Charlotte Burns

Application of Genetic Testing in Hypertrophic Cardiomyopathy for Preclinical Disease Detection.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular diseases, with a prevalence of at least 1 in 500 in the general population.1,2 HCM is characterized by left ventricular hypertrophy, in the absence of other loading conditions, such as hypertension.3 The hallmark feature of HCM is significant clinical heterogeneity in presentation, ranging from asymptomatic patients to those who have the most serious outcomes of heart failure and sudden cardiac death. Over 1500 mutations in at least 15 sarcomere-encoding genes have been identified.4–7 The significance of cardiac genetic testing in clinical practice is 2-fold. For the proband, identification of the underlying genetic cause in some cases can clarify the cause of hypertrophy, for example, clarifying phenocopies, such as PRKAG2-glycogen storage disease and Fabry disease. The greatest utility, however, is in cascade genetic testing of asymptomatic relatives, with clear benefits either for confirming a borderline clinical diagnosis, or suspicious clinical changes suggestive of early disease, or most importantly ruling out the disease in those who test gene-negative. Identification of a silent gene carrier will guide cascade testing of additional family members, in effect clarifying their risk status. Of most benefit, a negative genetic result can reassure offspring that they are not at risk of HCM. The escalation in our understanding of the genetic basis of HCM has been catalyzed by the implementation of next generation sequencing technologies. In response to faster and more affordable testing, commercial genetic testing for HCM now often comprises vast cardiac gene chips (ie, 50–200 or more genes). This approach, although comprehensive, also draws into sharp focus the limitations of our current knowledge. The challenges of cardiac genetic testing are increasingly documented, such as identification of variants of uncertain significance (VUS), incidental genetic findings,8 reclassification of variants,9 increased need …

Attitudes, knowledge and consequences of uncertain genetic findings in hypertrophic cardiomyopathy

With the surge of next-generation sequencing (NGS) technologies making almost all genetic tests more affordable and available, cardiac genetic testing now routinely encompasses a large number of genes within a panel setting. The additional sensitivity of this practice is limited and has the potential to inflict a spectrum of uncertainty. We sought to explore attitudes, preferences, recall and psychological consequences of informative and uninformative genetic results amongst probands diagnosed with hypertrophic cardiomyopathy (HCM). We conducted semi-structured interviews and analysed the qualitative data using a framework analysis process. In general, we found probands were more concerned with their clinical diagnosis than gene result and in some, recall and understanding of genetic diagnosis was poor. Several participants expected genetic testing would alleviate uncertainty, often holding an altruistic view of participation in testing, removing their sense of self and failing to appreciate fully the familial implications. With the key utility of HCM genetic testing and counselling being for greater risk prediction for at-risk relatives, effective communication within the family is critical. While communication appeared adequate, further questioning found it was often vague, failing to translate into meaningful action by relatives. Based on these findings, a framework of key outcomes to assist multidisciplinary teams in genetic counselling of probands receiving an HCM gene result was developed.

Factors influencing uptake of familial long QT syndrome genetic testing

Ongoing challenges of clinical assessment of long QT syndrome (LQTS) highlight the importance of genetic testing in the diagnosis of asymptomatic at‐risk family members. Effective access, uptake, and communication of genetic testing are critical for comprehensive cascade family screening and prevention of disease complications such as sudden cardiac death. The aim of this study was to describe factors influencing uptake of LQTS genetic testing, including those relating to access and family communication. We show those who access genetic testing are overrepresented by the socioeconomically advantaged, and that although overall family communication is good, there are some important barriers to be addressed. There were 75 participants (aged 18 years or more, with a clinical and/or genetic diagnosis of LQTS; response rate 71%) who completed a survey including a number of validated scales; demographics; and questions about access, uptake, and communication. Mean age of participants was 46 ± 16 years, 20 (27%) were males and 60 (80%) had genetic testing with a causative gene mutation in 42 (70%). Overall uptake of cascade testing within families was 60% after 4 years from proband genetic diagnosis. All participants reported at least one first‐degree relative had been informed of their risk, whereas six (10%) reported at least one first‐degree relative had not been informed. Those who were anxious or depressed were more likely to perceive barriers to communicating. Genetic testing is a key aspect of care in LQTS families and intervention strategies that aim to improve equity in access and facilitate effective family communication are needed.

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.

Clinical and genetic features of Australian families with long QT syndrome: A registry-based study

Familial long QT syndrome (LQTS) is a primary arrhythmogenic disorder caused by mutations in ion channel genes. The phenotype ranges from asymptomatic individuals to sudden cardiac arrest and death. LQTS is a rare but significant health problem for which global data should exist. This study sought to provide the first clinical and genetic description of Australian families with LQTS.

Multiple Gene Variants in Hypertrophic Cardiomyopathy in the Era of Next-Generation SequencingCLINICAL PERSPECTIVE

Background— Multiple likely pathogenic/pathogenic (LP/P; ≥2) variants in patients with hypertrophic cardiomyopathy were described 10 years ago with a prevalence of 5%. We sought to re-examine the significance of multiple rare variants in patients with hypertrophic cardiomyopathy in the setting of comprehensive and targeted panels. Methods and Results— Of 758 hypertrophic cardiomyopathy probands, we included 382 with ≥45 cardiomyopathy genes screened. There were 224 (59%) with ≥1 rare variant (allele frequency ⩽0.02%). Variants were analyzed using varying sized gene panels to represent comprehensive or targeted testing. Based on a 45-gene panel, 127 (33%) had a LP/P variant, 139 (36%) had variants of uncertain significance, and 66 (17%) had multiple rare variants. A targeted 8-gene panel yielded 125 (32%) LP/P variants, 52 (14%) variants of uncertain significance, and 14 (4%) 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 (odds ratio, 0.95; 95% confidence interval, 0.92–0.98; P=0.004) and family history of sudden cardiac death (odds ratio, 3.5; 95% confidence interval, 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. Those with multiple variants had worse event-free survival from all-cause death, cardiac transplantation, and cardiac arrest (log-rank P=0.008). Conclusions— No proband had multiple LP/P variants in contrast to previous reports. 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 hypertrophic cardiomyopathy.

