Tanya Sarina

Clinical predictors of genetic testing outcomes in hypertrophic cardiomyopathy

Purpose:Genetic testing for hypertrophic cardiomyopathy has been commercially available for almost a decade; however, low mutation detection rate and cost have hindered uptake. This study sought to identify clinical variables that can predict probands with hypertrophic cardiomyopathy in whom a pathogenic mutation will be identified.Methods:Probands attending specialized cardiac genetic clinics across Australia over a 10-year period (2002–2011), who met clinical diagnostic criteria for hypertrophic cardiomyopathy and who underwent genetic testing for hypertrophic cardiomyopathy were included. Clinical, family history, and genotype information were collected.Results:A total of 265 unrelated individuals with hypertrophic cardiomyopathy were included, with 138 (52%) having at least one mutation identified. The mutation detection rate was significantly higher in the probands with hypertrophic cardiomyopathy with an established family history of disease (72 vs. 29%, P < 0.0001), and a positive family history of sudden cardiac death further increased the detection rate (89 vs. 59%, P < 0.0001). Multivariate analysis identified female gender, increased left-ventricular wall thickness, family history of hypertrophic cardiomyopathy, and family history of sudden cardiac death as being associated with greatest chance of identifying a gene mutation. Multiple mutation carriers (n = 16, 6%) were more likely to have suffered an out-of-hospital cardiac arrest or sudden cardiac death (31 vs. 7%, P = 0.012).Conclusion:Family history is a key clinical predictor of a positive genetic diagnosis and has direct clinical relevance, particularly in the pretest genetic counseling setting.Genet Med 15 12, 972–977.Genetics in Medicine (2013); 15 12, 972–977. doi:10.1038/gim.2013.44

Psychological wellbeing and posttraumatic stress associated with implantable cardioverter defibrillator therapy in young adults with genetic heart disease

BACKGROUND Sudden cardiac death is a tragic complication of a number of genetic heart diseases. Implantable cardioverter defibrillator (ICD) therapy plays an important role in prevention of sudden death. The psychological consequences of ICD therapy in young people with genetic heart disease are poorly understood. This study sought to better understand psychological wellbeing and identify symptoms of posttraumatic stress in young people who had experienced an ICD shock. METHODS Eligible patients (ICD implanted over 12 months prior) with an inherited cardiomyopathy or primary arrhythmogenic disorder, enrolled in the Australian Genetic Heart Disease Registry were included. Ninety patients completed the Hospital Anxiety and Depression Scale (HADS). Those patients who had an ICD shock (n=31) also completed the Impact of Events Scale-Revised (IES-R). RESULTS While the mean HADS-Anxiety and IES-R scores were within the normal range in the total group (n=90), a significant subgroup reported symptoms of anxiety (38%), depression (17%) and posttraumatic stress (31%) indicative of the potential need for referral to clinical care. Overall, greater psychological distress in ICD patients was associated with female gender, a history of syncope, other comorbid medical conditions, and reporting of other distressing events (i.e., ICD complications). In those with an ICD shock, higher posttraumatic stress scores were associated with female gender and longer time to first shock. CONCLUSIONS Patients with genetic heart diseases can experience psychological difficulties, including anxiety, depression and posttraumatic stress, related to ICD implantation and subsequent shocks. This signals the importance of offering patients access to targeted interventions, including psychological care and support.

