Leveraging families to understand the genetic epidemiology of rare diseases driven by heterogeneous rare variation

Abstract

Idiopathic dilated cardiomyopathy (DCM) is a heritable heart muscle disease characterized by an enlarged left ventricle with reduced pumping ability. Despite being a major cause of heart failure and cardiac transplantation, DCM is rare in the population and is underreported without universal cardiac imaging. These phenotypic characteristics of DCM and its complex genetic architecture driven by heterogeneous rare variation pose challenges for understanding its genetic epidemiology. Using the DCM Precision Medicine Study as an example, this seminar will discuss how a family-based design that recruits patients with DCM and all available first-degree relatives can be used to address these challenges, highlighting advantages over alternative approaches. The methods discussed will be applicable in any setting in which the goal is to understand the genetic epidemiology of a rare disease driven by heterogeneous rare variation.