequency of 27 SNPs from a previously validated GRS in a cohort of patients presenting with myocardial infarction (MI). The observed frequency of each SNP was compared between MI patients identifying as Maori or European.