Genetic testing for potentially lethal, highly treatable inherited cardiomyopathies/channelopathies in clinical practice.
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ABSTRACT:
SUBMITTER: Tester DJ
PROVIDER: S-EPMC3073829 | biostudies-literature | 2011 Mar
REPOSITORIES: biostudies-literature
Publications
Genetic testing for potentially lethal, highly treatable inherited cardiomyopathies/channelopathies in clinical practice.
Tester David J DJ Ackerman Michael J MJ
Circulation 20110301 9
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Project description:Pediatric inherited cardiomyopathies (CMPs) and channelopathies (CNPs) remain important causes of death in this population, therefore, there is a need for prompt diagnosis and tailored treatment. Conventional evaluation fails to establish the diagnosis of pediatric CMPs and CNPs in a significant proportion, prompting further, more complex testing to make a diagnosis that could influence the implementation of lifesaving strategies. Genetic testing in CMPs and CNPs may help unveil the underlying cause, but needs to be carried out with caution given the lack of uniform recommendations in guidelines about the precise time to start the genetic evaluation or the type of targeted testing or whole-genome sequencing. A very diverse etiology and the scarce number of randomized studies of pediatric CMPs and CNPs make genetic testing of these maladies far more particular than their adult counterpart. The genetic diagnosis is even more puzzling if the psychological impact point of view is taken into account. This review aims to put together different perspectives, state-of-the art recommendations-synthetizing the major indications from European and American guidelines-and psychosocial outlooks to construct a comprehensive genetic assessment of pediatric CMPs and CNPs.
| S-EPMC7408669 | biostudies-literature
Project description:Inherited cardiomyopathies and arrhythmias (ICAs) are a prevalent and clinically heterogeneous group of genetic disorders that are associated with increased risk of sudden cardiac death and heart failure. Making a genetic diagnosis can inform the management of patients and their at-risk relatives and, as such, molecular genetic testing is now considered an integral component of the clinical care pathway. However, ICAs are characterised by high genetic and allelic heterogeneity, incomplete / age-related penetrance, and variable expressivity. Therefore, despite our improved understanding of the genetic basis of these conditions, and significant technological advances over the past two decades, identifying and recognising the causative genotype remains challenging. As clinical genetic testing for ICAs becomes more widely available, it is increasingly important for clinical laboratories to consolidate existing knowledge and experience to inform and improve future practice. These recommendations have been compiled to help clinical laboratories navigate the challenges of ICAs and thereby facilitate best practice and consistency in genetic test provision for this group of disorders. General recommendations on internal and external quality control, referral, analysis, result interpretation, and reporting are described. Also included are appendices that provide specific information pertinent to genetic testing for hypertrophic, dilated, and arrhythmogenic right ventricular cardiomyopathies, long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia.
| S-EPMC10474043 | biostudies-literature
Project description:Recent advances in next-genetic sequencing technology have facilitated an expansion in the use of exome and genome sequencing in the research and clinical settings. While this has aided in the genetic diagnosis of individuals with atypical clinical presentations, there has been a marked increase in the number of incidentally identified variants of uncertain diagnostic significance in genes identified as clinically actionable by the American College of Medical Genetics guidelines. Approximately 20 of these genes are associated with cardiac diseases, which carry a significant risk of sudden cardiac death. While identification of at-risk individuals is paramount, increased discovery of incidental variants of uncertain diagnostic significance has placed a burden on the clinician tasked with determining the diagnostic significance of these findings. Herein, we describe the scope of this emerging problem using cardiovascular genetics to illustrate the challenges associated with variants of uncertain diagnostic significance interpretation. We review the evidence for diagnostic weight of these variants, discuss the role of clinical genetics providers in patient care, and put forward general recommendations about the interpretation of incidentally identified variants found with clinical genetic testing.
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Project description:Ion channels are critical for neuronal excitability and provide important targets for anticonvulsant drugs. In the past few years, several monogenetic epilepsies have been linked to mutations in genes encoding either voltage-gated or ligand-gated channels. The recognition that certain epilepsy syndromes are "channelopathies" initiates a new era in understanding the molecular pathophysiology of seizure disorders. This review summarizes recent advances related to this exciting area of investigation.
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Project description:BackgroundDisorders related to dysfunction of coenzyme (CoQ10) metabolism, including AarF domain containing kinase 3 gene (ADCK3) mutations, have received attention due to the potential for response to CoQ10 supplementation.MethodsWe describe two new cases of neurological syndromes due to ADCK3 mutations that obtained striking benefit from CoQ10, and a third who did not. We also review 20 cases from the literature in which responses to CoQ10 were documented out of all 38 previously reported cases.ResultsDespite the remarkable responses in some cases with ataxia and movement disorders (myoclonus, dystonia, tremor), overall, we were not able to identify variables that predicted response to CoQ10 supplementation.ConclusionsBased on our experience and data from the literature, we recommend a minimum of 10 mg/kg/day of ubiquinone with titration up to 15 mg/kg/day, maintained at least for 6 months in order to obtain or exclude potential benefit from therapy.
