Purpose To characterize the genetic architecture of left ventricular noncompaction (LVNC) and investigate the extent to which it may represent a distinct pathology or a secondary phenotype associated with other cardiac diseases. Methods We performed rare variant association analysis with 840 LVNC cases and 125,748 gnomAD population controls, and compared results to similar analyses on dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Results We observed substantial genetic overlap indicating that LVNC often represents a phenotypic variation of DCM or HCM. In contrast, truncating variants in MYH7, ACTN2, and PRDM16 were uniquely associated with LVNC and may reflect a distinct LVNC etiology. In particular, MYH7 truncating variants (MYH7tv), generally considered nonpathogenic for cardiomyopathies, were 20-fold enriched in LVNC cases over controls. MYH7tv heterozygotes identified in the UK Biobank and healthy volunteer cohorts also displayed significantly greater noncompaction compared with matched controls. RYR2 exon deletions and HCN4 transmembrane variants were also enriched in LVNC, supporting prior reports of association with arrhythmogenic LVNC phenotypes. Conclusion LVNC is characterized by substantial genetic overlap with DCM/HCM but is also associated with distinct noncompaction and arrhythmia etiologies. These results will enable enhanced application of LVNC genetic testing and help to distinguish pathological from physiological noncompaction.

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Background-Although histopathologic studies suggest persistent myocardial abnormalities after Kawasaki disease (KD), the long-term effects on cardiac function remain to be revealed. We investigated biventricular volumes, function, and the presence of myocardial fibrosis by cardiac magnetic resonance imaging during long-term follow-up of KD. Methods and Results-Sixty patients with a history of KD (mean age, 16.9 years; 67% men; median interval after KD onset, 11.6 years) and 20 healthy control subjects (mean age, 17.9 years; 55% men) 12 to 24 years of age underwent cardiac magnetic resonance imaging. Biventricular end-diastolic volume, end-systolic volume, stroke volume, and ejection fraction were determined. Volumetric measurements were indexed for body surface area. Late contrast enhancement was used to detect areas of myocardial fibrosis. Biventricular volumes and function did not differ significantly between patients and control subjects. There were also no significant differences between patients with and without a history of left ventricular dysfunction resulting from KD-associated myocarditis or between patients with and without coronary artery aneurysms.Only those with prior ischemic heart disease had a significantly lower left ventricular ejection fraction compared with unaffected KD cases (left ventricular ejection fraction, 51% versus 57%; P=0.012). Late contrast enhancement was observed in only 2 patients with severe coronary artery aneurysms and was typical for myocardial infarction. Conclusions-In this cardiac magnetic resonance imaging study evaluating the cardiac function of patients with KD at longterm follow-up, we did not observe a difference in cardiac function between KD patients and control subjects, except for a subgroup of patients with ischemic heart disease as a result of severe coronary artery pathology.