Toward Genetics-Driven Early Intervention in Dilated Cardiomyopathy

Abstract

Background The etiology of idiopathic dilated cardiomyopathy (DCM) is unknown by definition, but its familial subtype is considered to have a genetic component. We hypothesize that most idiopathic DCM, whether familial or non-familial, has a genetic basis, in which case a genetics-driven approach to identifying at-risk family members for clinical screening and early intervention could reduce morbidity and mortality. Methods Based on this hypothesis, we have launched the NHLBI- and NHGRI-funded DCM Precision Medicine Study, which aims to enroll 1,300 individuals (600 non-Hispanic African ancestry, 600 non-Hispanic European ancestry, and 100 Hispanic) who meet rigorous clinical criteria for idiopathic DCM along with 2,600 of their relatives. Enrolled relatives will undergo clinical cardiovascular screening to identify asymptomatic disease, and all individuals with idiopathic DCM will undergo exome sequencing to identify relevant variants in genes previously implicated in DCM. Results will be returned by genetic counselors 12-14 months after enrollment. The data obtained will be used to describe the prevalence of familial DCM among idiopathic DCM cases and the genetic architecture of idiopathic DCM in multiple ethnicity-ancestry groups. We will also conduct a randomized controlled trial to test the effectiveness of Family Heart Talk, an intervention to aid family communication, for improving uptake of preventive screening and surveillance in at-risk first-degree relatives. Conclusions We anticipate this study will demonstrate that idiopathic DCM has a genetic basis and guide best practices for a genetics-driven approach to early intervention in at-risk relatives.

Evidence-Based Assessment of Genes in Dilated Cardiomyopathy

“…There is a marked deficit in the understanding of the DCM genetic architecture in non-European cohorts. The DCM Precision Medicine Study 24 , 44 is an ongoing effort specifically designed to address this knowledge gap. Future research efforts should continue to focus on populations of diverse racial and ethnic backgrounds in order to understand DCM genetic architecture more fully.…”

Dilated cardiomyopathy

“…To date, there is no published large multicentre study of families whose members have been systematically clinically screened for DCM and have also undergone exome or genome sequencing to identify a possible genetic cause. A multisite study funded by the US National Heart, Lung and Blood Institute is now underway to test the hypothesis that DCM, whether familial or nonfamilial, has mostly a rare variant genetic basis 53 .…”

iPSC Modeling of RBM20-Deficient DCM Identifies Upregulation of RBM20 as a Therapeutic Strategy

“…Thirty to fifty percent of DCM cases involve inherited mutations located in more than 50 individual genes, including many that affect sarcomeric proteins and contractile function ( Kinnamon et al, 2017 ; McNally and Mestroni, 2017 ; Wilcox and Hershberger, 2018 ). These genes are thought to partially explain the variable clinical presentation, age of disease onset, and outcome ( Hershberger et al, 2013 ).…”