New Perspectives on the Prevalence of Hypertrophic Cardiomyopathy Semsarian, Christopher, MBBS, PhD, MPH; Ingles, Jodie, GradDipGenCouns, PhD, MPH; Maron, Martin S., MD ...
Journal of the American College of Cardiology,
03/2015, Volume:
65, Issue:
12
Journal Article
Peer reviewed
Open access
Abstract Hypertrophic cardiomyopathy (HCM) is an important genetic heart muscle disease for which prevalence in the general population has not been completely resolved. For the past 20 years, most ...data have supported the occurrence of HCM at about 1 in 500. However, the authors have interrogated a number of relevant advances in cardiovascular medicine, including widespread fee-for-service genetic testing, population genetic studies, and contemporary diagnostic imaging, as well as a greater index of suspicion and recognition for both the clinically expressed disease and the gene-positive–phenotype-negative subset (at risk for developing the disease). Accounting for the potential impact of these initiatives on disease occurrence, the authors have revisited the prevalence of HCM in the general population. They suggest that HCM is more common than previously estimated, which may enhance its recognition in the practicing cardiovascular community, allowing more timely diagnosis and the implementation of appropriate treatment options for many patients.
Summary Dilated cardiomyopathy is defined by the presence of left ventricular dilatation and contractile dysfunction. Genetic mutations involving genes that encode cytoskeletal, sarcomere, and ...nuclear envelope proteins, among others, account for up to 35% of cases. Acquired causes include myocarditis and exposure to alcohol, drugs and toxins, and metabolic and endocrine disturbances. The most common presenting symptoms relate to congestive heart failure, but can also include circulatory collapse, arrhythmias, and thromboembolic events. Secondary neurohormonal changes contribute to reverse remodelling and ongoing myocyte damage. The prognosis is worst for individuals with the lowest ejection fractions or severe diastolic dysfunction. Treatment of chronic heart failure comprises medications that improve survival and reduce hospital admission—namely, angiotensin converting enzyme inhibitors and β blockers. Other interventions include enrolment in a multidisciplinary heart failure service, and device therapy for arrhythmia management and sudden death prevention. Patients who are refractory to medical therapy might benefit from mechanical circulatory support and heart transplantation. Treatment of preclinical disease and the potential role of stem-cell therapy are being investigated.
Sudden cardiac death: an update Isbister, Julia; Semsarian, Christopher
Internal medicine journal,
07/2019, Volume:
49, Issue:
7
Journal Article
Peer reviewed
Open access
Sudden cardiac death (SCD) is a devastating and all too common result of both acquired and genetic heart diseases. The profound sadness endured by families is compounded by the risk many of these ...deaths confer upon surviving relatives. For those with known cardiac disease, disease-specific therapy and risk stratification are key to reducing sudden death. For families of a SCD victim, uncovering a definitive cause of death can help relieve the agonising uncertainty and is a vital first step in screening surviving relatives and instituting therapy to reduce SCD risk. Increasing knowledge about the molecular mechanisms and genetic drivers of malignant arrhythmias in the diverse clinical entities that can cause SCD is vital if we are to optimise risk stratification and personalise patient care. Advances in diagnostic tools, disease-specific therapy and defibrillator technology are improving outcomes for patients and their families but there is still much progress to be made.
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.
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.
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.
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.).
Preimplantation genetic diagnosis (PGD) ensures a disease-causing variant is not passed to the next generation, including for inherited heart diseases. PGD is known to cause significant emotional ...burden, but little is known about how parents experience PGD to select against inherited heart disease. We aim to understand how people with inherited heart disease, and their partners, experience and make decisions about PGD. Participants were recruited from a specialised inherited heart disease clinic. Qualitative semi-structured interviews were conducted with adult participants who had considered PGD. A semi-structured interview schedule explored overall experiences and reasons for undergoing PGD. Broad topics included experience of disease, reproductive history, psychosocial and financial considerations. Interviews were recorded, transcribed verbatim and thematically analysed using a framework method. Twenty participants were included (15 with inherited cardiomyopathy, 3 with inherited arrhythmia syndrome and 2 partners). In contemplating PGD, participants considered 3 main issues: past experience of disease e.g. sudden cardiac death, sport restrictions and clinical heterogeneity; intergenerational responsibilities; and practical considerations such as finances and maternal age. Among those who chose to undergo PGD (n = 7/18), past experience of a significant cardiac event, such as family history of sudden cardiac death, was important in the decision process. The decision to undergo PGD for inherited heart disease is complex and influenced by individual values and experience of disease. We highlight key areas where further discussion may assist in PGD decision processes.
