Genomic context alters disease manifestation of cardiomyopathies

Project: Research project

Project Details

Description

Heart failure (HF) is an increasing medical problem that is disabling and costly, and affects more than 5 million Americans. One of the leading causes of HF is cardiomyopathy, a disorder with a high heritable component. Mutations in the two genes encoding the thick filament explain ~75% of inherited hypertrophic cardiomyopathy (HCM), leading to the observation that HCM is a disease of the sarcomere. In contrast, dilated cardiomyopathy (DCM) is far more genetically heterogeneous with mutations in genes encoding cytoskeletal, nucleoskeletal, mitochondrial, and calcium handling proteins. Rare mutations account for most genetic cardiomyopathy with few hotspots or recurring mutations. Current genetic testing now samples >80 genes, however this testing has only ~50% sensitivity. The ¿missing heritability¿ for cardiomyopathy may be due to multiple factors, including but not limited to 1) undiscovered primary or ¿driver¿ gene mutations and/or 2) an oligogenic genetic mechanism involving the interplay between driver variants and the genomic context in which they are expressed. This more complex inheritance is supported by the considerable phenotypic variability within families, where all members share the same primary mutation but with markedly differing age of onset and expression.

Historically, studies of the genetics of cardiomyopathy were limited to a small fraction of the genome with limited information on the larger genomic signature of HF. Whole genome sequencing (WGS) provides a more comprehensive picture of genomic context, including both rare and common variation, that shapes the manifestation of driver variant(s) extending beyond the coding region. We have WGS data coupled with clinical cardiac phenotype information from >300 individuals with cardiomyopathy, as well as >1000 individuals from the Northwestern Genetic Biobank called NUGene. I propose to define the genomic context of HCM and DCM and identify differences in their genetic signatures to better inform clinical decision making. In so doing, I will use this career development opportunity to establish my role as a leading cardiovascular genomics expert.
StatusActive
Effective start/end date7/1/186/30/21

Funding

  • American Heart Association (18CDA34110460)

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