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, Letnik:
65, Številka:
12
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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.
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.
In 490 cases of sudden cardiac death identified over a 3-year period (annual incidence of 1.3 per 100,000), causes were found in 60% through conventional autopsy, and a clinically relevant cardiac ...gene mutation was found in 27% of the remaining cases in which genetic testing was performed.
Sudden cardiac death among children and young adults is a devastating event for the family and wider community. Coronary artery disease is the predominant cause of sudden cardiac death in older persons,
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whereas among persons 1 to 35 years of age, sudden cardiac death is more often caused by structural heart disease, including hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, myocarditis, and primary arrhythmogenic disorders (such as the congenital long-QT syndrome, the Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia).
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Many of these cardiac causes of sudden cardiac death among children and young adults have an underlying genetic basis. . . .
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.
Molecular autopsy in victims of inherited arrhythmias Semsarian, Christopher, MBBS, PhD, MPH; Ingles, Jodie, BBiomedSci, GradDipGenCouns, PhD, MPH
Journal of arrhythmia,
October 2016, Letnik:
32, Številka:
5
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Abstract Sudden cardiac death (SCD) is a rare but devastating complication 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, inherited cardiac disorders comprise a substantial proportion of SCD cases aged less than 40 years. Inherited cardiac disorders include primary inherited arrhythmogenic disorders such as familial long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and inherited cardiomyopathies, most commonly hypertrophic cardiomyopathy (HCM). In up to 40% of young SCD victims (defined as 1–40 years old, excluding sudden unexplained death in infancy from 0 to 1 years, referred to as SIDS), no cause of death is identified at postmortem so-called “autopsy negative” or “sudden arrhythmic death syndrome” (SADS). Management of families following a SCD includes the identification of the cause of death, based either on premorbid clinical details or the pathological findings at the postmortem. When no cause of death is identified, genetic testing of DNA extracted from postmortem tissue (the molecular autopsy) may identify a cause of death in up to 30% of SADS cases. Targeted clinical testing in a specialized multidisciplinary clinic in surviving family members combined with the results from genetic testing, provide the optimal setting for the identification of relatives who may be at risk of having the same inherited heart disease and are therefore also predisposed to an increased risk of SCD.
The evolution of genetic testing in the past few years has been astounding. In a matter of only a few years, we now have comprehensive gene tests comprising vast panels of "cardiac" genes, whole ...exome sequencing (the entire coding region) and even whole genome sequencing (the entire genome). Making the call as to whether a DNA variant is causative or benign is difficult and the focus of intense research efforts. In most cases, the final answer will not be a simple yes/no outcome but rather a graded continuum of pathogenicity. This allows classification of variants in a more probabilistic way. How we convey this to a patient is the challenge, and certainly shines a spotlight on the important skills of the cardiac genetic counselor. This is an exciting step forward, but the overwhelming complexity of the information generated from these tests means our current practices of conveying genetic information to the family must be carefully considered. Despite the challenges, a genetic diagnosis in a family has great benefit both in reassuring unaffected family members and removing the need for lifetime clinical surveillance. The multidisciplinary specialized clinic model, incorporating genetic counselors, cardiologists and geneticists, provides the ideal framework for ensuring the best possible care for genetic heart disease families.
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