Postmortem genetic testing (molecular autopsy) for the common long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) genes reveals a pathogenic mutation in up to 30% ...of sudden unexplained death (SUD). The role of additional cardiac arrhythmia and cardiomyopathy genes in SUD is largely unknown.
The purpose of this study was to investigate the feasibility and outcomes of performing exome sequencing-based molecular autopsies in a cohort of consecutive SUD cases.
Autopsies performed from 2005 to 2009 were reviewed for SUD. Postmortem blood was collected, DNA was isolated, and whole exome sequencing was performed. Rare sequence variants in cardiac arrhythmia and cardiomyopathy genes were sought.
There were 50 SUD cases aged 1 to 40 years (mean 21.7 ± 12 years) in the 5-year period, with a male predominance of 1.9:1. The most common event at death was "sleep" (48%). Exome sequencing in a subgroup of 28 SUD cases revealed 3 rare variations in 3 SUD cases (10%; 2 from exome sequencing and 1 from previous Sanger sequencing) in the common LQTS genes: a splice site variation and a single base deletion in KCNH2, and a missense variation in KCNQ1. Six rare variations in an additional 25 common genes of cardiac arrhythmias and cardiomyopathies were identified in 6 SUD (21%).
Exome sequencing-based molecular autopsy is a useful strategy as part of the investigation of SUD cases. The findings further expand the role of the molecular autopsy in both identifying a cause of death in the decedent and evaluating at-risk family relatives.
Each of the cardiomyopathies, classically categorized as hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy, has a signature genetic theme. ...Hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning >10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted.
An international panel with clinical and scientific expertise in DCM genetics evaluated evidence supporting monogenic relationships of genes with idiopathic DCM. The panel used the Clinical Genome Resource semiquantitative gene-disease clinical validity classification framework with modifications for DCM genetics to classify genes into categories on the basis of the strength of currently available evidence. Representation of DCM genes on clinically available genetic testing panels was evaluated.
Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from 8 gene ontologies were classified as having definitive (
,
,
,
,
,
,
,
,
,
,
) or strong (
) evidence. Seven genes (14%;
,
,
,
,
,
,
) including 2 additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of these 19 genes, 6 were similarly classified for hypertrophic cardiomyopathy and 3 for arrhythmogenic right ventricular cardiomyopathy. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of the 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence.
In the curation of 51 genes, 19 had high evidence (12 definitive/strong, 7 moderate). It is notable that these 19 genes explain only a minority of cases, leaving the remainder of DCM genetic architecture incompletely addressed. Clinical genetic testing panels include most high-evidence genes; however, genes lacking robust evidence are also commonly included. We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes.
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.
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;
=0.004) and family history of sudden cardiac death (odds ratio, 3.5; 95% confidence interval, 1.3-9.9;
=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
=0.008).
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.
PurposeIntegrating genomic sequencing in clinical care requires standardization of variant interpretation practices. The Clinical Genome Resource has established expert panels to adapt the American ...College of Medical Genetics and Genomics/Association for Molecular Pathology classification framework for specific genes and diseases. The Cardiomyopathy Expert Panel selected MYH7, a key contributor to inherited cardiomyopathies, as a pilot gene to develop a broadly applicable approach.MethodsExpert revisions were tested with 60 variants using a structured double review by pairs of clinical and diagnostic laboratory experts. Final consensus rules were established via iterative discussions.ResultsAdjustments represented disease-/gene-informed specifications (12) or strength adjustments of existing rules (5). Nine rules were deemed not applicable. Key specifications included quantitative frameworks for minor allele frequency thresholds, the use of segregation data, and a semiquantitative approach to counting multiple independent variant occurrences where fully controlled case-control studies are lacking. Initial inter-expert classification concordance was 93%. Internal data from participating diagnostic laboratories changed the classification of 20% of the variants (n = 12), highlighting the critical importance of data sharing.ConclusionThese adapted rules provide increased specificity for use in MYH7-associated disorders in combination with expert review and clinical judgment and serve as a stepping stone for genes and disorders with similar genetic and clinical characteristics.
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