Genetic Studies of Cardiomyopathy

Idiopathic dilated cardiomyopathy (DCM) is a heritable, progressive disorder that ultimately leads to heart failure. The development of effective therapy is significantly hindered by the heterogeneous nature of DCM. This manifests as both locus heterogeneity (mutations in different genes) and phenotypic variation (individuals with the same causative mutation exhibit highly variable phenotypes). While causative mutations have been identified in more than 50 genes, they account for less than half of the heritable DCM cases. Even less is known about genetic modifiers that are presumably responsible for phenotypic variation. Therefore, discovering more causative and modifier genes is critical for the development of individualized medicine for DCM.

The Zebrafish Genetics Laboratory has established the first several adult zebrafish models that recapitulate different genetic types of human cardiomyopathies via genome editing technology. Using a transposon-based insertional mutagenesis screening approach, the feasibility of identifying genetic modifiers of cardiomyopathy via screening a zebrafish insertional cardiac (ZIC) mutant collection has been demonstrated. While deleterious modifiers that might uncover pathological events of cardiomyopathy are an interest, the priority of the Zebrafish Genetics Laboratory is to identify salutary modifiers that could represent novel therapeutic targets.

The lab is expanding the number of ZIC mutants to identify more genetic modifiers, developing new therapeutic strategies and assessing these therapeutic strategies in different types of cardiomyopathy. This will develop individualized medicine for different types of cardiomyopathy.