부산대학교 도서관

Introduction: Single-gene mutations are a known cause of dilated cardiomyopathy (DCM) in children, but the strength of association between gene-mutations and disease severity is uncertain. Combining exome-sequencing with serial assessment of disease severity may improve our understanding of this genotype-phenotype relationship. Hypothesis: Exome sequencing will identify disease - associated mutations for isolated DCM in children, and mutation carriers will have a more severe phenotype, and a worse clinical outcome than those without identifiable mutations. Methods: A longitudinal cohort study, across 14 pediatric referral centers in North America. Patients aged 0-18 with an echocardiographic diagnosis of DCM provided DNA for exome sequencing. Heart Failure (HF) symptoms, echocardiographic LV dilation and LV ejection fraction (EF) were assessed at presentation, and prospectively for up to 2 years. Endpoints of death or cardiac transplantation were recorded. Results: 279 DCM probands (53% female), median age 1.6 (0.4-10.4) years, were identified between 2012-2016. Median follow up time was 1.1 (0.2-4.0) years. Pathogenic mutations were identified in 19 of 37 genes evaluated, with TTN (17%), TNNT2 (11%), MYH7 (9%), RBM20 (9%) and LMNA (8%) mutations being the most common. While 17.9% of the cohort yielded an identifiable genetic cause, children >12yrs of age had the highest genetic yield, at 33% (p<0.05). Over 39% of patients had no known mutation identified, while 43% had only variants of unknown significance. Symptoms of HF occurred in 63.1% of patients at or within 12 months of presentation, but neither HF symptoms, LVEF nor LV dilation were associated with gene-positive status. Four (1.4 %) patients died and 144 (51.6%) received a heart transplant. Whereas LV dilation, reduced LVEF and HF symptoms were all associated with transplant-free survival (p<0.01), gene-positive status conferred no risk for death or transplant (p=0.4). Conclusions: Pediatric DCM patients with pathogenic mutations in known cardiomyopathy genes do not have more severe disease or increased risk of adverse outcome by 12 months after diagnosis. Further molecular characterization of this disease is required to identify patients at highest risk for deterioration and death. [ABSTRACT FROM AUTHOR]