Pathogenicity of Hypertrophic Cardiomyopathy Variants: A Path Forward Together

The challenges of correctly interpreting rare variants identified via genetic testing of patients with hypertrophic cardiomyopathy (HCM) are universal and ever present. HCM genetic testing has been offered for almost 2 decades, yet in spite of the leaps forward in our understanding, the genetic underpinnings of this disease remain elusive in many patients. Mainstream application of comprehensive cardiac gene panels, which are becoming more affordable as the technology develops, detect a clinically significant variant in 40% to 60% of patients with the majority of variants residing in genes encoding the cardiac sarcomere.1,2 The value of identifying a pathogenic variant in a proband extends to family members, who have the option to know conclusively whether they carry the causative variant, allowing more targeted clinical surveillance and clarifying risk to children. For many others, however, the identification of uncertain variants poses greater challenges, and the expertise, resources, and standardized criteria to classify them as causative or benign currently fall short. See Article by Furqan et al In this issue of Circulation: Cardiovascular Genetics , Furqan et al3 demonstrate the marked discordance seen between specialist HCM centers worldwide. Among sarcomeric human cardiomyopathy registry centers, 20.5% of variants seen in >1 center had classification discrepancies that impacted clinical management, that is, likely pathogenic/pathogenic or variant of uncertain significance or likely benign/benign. The primary reason, in 75% of cases, was access to privately held data by either the sarcomeric human cardiomyopathy registry center (60%) or from the genetic testing laboratory’s internal experience (60%). Segregation information from informative families accounted for 35% of discordant variants, …

The social gradient of taking a family history

clinic in central Arkansas. Factors examined included knowledge of hypertension in their family, culturally influenced teaching about hypertension and response to having a positive family history of hypertension. Using the US Surgeon General’s My Family Health Portrait, 90% of patients were able to recall enough family history to develop an informative pedigree with the assistance of a nurse practitioner. Importantly, the utility of the family history hinges on its accuracy. This accuracy is dependent on the patient’s ability to provide enough information necessary to construct a pedigree and is likely influenced by social factors such as ethnicity, education and health literacy. Social determinants of health are potent predictors of poor health outcomes globally, and have been identified as priority action areas by the World Health Organization. 9 The influence of socioeconomic status operates along a continuum, with the poorest health outcomes in the most disadvantaged groups. This social gradient is evident even in developed countries. The African American population is a minority racial group representing approximately 12% of the US population, and in general having lower levels of educational attainment, lower income, worse perceptions of the health services available in their community and worse overall morbidity and mortality. 10 In the study by Pettey et al. all 29 participants met the criteria for poverty. Low socioeconomic status was evident in the qualitative data collected, particularly issues relating to segregation of African American patients where family members were historically treated in ‘coloured wards’, lack of explanation from medical staff about the causes of ill health or death of family members, and acknowledgement of poor diet, physical

Relations between right ventricular morphology and clinical, electrical and genetic parameters in Brugada Syndrome.

Background Increasing evidence suggests the presence of structural changes affecting the right ventricular outflow tract (RVOT) in patients with Brugada Syndrome (BrS). The aim of this study was to characterise the RV morphology in BrS and explore associations between morphologic, clinical, electrical, and genetic parameters using non-invasive multimodality testing. Methods Consecutive BrS patients (recruited 2013–2015) underwent clinical assessment, dedicated RV imaging using cardiac magnetic resonance (CMR) imaging (unless contra-indicated), electrical assessment (electrocardiogram, Holter monitoring, signal-averaged ECG[SAECG]) and genotyping. Morphologic data were compared to matched control and unmatched ARVC (arrhythmogenic right ventricular cardiomyopathy) cohorts, and potential associations between morphologic parameters and other variables were explored. Results BrS patients (n = 42, male 86%, age 46±12 years) exhibited normal global RV volume and function, comparable to control, in contrast to significantly larger, impaired RVs in ARVC cohort (RVESV p = 0.0001; RVEDV p<0.0001, RVEF p = 0.002). Compared with control, BrS patients exhibited larger RVOT volumes (7.4 ± 0.7 vs 5.8 ± 0.7 mL/m2, p<0.0001) and wall motion abnormalities (RWMA) (31% vs 0%, p = 0.005); compared with ARVC cohort, the RVOT volumes were similar (7.4 ± 0.7 vs, 8.1 ± 1.7, p = 0.52) and there were less RWMA (31% vs 76%, p = 0.01). Overall 67% BrS patients had abnormal RVOT morphology. Patients with abnormal RVOT tended to be older (48 ± 12 y vs 41 ± 12y, p = 0.06). Rare genetic variants were only observed in patients with abnormal RVOT morphology (36% vs 0%, p = 0.02). Conclusions Patients with BrS frequently exhibit structural abnormalities localised to the RVOT and these changes may be age- and gene-dependent.

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.