Paediatric cardiomyopathies : an evolving landscape of genetic aetiology and diagnostic applications

Cardiomyopathies are a group of disorders that often affect the ability of the heart muscle to contract, generally leading to heart failure. Although not very frequent in children (one child in every 100,000 is diagnosed with cardiomyopathy), the outcomes are severe in 40% of affected children, and these young patients die or undergo cardiac transplantation within 5 years of diagnosis. In the majority of these cases, an aberration in the child’s DNA is the cause of the disease. Therefore, being able to identify the genes involved is very important. This knowledge may help to optimize therapy and is useful for reproductive decision-making and determining if any other members of the family are at risk for cardiomyopathy. Although genetic testing for cardiomyopathy has increasingly become part of mainstream clinical management, data on the yield in children remains limited. In this thesis, we report a genetic cause in 50% of children with dilated cardiomyopathy, a subtype of cardiomyopathy in which the heart becomes enlarged. We also sought out the optimal genetic testing strategy, thereby maximizing the chances of finding the causal DNA variant(s) and minimizing the chances of finding DNA changes for which the association with disease is unclear. In addition, in order to discriminate between relevant and benign variants in the DNA of a patient, we developed a novel online tool that ranks variants identified through DNA testing in both known and novel genes. We also identified two new genes, alpha kinase-3 (ALPK3) and superoxide dismutase 2 (SOD2), and we describe the phenotypes in these families with paediatric-onset cardiomyopathy. Lessons learned from studying paediatric cardiomyopathies will improve our understanding of the underlying biological processes that result in common complex heart diseases and will also have implications for the development of new therapeutic strategies.