Social determinants of health in the setting of hypertrophic cardiomyopathy

INTRODUCTION Social determinants of health play an important role in explaining poor health outcomes across many chronic disease states. The impact of the social gradient in the setting of an inherited heart disease, hypertrophic cardiomyopathy (HCM), has not been investigated. This study sought to profile the socioeconomic status of patients attending a specialized multidisciplinary clinic and to determine the impact on clinical factors, psychosocial wellbeing and adherence to medical advice. METHODS Patients with HCM and at-risk relatives attending a specialized multidisciplinary clinic in Sydney Australia between 2011 and 2013 were included. Clinical, socioeconomic, geographic remoteness and adherence data were available. A broader clinic and registry-based group completed a survey including psychological wellbeing, health-related quality of life, Morisky Medication Adherence Scale and individual-level socioeconomic information. RESULTS Over a 3-year period, 486 patients were seen in the specialized clinic. There was an over-representation of patients from socioeconomically advantaged and the least geographically remote areas. Socioeconomic disadvantage was associated with comorbidities, poor psychological wellbeing and health-related quality of life, lower understanding of HCM and more complex clinical management issues such as NYHA class, atrial fibrillation and left ventricular outflow tract obstruction. Approximately 10% of patients were non-adherent to medical advice, and poor medication adherence was seen in 30% of HCM patients with associated factors being younger age, minority ethnicity, anxiety and poor mental quality of life. CONCLUSIONS Of all the patients attending a specialized cardiac genetic clinic, there is an overrepresentation of patients from very advantaged and major metropolitan areas and suggests that those most in need of a multidisciplinary approach to care are not accessing it.

Nonfamilial Hypertrophic CardiomyopathyCLINICAL PERSPECTIVE: Prevalence, Natural History, and Clinical Implications

Background— Yield of causative variants in hypertrophic cardiomyopathy (HCM) is increased in some probands, suggesting different clinical subgroups of disease occur. We hypothesized that a negative family history and no sarcomere mutations represent a nonfamilial subgroup of HCM. We sought to determine the prevalence, natural history, and potential clinical implications of this nonfamilial subgroup of HCM. Methods and Results— Four hundred and thirteen unrelated probands with HCM seen in a specialized HCM center between 2002 and 2015 and genetic testing performed were included in this retrospective cohort study. There were 251 (61%) probands with no reported family history of HCM, including 166 (40% of total) probands with no sarcomere mutation, that is, nonfamilial HCM. Quantified family pedigree data revealed no difference in mean number of first-degree relatives screened between nonfamilial and sarcomere-positive groups. Adjusted predictors of nonfamilial status were older age (odds ratio, 1.04; 95% confidence interval, 1.02–1.06; P=0.0001), male sex (odds ratio, 1.96; 95% confidence interval, 1.11–3.45; P=0.02), hypertension (odds ratio, 2.80; 95% confidence interval, 1.57–5.00; P=0.0005), and nonasymmetric septal morphology (odds ratio, 3.41; 95% confidence interval, 1.64–7.08; P=0.001). They had a less severe clinical course with greater event-free survival from major cardiac events (P=0.04) compared with sarcomere-positive HCM probands. Genotype prediction scores showed good performance in identifying genotype-positive patients (area under the curve, 0.71–0.75) and, in combination with pedigree characteristics, were further improved. Conclusions— Approximately 40% of HCM probands have a nonfamilial subtype, with later onset and less severe clinical course. We propose a revised clinical pathway for management, highlighting the role of genetic testing, a detailed pedigree, and refined clinical surveillance recommendations for family members.Background— Yield of causative variants in hypertrophic cardiomyopathy (HCM) is increased in some probands, suggesting different clinical subgroups of disease occur. We hypothesized that a negative family history and no sarcomere mutations represent a nonfamilial subgroup of HCM. We sought to determine the prevalence, natural history, and potential clinical implications of this nonfamilial subgroup of HCM. Methods and Results— Four hundred and thirteen unrelated probands with HCM seen in a specialized HCM center between 2002 and 2015 and genetic testing performed were included in this retrospective cohort study. There were 251 (61%) probands with no reported family history of HCM, including 166 (40% of total) probands with no sarcomere mutation, that is, nonfamilial HCM. Quantified family pedigree data revealed no difference in mean number of first-degree relatives screened between nonfamilial and sarcomere-positive groups. Adjusted predictors of nonfamilial status were older age (odds ratio, 1.04; 95% confidence interval, 1.02–1.06; P =0.0001), male sex (odds ratio, 1.96; 95% confidence interval, 1.11–3.45; P =0.02), hypertension (odds ratio, 2.80; 95% confidence interval, 1.57–5.00; P =0.0005), and nonasymmetric septal morphology (odds ratio, 3.41; 95% confidence interval, 1.64–7.08; P =0.001). They had a less severe clinical course with greater event-free survival from major cardiac events ( P =0.04) compared with sarcomere-positive HCM probands. Genotype prediction scores showed good performance in identifying genotype-positive patients (area under the curve, 0.71–0.75) and, in combination with pedigree characteristics, were further improved. Conclusions— Approximately 40% of HCM probands have a nonfamilial subtype, with later onset and less severe clinical course. We propose a revised clinical pathway for management, highlighting the role of genetic testing, a detailed pedigree, and refined clinical surveillance recommendations for family members.

