Genetic Variation in Cardiomyopathy and Cardiovascular Disorders

McNally, Elizabeth M.; Puckelwartz, Megan J.

doi:10.1253/circj.cj-15-0536

Cited by 23 publications

(11 citation statements)

References 37 publications

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“…Even with next-generation sequencing and larger panels, the sensitivity for detecting the DCM-causing mutation may only reach 50%. More is not necessarily better as broad-based sequencing approaches (online supplementary table 2) may generate uncertainty by uncovering more novel variants of uncertain significance 24. Judging the relevance of such novel variations can be helped by screening families (see next section) so that with time, information on most of the mutations coupled with data from mechanism studies, will become available in databases linking to clinical phenotypes.…”

Section: Diagnosticsmentioning

confidence: 99%

Lamin and the heart

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Arbustini

Bonne

et al. 2017

Heart

118

116

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Lamins A and C are intermediate filament nuclear envelope proteins encoded by the gene. Mutations in cause autosomal dominant severe heart disease, accounting for 10% of dilated cardiomyopathy (DCM). Characterised by progressive conduction system disease, arrhythmia and systolic impairment, lamin A/C heart disease is more malignant than other common DCMs due to high event rates even when the left ventricular impairment is mild. It has several phenotypic mimics, but overall it is likely to be an under-recognised cause of DCM. In certain clinical scenarios, particularly familial DCM with early conduction disease, the pretest probability of finding an mutation may be quite high.Recognising lamin A/C heart disease is important because implantable cardioverter defibrillators need to be implanted early. Promising oral drug therapies are within reach thanks to research into the mitogen-activated protein kinase (MAPK) and affiliated pathways. Personalised heart failure therapy may soon become feasible for, alongside personalised risk stratification, as variant-related differences in phenotype severity and clinical course are being steadily elucidated.Genotyping and family screening are clinically important both to confirm and to exclude mutations, but it is the three-pronged integration of such genetic information with functional data from in vivo cardiomyocyte mechanics, and pathological data from microscopy of the nuclear envelope, that is properly reshaping our knowledge base, one variant at a time. This review explains the biology of lamin A/C heart disease (genetics, structure and function of lamins), clinical presentation (diagnostic pointers, electrocardiographic and imaging features), aspects of screening and management, including current uncertainties, and future directions.

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Section: Diagnosticsmentioning

confidence: 99%

Lamin and the heart

Captur

Arbustini

Bonne

et al. 2017

Heart

118

116

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“…The persistence of a thin compact myocardium with deep intertrabecular recesses is termed ventricular non-compaction in mice, and left ventricular non-compaction (LVNC) in humans. 3-6 LVNC is a relatively common and severe genetic cardiomyopathy, [7][8][9][10] in which approximately 50% of patients show biventricular involvement. 4,11, 12 Often, transgenic mice have been utilized to study LVNC.…”

mentioning

confidence: 99%

Micro-Computed Tomography for the Quantitative 3-Dimensional Assessment of the Compact Myocardium in the Mouse Embryo

