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Significant Differences in Genetic Risk Profiles Between Maori and European Presenting with Myocardial Infarction
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.
Abstracts
S308
Results: In 683 MI patients, 64 (9.8%) identified as Maori, 572 (83.8%) as European and 47 (6.7%) as other. We observed significantly higher frequency of risk alleles in 11 of the 27 SNPs in Maori compared to European patients, with frequencies 9-28% higher, and in 6 of the 27 SNPs the risk allele was significantly less frequency (9-20%) in Maori patients. Overall, the unweighted GRS was higher in Maori than European patients (28.5 ± 3.0 versus 26.7 ± 3.4, p < 0.0001). Conclusion: We observed significant differences in the distribution of risk alleles in Maori MI patients. Understanding how these differences impact on health outcomes in Maori requires careful evaluation before internationally developed GRS tools can be applied. http://dx.doi.org/10.1016/j.hlc.2017.06.612 612 To Treat or Not to Treat: A Therapeutic Dilemma in a Gene Positive, Phenotypic Negative CPVT Woman Throughout Her Pregnancies E. Kotschet ∗ , M. Hunter, A. Kroushev, E. Wallace Monash Heart, Melbourne, Australia Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterised by polymorphic VT, which may cause palpitations, syncope or sudden death, often triggered by exercise or emotion, in the absence of structural heart disease. The mainstay of therapy is high dose beta blockade. Implantable defibrillators are considered, if prior cardiac arrest. There are isolated case reports of patients with CPVT experiencing pregnancy. We describe the treatment challenges in a 23-year-old woman with RyR2 gene mutation, but no prior symptoms, during three consecutive pregnancies. She was diagnosed through cascade testing, following a cousin’s arrest. Atenolol was commenced at 24 weeks’ gestations after the positive gene test, given a stress test revealed rare VPCs. She had an elective Caesarean section given a prior spinal fusion. A 2.75 kg growth-restricted baby was born at 39 weeks. The patient self-ceased atenolol, and remained off therapy in her second pregnancy given low birth weight of her first child. At 39 weeks, a repeat Caesarean section delivered a healthy 3.21 kg baby. Her third pregnancy was uncomplicated, also off therapy, and she delivered a 2.93 kg baby at 39 weeks. There were no cardiac symptoms reported. Conclusion: This case demonstrates the clinical dilemma faced in gene positive, phenotypic negative women undergoing pregnancy, where beta blockers are recommended, but patient declines due to baby growth issues. http://dx.doi.org/10.1016/j.hlc.2017.06.613
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613 Whole Genome Sequencing of First Degree Relatives with Spontaneous Coronary Artery Dissection J. Fahey Monash Heart, Melbourne, Australia Background: Spontaneous coronary artery dissection (SCAD) can present as acute coronary syndrome, including STEMI or sudden cardiac death. There is a strong female preponderance of cases. An association with fibromuscular dyplasia of non-coronary arterial beds is recognised. The mechanism of SCAD is not known but is completely distinct from coronary atherosclerosis. SCAD is not usually thought of as having a genetic component, however within our cardiology department a mother and daughter have both survived a SCAD event, raising the possibility of a genetic predisposition in these two family members. Aim: To sequence and analyse the genome of a mother and her daughter, both with SCAD. Methods: Routine extraction of genomic DNA from peripheral blood leucocytes. Whole genome sequencing by genome fragmentation and massive parallel sequencing. Analysis of the resulting huge electronic files by comparison with reference human genomes. Distillation of the large number of variants of uncertain significance (VUS) in terms of their potential causative relationship to the phenotype by bioinformatic methods to focus upon: (1) coding sequences (exome sequencing) (2) those variants predicted to alter amino acid sequence, especially those resulting in truncation of a protein and (3) known arterial wall structural proteins. Results and Conclusions: The list of biologically plausible genetic variants shared between the mother and daughter with SCAD indeed represents a list of candidate genes potentially involved in the molecular mechanism of SCAD, a currently mysterious condition. This rare occurrence of two SCAD cases within a family is an opportunity to illuminate the underlying cause of the disease. http://dx.doi.org/10.1016/j.hlc.2017.06.614 Cardiac Surgery (614–635) 614 A Case Report of an Aortic Root Abscess That Was Left Alone N. Lan ∗ , X. Xu Fiona Stanley Hospital, Perth, Australia Is surgery the only option for good outcomes in aortic root abscess? We report a case that was managed medically with a positive result. A 63-year-old male presented with a five-day history of fevers and lethargy in the context of a recently treated leg cellulitis. He has a background of infective endocarditis in 2012 requiring aortic valve replacement and infective endocarditis in 2013 requiring redo aortic valve replacement and mitral
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
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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.
