Jodie Ingles

Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling

Objective: To report the frequency of single and multiple gene mutations in an Australian cohort of patients with hypertrophic cardiomyopathy (HCM). Methods: Genetic screening of seven HCM genes (β-MHC, MyBP-C, cTnT, cTnI, ACTC, MYL2, and MYL3) was undertaken in 80 unrelated probands. Screening was by denaturing high performance liquid chromatography and direct DNA sequencing. Clinical data were collected on all patients and on genotyped family members. Results: 26 mutations were identified in 23 families (29%). Nineteen probands (24%) had single mutations (11 β-MHC, 4 MyBP-C, 3 cTnI, 1 cTnT). Multiple gene mutations were identified in four probands (5%): one had a double mutation and the others had compound mutations. Six of 14 affected individuals from multiple mutation families (43%) experienced a sudden cardiac death event, compared with 10 of 55 affected members (18%) from single mutation families (p = 0.05). There was an increase in septal wall thickness in patients with compound mutations (mean (SD): 30.7 (3.1) v 24.4 (7.4) mm; p<0.05). Conclusions: Multiple gene mutations occurring in HCM families may result in a more severe clinical phenotype because of a “double dose” effect. This highlights the importance of screening the entire panel of HCM genes even after a single mutation has been identified.

A Prospective Study of Sudden Cardiac Death among Children and Young Adults

BACKGROUND Sudden cardiac death among children and young adults is a devastating event. We performed a prospective, population-based, clinical and genetic study of sudden cardiac death among children and young adults. METHODS We prospectively collected clinical, demographic, and autopsy information on all cases of sudden cardiac death among children and young adults 1 to 35 years of age in Australia and New Zealand from 2010 through 2012. In cases that had no cause identified after a comprehensive autopsy that included toxicologic and histologic studies (unexplained sudden cardiac death), at least 59 cardiac genes were analyzed for a clinically relevant cardiac gene mutation. RESULTS A total of 490 cases of sudden cardiac death were identified. The annual incidence was 1.3 cases per 100,000 persons 1 to 35 years of age; 72% of the cases involved boys or young men. Persons 31 to 35 years of age had the highest incidence of sudden cardiac death (3.2 cases per 100,000 persons per year), and persons 16 to 20 years of age had the highest incidence of unexplained sudden cardiac death (0.8 cases per 100,000 persons per year). The most common explained causes of sudden cardiac death were coronary artery disease (24% of cases) and inherited cardiomyopathies (16% of cases). Unexplained sudden cardiac death (40% of cases) was the predominant finding among persons in all age groups, except for those 31 to 35 years of age, for whom coronary artery disease was the most common finding. Younger age and death at night were independently associated with unexplained sudden cardiac death as compared with explained sudden cardiac death. A clinically relevant cardiac gene mutation was identified in 31 of 113 cases (27%) of unexplained sudden cardiac death in which genetic testing was performed. During follow-up, a clinical diagnosis of an inherited cardiovascular disease was identified in 13% of the families in which an unexplained sudden cardiac death occurred. CONCLUSIONS The addition of genetic testing to autopsy investigation substantially increased the identification of a possible cause of sudden cardiac death among children and young adults. (Funded by the National Health and Medical Research Council of Australia and others.).

Mutations in Alpha-Actinin-2 Cause Hypertrophic Cardiomyopathy: A Genome-Wide Analysis

OBJECTIVES This study describes a genome-wide linkage analysis of a large family with clinically heterogeneous hypertrophic cardiomyopathy (HCM). BACKGROUND Familial HCM is a disorder characterized by genetic heterogeneity. In as many as 50% of HCM cases, the genetic cause remains unknown, suggesting that other genes may be involved. METHODS Clinical evaluation, including clinical history, physical examination, electrocardiography, and 2-dimensional echocardiography, was performed, and blood was collected from family members (n = 23) for deoxyribonucleic acid analysis. The family was genotyped with markers from the 10-cM AB PRISM Human Linkage mapping set (Applied Biosystems, Foster City, California), and 2-point linkage analysis was performed. RESULTS Affected family members showed marked clinical diversity, ranging from asymptomatic individuals to those with syncope, heart failure, and premature sudden death. The disease locus for this family was mapped to chromosome 1q42.2-q43, near the marker D1S2850 (logarithm of odds ratio = 2.82, theta = 0). A missense mutation, Ala119Thr, in the alpha-actinin-2 (ACTN2) gene was identified that segregated with disease in the family. An additional 297 HCM probands were screened for mutations in the ACTN2 gene using high-resolution melt analysis. Three causative ACTN2 mutations, Thr495Met, Glu583Ala, and Glu628Gly, were identified in an additional 4 families (total 1.7%) with HCM. CONCLUSIONS This is the first genome-wide linkage analysis that shows mutations in ACTN2 cause HCM. Mutations in genes encoding Z-disk proteins account for a small but significant proportion of genotyped HCM families.