Merchant

Kosaka

Yost

et al. 2016

Circ J

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Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp ently 2 dimensional (D), whereas the heart is a 3D structure, 3D morphology could represent an additional valid source of information for ventricular non-compaction in transgenic mice. Although it is possible to use computation techniques including image registration and distortion correction to reconstruct the 3D cardiac morphology from stacked 2D sections, 26 the processes are technically demanding, laborious and time-consuming. Moreover, the 3D reconstructions still rely on 2D sections, whose destructive nature precludes their use for in vivo or in situ assessment.Non-invasive, non-destructive 3D imaging of myocardial compaction in the embryonic mouse heart is faced with two technical challenges. First, an imaging modality with the appropriate combination of tissue penetration, contrast and spatial resolution needs to be identified. The spatial resolution of magnetic resonance imaging (MRI) and computed tomography (CT) has reached microscopic scales (1 s and 10 s of he mammalian embryonic cardiac ventricles are composed of an outer layer of compact myocardium and an inner layer of trabecular myocardium. 1,2 During development, compact myocardium increases in thickness while trabeculations almost completely disappear. The persistence of a thin compact myocardium with deep intertrabecular recesses is termed ventricular non-compaction in mice, and left ventricular non-compaction (LVNC) in humans. 3-6 LVNC is a relatively common and severe genetic cardiomyopathy, 7-10 in which approximately 50% of patients show biventricular involvement. 4,11,12 Often, transgenic mice have been utilized to study LVNC. 13,14 Detailed and accurate quantification of compaction in these mice is essential to define the phenotype.Morphological analyses of the compact myocardium have been traditionally performed through histological techniques involving image analysis of cardiac sections stained with hematoxylin and eosin (H&E). Background: Ventricular non-compaction is characterized by a thin layer of compact ventricular myocardium and it is an important abnormality in the mouse heart. It is reminiscent of left ventricular non-compaction, a fairly common human congenital cardiomyopathy. Non-compaction in transgenic mice has been classically evaluated by measuring the thickness of the compact myocardium through histological techniques involving image analysis of 2-dimensional (D) sections. Given the 3D nature of the heart, the aim of this study was to determine whether a technique for the non-destructive, 3D assessment of the mouse embryonic compact myocardium could be developed.

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“…Further, combination of gene expression analysis and clinical phenotypic assessments are necessary to uncover unknown modifier genes in HCM patients (Han et al, 2014). The development of online databases for HCM variants could aid physicians in the timing and implementation of electrical or surgical treatment options (McNally and Puckelwartz, 2015). As mentioned in the preceding sections, inclusion of ethnicity data in such databases has important genetic consequences and thus is clinically relevant.…”

Section: Current Efforts Toward Precision Medicine For Hcmmentioning

confidence: 99%

Recent Advances in the Molecular Genetics of Familial Hypertrophic Cardiomyopathy in South Asian Descendants

et al. 2016

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The South Asian population, numbered at 1.8 billion, is estimated to comprise around 20% of the global population and 1% of the American population, and has one of the highest rates of cardiovascular disease. While South Asians show increased classical risk factors for developing heart failure, the role of population-specific genetic risk factors has not yet been examined for this group. Hypertrophic cardiomyopathy (HCM) is one of the major cardiac genetic disorders among South Asians, leading to contractile dysfunction, heart failure, and sudden cardiac death. This disease displays autosomal dominant inheritance, and it is associated with a large number of variants in both sarcomeric and non-sarcomeric proteins. The South Asians, a population with large ethnic diversity, potentially carries region-specific polymorphisms. There is high variability in disease penetrance and phenotypic expression of variants associated with HCM. Thus, extensive studies are required to decipher pathogenicity and the physiological mechanisms of these variants, as well as the contribution of modifier genes and environmental factors to disease phenotypes. Conducting genotype-phenotype correlation studies will lead to improved understanding of HCM and, consequently, improved treatment options for this high-risk population. The objective of this review is to report the history of cardiovascular disease and HCM in South Asians, present previously published pathogenic variants, and introduce current efforts to study HCM using induced pluripotent stem cell-derived cardiomyocytes, next-generation sequencing, and gene editing technologies. The authors ultimately hope that this review will stimulate further research, drive novel discoveries, and contribute to the development of personalized medicine with the aim of expanding therapeutic strategies for HCM.

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Genetic Variation in Cardiomyopathy and Cardiovascular Disorders

Cited by 23 publications

References 37 publications

Lamin and the heart

Lamin and the heart

Micro-Computed Tomography for the Quantitative 3-Dimensional Assessment of the Compact Myocardium in the Mouse Embryo

Recent Advances in the Molecular Genetics of Familial Hypertrophic Cardiomyopathy in South Asian Descendants

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