Abstracts
S308
Results: In 683 MI patients, 64 (9.8%) identified as Maori, 572 (83.8%) as European and 47 (6.7%) as other. We observed significantly higher frequency of risk alleles in 11 of the 27 SNPs in Maori compared to European patients, with frequencies 9-28% higher, and in 6 of the 27 SNPs the risk allele was significantly less frequency (9-20%) in Maori patients. Overall, the unweighted GRS was higher in Maori than European patients (28.5 ± 3.0 versus 26.7 ± 3.4, p < 0.0001). Conclusion: We observed significant differences in the distribution of risk alleles in Maori MI patients. Understanding how these differences impact on health outcomes in Maori requires careful evaluation before internationally developed GRS tools can be applied. http://dx.doi.org/10.1016/j.hlc.2017.06.612 612 To Treat or Not to Treat: A Therapeutic Dilemma in a Gene Positive, Phenotypic Negative CPVT Woman Throughout Her Pregnancies E. Kotschet ∗ , M. Hunter, A. Kroushev, E. Wallace Monash Heart, Melbourne, Australia Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterised by polymorphic VT, which may cause palpitations, syncope or sudden death, often triggered by exercise or emotion, in the absence of structural heart disease. The mainstay of therapy is high dose beta blockade. Implantable defibrillators are considered, if prior cardiac arrest. There are isolated case reports of patients with CPVT experiencing pregnancy. We describe the treatment challenges in a 23-year-old woman with RyR2 gene mutation, but no prior symptoms, during three consecutive pregnancies. She was diagnosed through cascade testing, following a cousin’s arrest. Atenolol was commenced at 24 weeks’ gestations after the positive gene test, given a stress test revealed rare VPCs. She had an elective Caesarean section given a prior spinal fusion. A 2.75 kg growth-restricted baby was born at 39 weeks. The patient self-ceased atenolol, and remained off therapy in her second pregnancy given low birth weight of her first child. At 39 weeks, a repeat Caesarean section delivered a healthy 3.21 kg baby. Her third pregnancy was uncomplicated, also off therapy, and she delivered a 2.93 kg baby at 39 weeks. There were no cardiac symptoms reported. Conclusion: This case demonstrates the clinical dilemma faced in gene positive, phenotypic negative women undergoing pregnancy, where beta blockers are recommended, but patient declines due to baby growth issues. http://dx.doi.org/10.1016/j.hlc.2017.06.613
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613 Whole Genome Sequencing of First Degree Relatives with Spontaneous Coronary Artery Dissection J. Fahey Monash Heart, Melbourne, Australia Background: Spontaneous coronary artery dissection (SCAD) can present as acute coronary syndrome, including STEMI or sudden cardiac death. There is a strong female preponderance of cases. An association with fibromuscular dyplasia of non-coronary arterial beds is recognised. The mechanism of SCAD is not known but is completely distinct from coronary atherosclerosis. SCAD is not usually thought of as having a genetic component, however within our cardiology department a mother and daughter have both survived a SCAD event, raising the possibility of a genetic predisposition in these two family members. Aim: To sequence and analyse the genome of a mother and her daughter, both with SCAD. Methods: Routine extraction of genomic DNA from peripheral blood leucocytes. Whole genome sequencing by genome fragmentation and massive parallel sequencing. Analysis of the resulting huge electronic files by comparison with reference human genomes. Distillation of the large number of variants of uncertain significance (VUS) in terms of their potential causative relationship to the phenotype by bioinformatic methods to focus upon: (1) coding sequences (exome sequencing) (2) those variants predicted to alter amino acid sequence, especially those resulting in truncation of a protein and (3) known arterial wall structural proteins. Results and Conclusions: The list of biologically plausible genetic variants shared between the mother and daughter with SCAD indeed represents a list of candidate genes potentially involved in the molecular mechanism of SCAD, a currently mysterious condition. This rare occurrence of two SCAD cases within a family is an opportunity to illuminate the underlying cause of the disease. http://dx.doi.org/10.1016/j.hlc.2017.06.614 Cardiac Surgery (614–635) 614 A Case Report of an Aortic Root Abscess That Was Left Alone N. Lan ∗ , X. Xu Fiona Stanley Hospital, Perth, Australia Is surgery the only option for good outcomes in aortic root abscess? We report a case that was managed medically with a positive result. A 63-year-old male presented with a five-day history of fevers and lethargy in the context of a recently treated leg cellulitis. He has a background of infective endocarditis in 2012 requiring aortic valve replacement and infective endocarditis in 2013 requiring redo aortic valve replacement and mitral