Nonfamilial hypertrophic cardiomyopathy

Background— Yield of causative variants in hypertrophic cardiomyopathy (HCM) is increased in some probands, suggesting different clinical subgroups of disease occur. We hypothesized that a negative family history and no sarcomere mutations represent a nonfamilial subgroup of HCM. We sought to determine the prevalence, natural history, and potential clinical implications of this nonfamilial subgroup of HCM. Methods and Results— Four hundred and thirteen unrelated probands with HCM seen in a specialized HCM center between 2002 and 2015 and genetic testing performed were included in this retrospective cohort study. There were 251 (61%) probands with no reported family history of HCM, including 166 (40% of total) probands with no sarcomere mutation, that is, nonfamilial HCM. Quantified family pedigree data revealed no difference in mean number of first-degree relatives screened between nonfamilial and sarcomere-positive groups. Adjusted predictors of nonfamilial status were older age (odds ratio, 1.04; 95% confidence interval, 1.02–1.06; P=0.0001), male sex (odds ratio, 1.96; 95% confidence interval, 1.11–3.45; P=0.02), hypertension (odds ratio, 2.80; 95% confidence interval, 1.57–5.00; P=0.0005), and nonasymmetric septal morphology (odds ratio, 3.41; 95% confidence interval, 1.64–7.08; P=0.001). They had a less severe clinical course with greater event-free survival from major cardiac events (P=0.04) compared with sarcomere-positive HCM probands. Genotype prediction scores showed good performance in identifying genotype-positive patients (area under the curve, 0.71–0.75) and, in combination with pedigree characteristics, were further improved. Conclusions— Approximately 40% of HCM probands have a nonfamilial subtype, with later onset and less severe clinical course. We propose a revised clinical pathway for management, highlighting the role of genetic testing, a detailed pedigree, and refined clinical surveillance recommendations for family members.Background— Yield of causative variants in hypertrophic cardiomyopathy (HCM) is increased in some probands, suggesting different clinical subgroups of disease occur. We hypothesized that a negative family history and no sarcomere mutations represent a nonfamilial subgroup of HCM. We sought to determine the prevalence, natural history, and potential clinical implications of this nonfamilial subgroup of HCM. Methods and Results— Four hundred and thirteen unrelated probands with HCM seen in a specialized HCM center between 2002 and 2015 and genetic testing performed were included in this retrospective cohort study. There were 251 (61%) probands with no reported family history of HCM, including 166 (40% of total) probands with no sarcomere mutation, that is, nonfamilial HCM. Quantified family pedigree data revealed no difference in mean number of first-degree relatives screened between nonfamilial and sarcomere-positive groups. Adjusted predictors of nonfamilial status were older age (odds ratio, 1.04; 95% confidence interval, 1.02–1.06; P =0.0001), male sex (odds ratio, 1.96; 95% confidence interval, 1.11–3.45; P =0.02), hypertension (odds ratio, 2.80; 95% confidence interval, 1.57–5.00; P =0.0005), and nonasymmetric septal morphology (odds ratio, 3.41; 95% confidence interval, 1.64–7.08; P =0.001). They had a less severe clinical course with greater event-free survival from major cardiac events ( P =0.04) compared with sarcomere-positive HCM probands. Genotype prediction scores showed good performance in identifying genotype-positive patients (area under the curve, 0.71–0.75) and, in combination with pedigree characteristics, were further improved. Conclusions— Approximately 40% of HCM probands have a nonfamilial subtype, with later onset and less severe clinical course. We propose a revised clinical pathway for management, highlighting the role of genetic testing, a detailed pedigree, and refined clinical surveillance recommendations for family members.