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Project description:The inherited cardiomyopathies, hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and left ventricular non-compaction (LVNC), have been frequently associated with mutations in sarcomeric proteins. In recent years, advances in DNA sequencing technology has allowed the study of the giant proteins of the sarcomere, such as titin and nebulin. Obscurin has been somewhat neglected in these studies, largely because its functional role is far from clear, although there was an isolated report in 2007 of obscurin mutations associated with HCM. Recently, whole exome sequencing methodology (WES) has been used to address mutations in OBSCN, the gene for obscurin, and OBSCN variants were found to be relatively common in inherited cardiomyopathies. In different studies, 5 OBSCN unique variants have been found in a group of 30 end-stage failing hearts, 6 OBSCN unique variants in 74 HCM cases and 3 OBSCN unique variants in 10 LVNC patients. As yet, the number of known potentially disease-causing OBSCN variants is quite small. The reason for this is that mutations in the OBSCN gene have not been recognised as potentially disease-causing until recently, and were not included in large-scale genetic surveys. OBSCN mutations may be causative of HCM, DCM and LVNC and other cardiomyopathies, or they may work in concert with other variants in the same or other genes to initiate the pathology. Currently, the function of obscurin is not well understood, but we anticipate that many more OBSCN variants linked to cardiomyopathy will be found when the large cohorts of patient sequences available are tested. It is to be hoped that the establishment of the importance of obscurin in pathology will stimulate a thorough investigation of obscurin function.
| S-EPMC5498328 | biostudies-other
Project description:Pediatric sudden cardiac death (SCD) is the sudden unexpected death of a child or adolescent due to a presumed cardiac etiology. Heritable causes of pediatric SCD are predominantly cardiomyopathies and cardiac ion channelopathies. This review illustrates recent advances in determining the genetic cause of established and emerging channelopathies and cardiomyopathies, and how broader genomic sequencing is uncovering complex interactions between genetic architecture and disease manifestation. We discuss innovative models and experimental platforms for resolving the variant of uncertain significance as both the variants and genes associated with disease continue to evolve. Finally, we highlight the growing problem of incidentally identified variants in cardiovascular disease-causing genes and review innovative methods to determining whether these variants may ultimately result in penetrant disease. Overall, we seek to illustrate both the promise and inherent challenges in bridging the traditional role for genetics in diagnosing cardiomyopathies and channelopathies to one of true risk-predictive precision medicine.
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Project description:The normal function of the heart relies on a series of complex metabolic processes orchestrating the proper generation and use of energy. In this context, mitochondria serve a crucial role as a platform for energy transduction by supplying ATP to the varying demand of cardiomyocytes, involving an intricate network of pathways regulating the metabolic flux of substrates. The failure of these processes results in structural and functional deficiencies of the cardiac muscle, including inherited cardiomyopathies. These genetic diseases are characterized by cardiac structural and functional anomalies in the absence of abnormal conditions that can explain the observed myocardial abnormality, and are frequently associated with heart failure. Since their original description, major advances have been achieved in the genetic and phenotype knowledge, highlighting the involvement of metabolic abnormalities in their pathogenesis. This review provides a brief overview of the role of mitochondria in the energy metabolism in the heart and focuses on metabolic abnormalities, mitochondrial dysfunction, and storage diseases associated with inherited cardiomyopathies.
| S-EPMC6947282 | biostudies-literature
Project description:Purpose of reviewCardiomyopathies due to genetic mutations are a heterogeneous group of disorders that comprise diseases of contractility, myocardial relaxation, and arrhythmias. Our goal here is to discuss a limited list of genetically inherited cardiomyopathies and the specific therapeutic strategies used to treat them.Recent findingsResearch into the molecular pathophysiology of the development of these cardiomyopathies is leading to the development of novel treatment approaches. Therapies targeting these specific mutations with gene therapy vectors are on the horizon, while other therapies which indirectly affect the physiologic derangements of the mutations are currently being studied and used clinically. Many of these therapies are older medications being given new roles such as mexiletine for Brugada syndrome and diflunisal for transthyretin amyloid cardiomyopathy. A newer targeted therapy, the inhibitor of myosin ATPase MYK-461, has been shown to suppress the development of ventricular hypertrophy, fibrosis, and myocyte disarray and is being studied as a potential therapy in patients with hypertrophic cardiomyopathy. While this field is too large to be completely contained in a single review, we present a large cross section of recent developments in the field of therapeutics for inherited cardiomyopathies. New therapies are on the horizon, and their development will likely result in improved outcomes for patients inflicted by these conditions.
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Project description:In sub-Saharan Africa (SSA), the burden of noncommunicable diseases (NCDs) is rising disproportionately in comparison to the rest of the world, affecting urban, semi-urban and rural dwellers alike. NCDs are predicted to surpass infections like human immunodeficiency virus, tuberculosis and malaria as the leading cause of mortality in SSA over the next decade. Heart failure (HF) is the dominant form of cardiovascular disease (CVD), and a leading cause of NCD in SSA. The main causes of HF in SSA are hypertension, cardiomyopathies, rheumatic heart disease, pericardial disease, and to a lesser extent, coronary heart disease. Of these, the cardiomyopathies deserve greater attention because of the relatively poor understanding of mechanisms of disease, poor outcomes and the disproportionate impact they have on young, economically active individuals. Morphofunctionally, cardiomyopathies are classified as dilated, hypertrophic, restrictive and arrhythmogenic; regardless of classification, at least half of these are inherited forms of CVD. In this review, we summarise all studies that have investigated the incidence of cardiomyopathy across Africa, with a focus on the inherited cardiomyopathies. We also review data on the molecular genetic underpinnings of cardiomyopathy in Africa, where there is a striking lack of studies reporting on the genetics of cardiomyopathy. We highlight the impact that genetic testing, through candidate gene screening, association studies and next generation sequencing technologies such as whole exome sequencing and targeted resequencing has had on the understanding of cardiomyopathy in Africa. Finally, we emphasise the need for future studies to fill large gaps in our knowledge in relation to the genetics of inherited cardiomyopathies in Africa.
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