Navigating Genetic and Phenotypic Uncertainty in Left Ventricular Noncompaction
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Once called spongiform cardiomyopathy for its distinct lace-like morphology, left ventricular noncompaction (LVNC) describes a ventricular wall with a prominent noncompacted layer; the excessive trabeculations and deep intertrabecular recesses are separated by thin compacted myocardium.1,2 The diagnosis of LVNC is made primarily by imaging studies to index the thickness of the trabeculated layer to that of the compacted layer. With the advent of cardiac magnetic resonance allowing for high-resolution imaging of the myocardium, hypertrabeculation in the LV has become increasingly recognized in clinical practice. Significant individual variability exists in the extent of trabeculation, however, making its diagnosis extremely challenging. In addition, LVNC frequently occurs in association with other cardiomyopathies,2 congenital heart defects,3 neuromuscular disorders, and genetic syndromes. As a result, there has been ongoing debate as to whether LVNC is an independent disease entity, a clinical phenotype shared among various cardiomyopathies, or a mere bystander.2 Contributing to this debate is the little data on the genetic architecture underlying LVNC. Although the next-generation sequencing has facilitated comprehensive and cost-effective approaches to identify potentially causative genetic variation in LVNC, the ability to identify such variation has outpaced our capacity to clearly interpret its clinical significance. Thus, in this era of rapidly evolving clinical imaging and sequencing technologies, there is a pressing need to integrate the accumulating imaging and genetic data in a large cohort, to better understand the entity that is LVNC.
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In this issue of Circulation: Cardiovascular Genetics, Jefferies et al4 expand on the known genetic causes of LVNC and provide insights into the genetic landscape of LVNC and LV hypertrabeculation (LVHT) in the largest prospective cohort to date. By leveraging whole exome sequencing and cardiac magnetic resonance, the research team has assembled a deeply genotyped and phenotyped study …