NHLBI GO-ESP: Family Studies (Dilated Cardiomyopathy)

The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. The goals for this project are to conduct exome sequencing for novel dilated cardiomyopathy (DCM) gene discovery in families with DCM. These families have already been sequenced for 15 DCM genes, accounting for approximately 75% of known genetic cause, without rare coding variants identified.]]>
Diagnostic criteria for affected status are based upon the presence of left ventricular enlargement (LVE) and systolic dysfunction (left ventricular ejection fraction (LVEF) >0.50), after excluding confounders, congruent with the recommendations of the European working group and our previous extensive experience. We most commonly use an echocardiographic (echo)-derived left ventricular end-diastolic dimension (LVEDD) to determine LVE, where the LVEDD is derived from sex- and height-specific partitioning values from the Framingham study. We also note that some FDC families present with prominent conduction system disease (e.g., LMNA or SCN5A mutations), and in such cases it may be appropriate to use additional diagnostic criteria for affected status as was done by Olson and colleagues for SCN5A mapping and as recommended by the European working group.]]>
The central goal of this study has been to discover genetic cause of DCM. In 1992 the plan was to identify and phenotype very large multiplex families with FDC for genome-wide linkage analysis and gene mapping studies. With first NIH funding in 1998, we expanded recruitment to FDC families of all sizes to acquire a well-phenotyped DCM genetic repository so that with identification of a novel DCM gene we would be able to search for allelic variants, thereby gaining evidence to support its relevance. As FDC genes were discovered, we began to rule out rare variants in the known FDC genes by Sanger sequencing in our large families in order to triage the time and resource intensive genotyping and linkage effort into large pedigrees with unknown genetic cause. By 2006 we had phenotyped >300 DCM probands from families of all sizes with well established family screening, phenotyping and recontact protocols. Our current studies are using exome sequencing to identify novel DCM genes in families negative for mutations in 16 known DCM genes.]]>