Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes

Ingles, Jodie; Goldstein, Jennifer; Thaxton, Courtney; Caleshu, Colleen; Corty, Edward W.; Crowley, Stephanie B.; Dougherty, Kristen; Harrison, Steven M.; McGlaughon, Jennifer; Milko, Laura V.; Morales, Ana; Seifert, Bryce A.; Strande, Natasha T.; Thomson, Kate; Tintelen, J. Peter van; Wallace, Kathleen; Walsh, Roddy; Wells, Quinn S.; Whiffin, Nicola; Witkowski, Leora; Semsarian, Christopher; Ware, James S.; Hershberger, Ray E.; Funke, Birgit

doi:10.1161/circgen.119.002460

Cited by 298 publications

(255 citation statements)

References 35 publications

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“…This approach uses a semi-quantitative scoring system that has been validated across several Mendelian diseases, and as a result, the evidence supporting the association between a specific gene and a disease is classified as definitive, strong, moderate, limited, absent or conflicting. This approach has been used by the ClinGen Cardiovascular Disease Working Group 57 for gene curation for hypertrophic cardiomyopathy 58 , and curation of genes associated with arrhythmogenic right ventricular cardiomyopathy and DCM is now underway.…”

Section: Gene Curationmentioning

confidence: 99%

Dilated cardiomyopathy

Schultheiss

Fairweather

Caforio

et al. 2019

Nat Rev Dis Primers

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www.nature.com/nrdp P r i m e r 0123456789(); P r i m e r 0123456789(); 4 | Article citation ID: (2019) 5:32 www.nature.com/nrdp P r i m e r 0123456789(); P r i m e r 0123456789(); P r i m e r 0123456789(); 7 NATURE REVIEwS | DIsEAsE PRIMERs | Article citation ID: (2019) 5:32 P r i m e r 0123456789(); P r i m e r 0123456789(); 9 NATURE REVIEwS | DIsEAsE PRIMERs | Article citation ID: (2019) 5:32 P r i m e r 0123456789(); P r i m e r 0123456789(); P r i m e r 0123456789(); (2019) 5:32 www.nature.com/nrdp P r i m e r 0123456789(); P r i m e r 0123456789();

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Section: Gene Curationmentioning

confidence: 99%

Dilated cardiomyopathy

Schultheiss

Fairweather

Caforio

et al. 2019

Nat Rev Dis Primers

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392

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“…In addition, a number of loci overlap with well-established cardiac genes (TNT, TNNT2), linked to sarcomeric function and cardiac morphogeneis, that are related to a spectrum of hyper-trabeculation phenotypes. [55][56][57] As well as multiple loci associated with cardiovascular traits, this study has also robustly implicated a number of loci which have yet to be associated with known phenotypes -whether physiological or disease-related -pointing to previously unexplored pathways related to trabecular formation.…”

Section: Discussionmentioning

confidence: 67%

Genomic analysis reveals a functional role for myocardial trabeculae in adults

Meyer

Dawes

Serrani

et al. 2019

Preprint

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Since being first described by Leonardo da Vinci in 1513 it has remained an enigma why the endocardial surfaces of the adult heart retain a complex network of muscular trabeculae -with their persistence thought to be a vestige of embryonic development. For causative physiological inference we harness population genomics, image-based intermediate phenotyping and in silico modelling to determine the effect of this complex cardiovascular trait on function. Using deep learning-based image analysis we identified genetic associations with trabecular complexity in 18,097 UK Biobank participants which were replicated in an independently measured cohort of 1,129 healthy adults. Genes in these associated regions are enriched for expression in the fetal heart or vasculature and implicate loci associated with haemodynamic phenotypes and developmental pathways. A causal relationship between increasing trabecular complexity and both ventricular performance and electrical activity are supported by complementary biomechanical simulations and Mendelian randomisation studies. These findings show that myocardial trabeculae are a previously-unrecognised determinant of cardiovascular physiology in adult humans.1 complexity and use Mendelian randomisation to provide a causal inference framework. We then use a finite-element model of the heart with physiologically-realistic loading conditions to determine the haemodynamic effect of varying trabecular complexity whilst keeping other parameters constant. This multi-disciplinary approach to physiological inference suggests a causal relationship between trabecular complexity and ventricular efficiency implicating loci associated with haemodynamic phenotypes and developmental pathways. Data overviewUK Biobank is a prospective cohort study collecting deep genetic and phenotypic data on approximately 500,000 individuals from across the United Kingdom, aged between 40 and 69 at recruitment, providing opportunities for the discovery of the genetic basis of complex traits. 16 Of these, 100,000 participants are being recalled for enhanced phenotyping which includes cardiac magnetic resonance (CMR) imaging. 17 Non-invasive data on a range of haemodynamic parameters are also collected at the time of imaging. Following automated image-quality control 18 and exclusion of subjects with missing covariates, 18,097 unrelated participants that formed a well mixed population of European ethnicity (Figure 7 in the Supplement) were used for discovery (Table 1 and Figure 1D). An independent cohort comprising 1,129 healthy adults recruited in London, UK with both genotypes and CMR imaging was used for validation. 19 Fractal dimension analysis of left ventricular trabeculationWe used a fully convolutional network for automated left ventricular segmentation and volumetry. 20 The complexity of myocardial trabeculae ( Figure 1A) was quantified by the scale-invariant ratio of fractal dimension (FD, Figure 1C). 21 To account for variations in cardiac size and for consistent anatomical comparisons within and between ...

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“…Findings from a large multicentre cohort demonstrated that the presence of a sarcomere mutation is associated with earlier disease onset, and serves as a strong predictor of adverse clinical outcomes, including ventricular arrhythmia and HF [54]-underscoring the importance of genotypes in assessing the prognosis of patients and directing clinical management in HCM. Although genetic testing provides a definitive molecular diagnosis and could potentially reduce medical costs from serial clinical evaluations, there are some challenges in current genetic testing for HCM [55]. A number of genes commonly included in HCM gene panels may currently have insufficient evidence of disease association, thus well-validated gene panels are fundamentally critical to avoid genetic misdiagnosis.…”

Section: Genetic Testingmentioning

confidence: 99%

Hypertrophic Cardiomyopathy: An Overview of Genetics and Management

et al. 2019

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Hypertrophic cardiomyopathy (HCM) is a genetically heterogeneous cardiac muscle disorder with a diverse natural history, characterized by unexplained left ventricular hypertrophy (LVH), with histopathological hallmarks including myocyte enlargement, myocyte disarray and myocardial fibrosis. Although these features can cause significant cardiac symptoms, many young individuals with HCM are asymptomatic or mildly symptomatic. Sudden cardiac death (SCD) may occur as the initial clinical manifestation. Over the past few decades, HCM has been considered a disease of sarcomere, and typically as an autosomal dominant disease with variable expressivity and incomplete penetrance. Important insights into the genetic landscape of HCM have enhanced our understanding of the molecular pathogenesis, empowered gene-based diagnostic testing to identify at-risk individuals, and offered potential targets for the development of therapeutic agents. This article reviews the current knowledge on the clinical genetics and management of HCM.

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Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes

Abstract: Supplemental Digital Content is available in the text.

Cited by 298 publications

References 35 publications

Dilated cardiomyopathy

Dilated cardiomyopathy

Genomic analysis reveals a functional role for myocardial trabeculae in adults

Hypertrophic Cardiomyopathy: An Overview of Genetics and Management

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