Sudden cardiac death in the young: the molecular autopsy and a practical approach to surviving relatives

The sudden death of a young, apparently fit and healthy person is amongst the most challenging scenarios in clinical medicine. Sudden cardiac death (SCD) is a devastating and tragic outcome of a number of underlying cardiovascular diseases. While coronary artery disease and acute myocardial infarction are the most common causes of SCD in older populations, genetic (inherited) cardiac disorders comprise a substantial proportion of SCD cases aged 40 years and less. This includes the primary arrhythmogenic disorders such as long QT syndromes and inherited cardiomyopathies, namely hypertrophic cardiomyopathy. In up to 30% of young SCD, no cause of death is identified at postmortem, so-called autopsy-negative or sudden arrhythmic death syndrome (SADS). Management of families following SCD begins with a concerted effort to identify the cause of death in the decedent, based on either premorbid clinical details or the pathological findings at postmortem. Where no cause of death is identified, genetic testing of deoxyribonucleic acid extracted from postmortem blood (the molecular autopsy) may identify a cause of death in up to 30% of SADS cases. Irrespective of the genetic testing considerations, all families in which a sudden unexplained death has occurred require targeted and standardized clinical testing in an attempt to identify relatives who may be at-risk of having the same inherited heart disease and therefore also predisposed to an increased risk of SCD. Optimal care of SCD families therefore requires dedicated and appropriately trained staff in the setting of a specialized multidisciplinary cardiac genetic clinic.

Sudden cardiac death in the young: a clinical genetic approach

The sudden death of a young person is a devastating event for both the family and community. Over the last decade, significant advances have been made in understanding both the clinical and genetic basis of sudden cardiac death in the young. Many of the causes of sudden death in the young are due to genetic heart disorders, which can lead to both structural (e.g. hypertrophic cardiomyopathy) and arrhythmogenic (e.g. familial long QT syndrome) abnormalities. Most commonly, sudden cardiac death in the young can be the first presentation of an underlying heart problem, leaving the family at a loss as to why an otherwise healthy young person has died. Not only is this a tragic event for those involved, but it also presents a medical challenge to the clinician involved in the management of the surviving family members. Evaluation of families requires a multidisciplinary approach, which should include cardiologists, a clinical geneticist, a genetic counsellor and the forensic pathologist directly involved in the sudden death case. This multifaceted cardiac genetic service is crucial in the evaluation and management of the clinical, genetic, psychological and social complexities observed in families in which there has been a young sudden cardiac death.

A cost-effectiveness model of genetic testing for the evaluation of families with hypertrophic cardiomyopathy

Background Traditional management of families with hypertrophic cardiomyopathy (HCM) involves periodic lifetime clinical screening of family members, an approach that does not identify all gene carriers owing to incomplete penetrance and significant clinical heterogeneity. Limitations in availability and cost have meant genetic testing is not part of routine clinical management for many HCM families. Objective To determine the cost-effectiveness of the addition of genetic testing to HCM family management, compared with clinical screening alone. Methods A probabilistic Markov decision model was used to determine cost per quality-adjusted life-year and cost for each life-year gained when genetic testing is included in the management of Australian families with HCM, compared with the conventional approach of periodic clinical screening alone. Results The incremental cost-effectiveness ratio (ICER) was

Psychosocial impact of specialized cardiac genetic clinics for hypertrophic cardiomyopathy

A785 (£510 or €587) per quality-adjusted life-year gained, and

Clinical predictors of genetic testing outcomes in hypertrophic cardiomyopathy

A12 720 (£8261 or €9509) per additional life-year gained making genetic testing a very cost-effective strategy. Sensitivity analyses showed that the cost of proband genetic testing was an important variable. As the cost of proband genetic testing decreased, the ICER decreased and was cost saving when the cost fell below

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

A248 (£161 or €185). In addition, the mutation identification rate was also important in reducing the overall ICER, although even at the upper limits, the ICER still fell well within accepted willingness to pay bounds. Conclusions The addition of genetic testing to the management of HCM families is cost-effective in comparison with the conventional approach of regular clinical screening. This has important implications for the evaluation of families with HCM, and suggests that all should have access to specialised cardiac genetic clinics that can offer genetic testing.

Guidelines for Genetic Testing of Inherited Cardiac Disorders

Purpose: The diagnosis of hypertrophic cardiomyopathy, an autosomal dominant chronic heart disease, can have significant implications, including increased risk of sudden death, exercise limitations, and risk of transmission to offspring. This study sought to describe the psychosocial factors associated with attending a specialty cardiac genetic clinic, and to determine whether these may be predictors of comorbid anxiety and depression in this population.Methods: Questionnaires were sent to 184 individuals attending the Royal Prince Alfred Hospital Hypertrophic Cardiomyopathy Clinic. Questionnaires were anonymous and comprised demographics, the Hospital Anxiety and Depression Scale, Patient Experience Scales, and Patient Satisfaction Scales.Results: Completed questionnaires were returned by 109 participants (59.2% response rate), of which 76.9% had a diagnosis of hypertrophic cardiomyopathy, while 23.1% were at-risk relatives attending for clinical screening. Patient satisfaction scores were generally high to very high across all groups, though only 24% of HCM patients showed good adjustment to hypertrophic cardiomyopathy and 10% had low worry about hypertrophic cardiomyopathy scores. Within the disease group, logistic regression analysis adjusting for age, gender, and education revealed adjustment to hypertrophic cardiomyopathy and worry about hypertrophic cardiomyopathy scores to be significantly associated with anxiety, while adjustment scores and location of patient follow-up (i.e., Hypertrophic Cardiomyopathy clinic or another cardiologist) to be significantly associated with depression scores.Conclusion: HCM patients who attend specialized cardiac genetic clinics are better adjusted and worry less, than those who do not attend. An integrated approach, including a genetic counselor, is important in the management of HCM families.