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NHLBI TOPMed: The Genetic Causes of Unexplained Cardiomyopathies (UNID_CM)

This study is part of the NHLBI Trans-Omics for Precision Medicine (TOPMed) Whole Genome Sequencing Program. TOPMed is part of a broader Precision Medicine Initiative, which aims to provide disease treatments that are tailored to an individual's unique genes and environment. TOPMed will contribute to this initiative through the integration of whole-genome sequencing (WGS) and other -omics (e.g., metabolic profiles, protein and RNA expression patterns) data with molecular, behavioral, imaging, environmental, and clinical data. In doing so, this program aims to uncover factors that increase or decrease the risk of disease, to identify subtypes of disease, and to develop more targeted and personalized treatments.

NHLBI TOPMed: The Genetic Causes of Unexplained Cardiomyopathies (UNID_CM) study performed whole genome sequencing (WGS) at usual and high read depths and transcriptome analyses (RNAseq) of blood (30x read depth) and cardiac tissues (90x read depth) from patients with Cardiomyopathies (Hypertrophic and Dilated). Samples were collected from patients with and without pathogenic mutations in cardiomyopathy genes. The goals of analyses were to advance the understanding of the molecular causes of heart diseases and to provide a robust collection of candidate molecules and mechanisms that cause or contribute to mutation-negative cardiomyopathy.
We assessed the burden of these variants by comparison to variants described in publicly available mutation databases (e.g. CLINVAR for coding variants) and genomic sequence from unaffected (e.g. congenital heart disease subjects) and individuals with mutation-positive cardiomyopathies. We expect these analyses will define causes for mutation-negative cardiomyopathy. In addition, we predict that these “omic” datasets will substantially increase knowledge of the molecules, pathways, and mechanism that incite cardiac remodeling not only in cardiomyopathies but also in prevalent cardiovascular disorders.