Genetic Prognosis Explored for Pediatric Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) in children is a disease in which, due to abnormalities in the muscle, one or both ventricles in a child’s heart become enlarged and contract poorly. A variety of processes that result in myocardial damage can lead to dilated cardiomyopathy and coronary artery disease.

Genetic DCM was initially thought to be primarily caused by variants in genes encoding cytoskeletal and sarcomeric proteins. However, recent advances in sequencing and array-based technologies have increased our understanding of the genetic basis of DCM. In addition to genes encoding sarcomeric and cytoskeletal proteins, genes coding for transcription factors, ion channels, the nuclear membrane, and mitochondrial proteins are now also known to be involved in isolated DCM.

Image: Histopathology of a biopsy from a patient with Dilated Cardiomyopathy. The myocytes have lost myofibrils and empty spaces have appeared within the cytoplasm (Photo courtesy of Professor Michael John Davies, MD, FRCPath)

Pediatric Cardiologists at the Erasmus University Medical Center (Rotterdam, The Netherlands) and their colleagues performed a multicenter observational study in children diagnosed with dilated cardiomyopathy, from 2010 to 2017. The team originally included 144 children. Initial diagnostic categories were idiopathic dilated cardiomyopathy in 67 children (47%), myocarditis in 23 (16%), neuromuscular in seven (5%), familial in 18 (13%), inborn error of metabolism in four (3%), malformation syndrome in two (1%), and “other” in 23 (16%).

The genetic data collected were obtained retrospectively and reflect the genetic evaluation that was common practice at that time: single gene testing (e.g., Sanger sequencing of MYH7), targeted next-generation sequencing (NGS) of a gene panel (range 28-70 genes), exome sequencing (ES) with analysis of genes related to cardiomyopathy or open exome analysis. Additional genetic testing (e.g., SNP-array) was performed in a subset of patients in whom a malformation syndrome was suspected. The team defined two groups: patients with a likely pathogenic (LP) or pathogenic (P) variant (class 4 or 5) and patients without a pathogenic variant, including patients with one or more variants of unknown significance (VUS, class 3).

The investigators reported that they found a likely pathogenic or pathogenic variant in 38 children (36%), most often in MYH7 (n = 8). In one patient initially diagnosed with myocarditis, a pathogenic LMNA variant was found. During the study, 39 patients (27%) reached study endpoint (SE: all-cause death or heart transplantation). Patients with a likely pathogenic or pathogenic variant were more likely to reach SE compared with those without (hazard ratio 2.8; 95% CI 1.3–5.8), while transplant-free survival was significantly lower. Clinical characteristics at diagnosis did not differ between the two groups

The authors concluded that genetic testing is a valuable tool for predicting prognosis in children with dilated cardiomyopathy, with carriers of a likely pathogenic or pathogenic variant having a worse prognosis overall. Genetic testing should be incorporated in clinical work-up of all children with dilated cardiomyopathy regardless of presumed disease pathogenesis. The study was published on September 30, 2022 in the journal Circulation: Genomic and Precision Medicine.

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Erasmus University Medical Center