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Principal Investigator: Jennifer Below
Organization: VANDERBILT UNIVERSITY MEDICAL CENTER
Fiscal Year: 2024
Award: $679,562
Funding agency: National Heart Lung and Blood Institute
SUMMARY
Dilated cardiomyopathy (DCM) affects up to 1:250 individuals and is responsible for ~40% of cardiac transplants.
Guidelines recommend genetic testing in DCM probands to help establish diagnosis, guide medical care, inform
risk stratification, and identify at-risk relatives. However, causal variants are identified in fewer than half of
patients, ~30-40% of tests return variants of uncertain significance (VUS), and a modest number of genes have
adequate genotype-phenotype data to inform medical management. In this proposal we address 4 gaps in DCM
research: 1) Most data are from individuals of European ancestry referred for genetic testing, creating bias in
estimates of the contribution, penetrance, and phenotype in the broader clinical and community population. 2)
Most established DCM genes have insufficient genotype-phenotype data to inform gene-specific clinical
management. 3) The evidence for most candidate genes is equivocal due to lack of study in cohorts sufficiently
large to evaluate pathogenicity. 4) Some disease loci likely remain undiscovered because GWAS and linkage
approaches used in prior studies are not well-powered for diseases, such as DCM, with variable age of onset,
both high genetic and allelic heterogeneity, and incomplete penetrance. We will address these fundamental
knowledge gaps using innovative genetic methods and a novel, large-scale DCM research platform that includes
harmonized phenotypic, genotyping, sequencing, and identity-by-descent (IBD) data from 5 large biobanks
comprising ~1M participants and >10,000 DCM cases. Specifically, we propose to use rare variant and IBD-
based methods to: Aim 1) Define the contribution and phenotypic manifestations of established disease genes
in multiple diverse, non-referral DCM populations; Aim 2) Assess the pathogenicity of candidate DCM genes with
equivocal evidence and establish a novel platform to evaluate VUS in established genes; and Aim 3: Discover
novel DCM genes via IBD mapping and rare variant association within and across biobanks at scale. To balance
the innovation of these aims, we present compelling preliminary data demonstrating the feasibility of our
approaches which identified a cluster of distantly related individuals harboring a common pathogenic variant in
RBM20. We anticipate these analyses will substantially expand our understanding of the genetic factors
underlying DCM risk and their clinical manifestations. Once established, our platform will support future clinical
and genetic research and advance the long-term goal of implementing targeted interventions at the clinic and
population level to reduce the burden of DCM for all patients.
Terms: <Address><Affect><Age><Age of Onset><Alleles><Allelomorphs><Arrhythmia><Candidate Disease Gene><Candidate Gene><Cardiac><Cardiac Arrhythmia><Cardiac Transplantation><Cardiology><Caring><Clinic><Clinical><Clinical Management><Clinical Research><Clinical Study><Clinical genetics><Communities><Congestive Cardiomyopathy><DNA><Data><Data Set><Deoxyribonucleic Acid><Diagnosis><Dilated Cardiomyopathy><Disease><Disorder><Distant><England><Equilibrium><European ancestry><Future><GWA study><GWAS><Genes><Genetic><Genetic Diversity><Genetic Research><Genetic Variation><Genomic Segment><Genomics><Genotype><Goals><Guidelines><Heart Arrhythmias><Heart Grafting><Heart Transplantation><Heritability><Heterogeneity><Human Genetics><IBD analysis><IBD inference><Individual><Informatics><Intervention><Intervention Strategies><Knowledge><Link><Literature><Maps><Medical><Medical Genetics><Methods><Participant><Pathogenicity><Patient Care><Patient Care Delivery><Patients><Penetrance><Phenotype><Population><Precision care><Recommendation><Relative Risks><Reporting><Research><Research Resources><Resources><Risk><Risk-associated variant><Sample Size><Site><Testing><Uncertainty><Variant><Variation><Work><ages><balance><balance function><barrier to care><barrier to health care><barrier to healthcare><barrier to treatment><biobank><biorepository><candidate identification><cardiac graft><care for patients><care of patients><caring for patients><causal allele><causal gene><causal mutation><causal variant><causative mutation><causative variant><clinical effect><clinical significance><clinically significant><cohort><data harmonization><defined contribution><disease causing variant><disease-causing mutation><doubt><exome sequencing><exome-seq><gene testing><gene-based testing><genetic testing><genome segment><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><genomic region><harmonized data><heart transplant><identical by descent><identity by descent><improved><individualized care><individualized patient care><innovate><innovation><innovative><interventional strategy><novel><obstacle to care><obstacle to healthcare><pathogenic variant><personalized care><personalized patient care><personalized screening><phenome><phenotypic data><precision screening><proband><rare allele><rare mutation><rare variant><risk allele><risk gene><risk genotype><risk loci><risk locus><risk stratification><risk variant><screening><screenings><stratify risk><trait><unclassified variant><variant detection><variant of uncertain clinical significance><variant of uncertain significance><variant of undetermined significance><variant of unknown significance><whole genome association analysis><whole genome association studies><whole genome association study>