Nonfamilial Hypertrophic CardiomyopathyCLINICAL PERSPECTIVE

Background— Yield of causative variants in hypertrophic cardiomyopathy (HCM) is increased in some probands, suggesting different clinical subgroups of disease occur. We hypothesized that a negative family history and no sarcomere mutations represent a nonfamilial subgroup of HCM. We sought to determine the prevalence, natural history, and potential clinical implications of this nonfamilial subgroup of HCM. Methods and Results— Four hundred and thirteen unrelated probands with HCM seen in a specialized HCM center between 2002 and 2015 and genetic testing performed were included in this retrospective cohort study. There were 251 (61%) probands with no reported family history of HCM, including 166 (40% of total) probands with no sarcomere mutation, that is, nonfamilial HCM. Quantified family pedigree data revealed no difference in mean number of first-degree relatives screened between nonfamilial and sarcomere-positive groups. Adjusted predictors of nonfamilial status were older age (odds ratio, 1.04; 95% confidence interval, 1.02–1.06; P=0.0001), male sex (odds ratio, 1.96; 95% confidence interval, 1.11–3.45; P=0.02), hypertension (odds ratio, 2.80; 95% confidence interval, 1.57–5.00; P=0.0005), and nonasymmetric septal morphology (odds ratio, 3.41; 95% confidence interval, 1.64–7.08; P=0.001). They had a less severe clinical course with greater event-free survival from major cardiac events (P=0.04) compared with sarcomere-positive HCM probands. Genotype prediction scores showed good performance in identifying genotype-positive patients (area under the curve, 0.71–0.75) and, in combination with pedigree characteristics, were further improved. Conclusions— Approximately 40% of HCM probands have a nonfamilial subtype, with later onset and less severe clinical course. We propose a revised clinical pathway for management, highlighting the role of genetic testing, a detailed pedigree, and refined clinical surveillance recommendations for family members.Background— Yield of causative variants in hypertrophic cardiomyopathy (HCM) is increased in some probands, suggesting different clinical subgroups of disease occur. We hypothesized that a negative family history and no sarcomere mutations represent a nonfamilial subgroup of HCM. We sought to determine the prevalence, natural history, and potential clinical implications of this nonfamilial subgroup of HCM. Methods and Results— Four hundred and thirteen unrelated probands with HCM seen in a specialized HCM center between 2002 and 2015 and genetic testing performed were included in this retrospective cohort study. There were 251 (61%) probands with no reported family history of HCM, including 166 (40% of total) probands with no sarcomere mutation, that is, nonfamilial HCM. Quantified family pedigree data revealed no difference in mean number of first-degree relatives screened between nonfamilial and sarcomere-positive groups. Adjusted predictors of nonfamilial status were older age (odds ratio, 1.04; 95% confidence interval, 1.02–1.06; P =0.0001), male sex (odds ratio, 1.96; 95% confidence interval, 1.11–3.45; P =0.02), hypertension (odds ratio, 2.80; 95% confidence interval, 1.57–5.00; P =0.0005), and nonasymmetric septal morphology (odds ratio, 3.41; 95% confidence interval, 1.64–7.08; P =0.001). They had a less severe clinical course with greater event-free survival from major cardiac events ( P =0.04) compared with sarcomere-positive HCM probands. Genotype prediction scores showed good performance in identifying genotype-positive patients (area under the curve, 0.71–0.75) and, in combination with pedigree characteristics, were further improved. Conclusions— Approximately 40% of HCM probands have a nonfamilial subtype, with later onset and less severe clinical course. We propose a revised clinical pathway for management, highlighting the role of genetic testing, a detailed pedigree, and refined clinical surveillance recommendations for family members.