Navigating Genetic and Phenotypic Uncertainty in Left Ventricular Noncompaction

Rhee, June‐Wha; Grove, Megan E.; Ashley, Euan A.

doi:10.1161/circgenetics.117.001857

Cited by 7 publications

(6 citation statements)

References 31 publications

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“…Disrupted mitochondrial function and metabolic abnormalities also have a causal role. 353,354,[505][506][507][508] Treatment focuses on improving cardiac efficiency and reducing mechanical stress in those patients with systolic dysfunction. Arrhythmia therapy and ICD implantation to prevent sudden death are the mainstays of treatment when deemed necessary and appropriate.…”

Section: Diagnosis Of Lvnc Genetic Evaluation Of Lvncmentioning

confidence: 99%

“…In addition, disrupted mitochondrial function and metabolic abnormalities have a causal role. 353,354,[505][506][507][508] In a study of 194 relatives of 50 unrelated LVNC probands, 505 64% showed familial cardiomyopathy that also included HCM and DCM. Due to the substantial overlap of LVNC with other forms of cardiomyopathy, genetic testing panels should encompass genes in which variants are associated with these other forms of cardiomyopathy.…”

Section: Treatmentmentioning

confidence: 99%

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2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy

et al. 2019

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This international consensus statement is intended to help cardiologists and other health care professionals involved in the care of adult and pediatric patients with arrhythmogenic cardiomyopathy (ACM), which encompasses a broad range of disorders, by providing recommendations for evaluation and management and supporting shared decision making between health care providers and patients in a document format that is also useful at the point of care.This consensus statement was written by experts in the field chosen by the Heart Rhythm Society (HRS) and collaborating organizations.

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Section: Diagnosis Of Lvnc Genetic Evaluation Of Lvncmentioning

confidence: 99%

Section: Treatmentmentioning

confidence: 99%

2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy

et al. 2019

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“…Although a diagnosis of LVNC is traditionally made with echocardiography or cardiac MRI, 20% to 30% of LVNC cases are estimated to have an underlying pathogenic variant and genetic testing is increasingly playing an important role in the diagnosis and management of this disease. 11,12 The decreasing cost and increasing availability of human genetic testing has resulted in a rapid increase in the number of genes that have been reported to be implicated in the development of LVNC. In the clinical setting, the increasing number of LVNC-associated genes not only creates interpretative challenges for the physician, but also can lead to burdensome medical attention and unnecessary anxiety for the patient and their family.…”

Section: Discussionmentioning

confidence: 99%

Genetic Basis of Left Ventricular Noncompaction

Rojanasopondist

Nesheiwat

Piombo

et al. 2022

Circ: Genomic and Precision Medicine

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Background: Left ventricular noncompaction (LVNC) is the third most common pediatric cardiomyopathy characterized by a thinned myocardium and prominent trabeculations. Next-generation genetic testing has led to a rapid increase in the number of genes reported to be associated with LVNC, but we still have little understanding of its pathogenesis. We sought to grade the strength of the gene-disease relationship for all genes reported to be associated with LVNC and identify molecular pathways that could be implicated. Methods: Following a systematic PubMed review, all genes identified with LVNC were graded using a validated, semi-quantitative system based on all published genetic and experimental evidence created by the Clinical Genome Resource (ClinGen). Genetic pathway analysis identified molecular processes and pathways associated with LVNC. Results: We identified 189 genes associated with LVNC: 11 (6%) were classified as definitive, 21 (11%) were classified as moderate, and 140 (74%) were classified as limited, but 17 (9%) were classified as no evidence. Of the 32 genes classified as definitive or moderate, the most common gene functions were sarcomere function (n=11; 34%), transcriptional/translational regulator (n=6; 19%), mitochondrial function (n=3; 9%), and cytoskeletal protein (n=3; 9%). Furthermore, 18 (56%) genes were implicated in noncardiac syndromic presentations. Lastly, 3 genetic pathways (cardiomyocyte differentiation via BMP receptors, factors promoting cardiogenesis in vertebrates, and Notch signaling) were found to be unique to LVNC and not overlap with pathways identified in dilated cardiomyopathy and hypertrophic cardiomyopathy. Conclusions: LVNC is a genetically heterogeneous cardiomyopathy. Distinct from dilated or hypertrophic cardiomyopathies, LVNC appears to arise from abnormal developmental processes.

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“…LVNC is a form of cardiomyopathy in which the left ventricle has prominent trabeculations and a non-compacted layer of the myocardium, which can lead to heart failure, thromboembolisation, arrhythmias and SCD 13. The prevalence of LVNC is unknown, partly due to differing diagnostic criteria and phenotypic overlap with sarcomeric cardiomyopathy and congenital heart defects 14. Similar to DCM, LVNC has a heterogeneous genetic basis, with variants in cytoskeletal, ion channel, sarcomeric and nuclear membrane genes (table 2).…”

Section: Clinical and Genetic Description Of Heritable Non-syndromic ...mentioning

confidence: 99%

Modern genomic techniques in the identification of genetic causes of cardiomyopathy

Spracklen

Keavney

Ntusi

et al. 2022

Heart

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Over the past three decades numerous disease-causing genes have been linked to the pathogenesis of heritable cardiomyopathies, but many causal genes are yet to be identified. Next-generation sequencing (NGS) platforms have revolutionised clinical testing capacity in familial cardiomyopathy. In this review, we summarise how NGS technologies have advanced our understanding of genetic non-syndromic cardiomyopathy over the last decade. First, 26 putative new disease-causing genes have been identified to date, mostly from whole-exome sequencing, and some of which (FLNC, MTO1, HCN4) have had a considerable clinical impact and are now included in routine diagnostic gene panels. Second, we consider challenges in variant interpretation and the importance of large-scale NGS population control cohorts for this purpose. Third, an emerging role of common variation in some forms of genetic cardiomyopathy is being elucidated through recent studies which have illustrated an additive effect of numerous polymorphic loci on cardiac parameters; this may explain phenotypic variability and low rates of genetic diagnosis from sequencing studies. Finally, we discuss the clinical utility of genetic testing in cardiomyopathy in Western settings, where NGS panel testing of core disease genes is currently recommended with possible implications for patient management. Given the findings of recent studies, whole-exome or whole-genome sequencing should be considered in patients of non-European ancestry with clearly familial disease, or severe paediatric disease, when no result is obtained on panel sequencing. The clinical utility of polygenic risk assessment needs to be investigated further in patients with unexplained dilated cardiomyopathy and hypertrophic cardiomyopathy in whom a pathogenic variant is not identified.

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Navigating Genetic and Phenotypic Uncertainty in Left Ventricular Noncompaction

Cited by 7 publications

References 31 publications

2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy

2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy

Genetic Basis of Left Ventricular Noncompaction

Modern genomic techniques in the identification of genetic causes of cardiomyopathy

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