Our History: The Familial Dilated Cardiomyopathy Research Project

This page provides information about the goals, history, and accomplishments of our research project on familial dilated cardiomyopathy (FDC).

A History of the FDC Research Project tells how our FDC research effort started and has progressed.

What We've Accomplished reports what we have done - our families, our trips, our gene mapping progress and our publications.

A History of the FDC Research Project (updated January 2010)

Ray  Hershberger, MD started the FDC research project in 1993 at Oregon Health & Science University.  He has recruited all personnel to the Project, and directs all aspects of the FDC research effort.

In September, 1995 Mike Litt, PhD brought his expertise in linkage analysis and gene mapping to the FDC research project.  In 1996 a small grant was received to support the initial genotyping that was used for preliminary data for the first NIH submission.

National Institutes of Health (NIH) funding from the National Heart, Lung and Blood Institute (HNLBI, grant number HL 58626) was initially activated in May, 1998. Shortly following, Petra Jakobs, PhD, joined the laboratory effort.  In 2000 we obtained a capillary-based rapid genotyping instrument to facilitate genotyping activities. In late 1998, Emily Burkett (Hanson), MS, CGC (certified genetic counselor) joined the Project to assist with rapid expansion of FDC large and small families. In 2001, Jessica Kushner, MS, CGC joined the group.
 
NIH funding from a competitive renewal was activated for five years on May 1, 2002. In 2003 we acquired a 16 capillary-based instrument to expedite genotyping and gene sequencing in our laboratory.
 
Duanxiang Li, MD, MS, a laboratory-based cardiovascular scientist from Baylor University, joined the FDC research group August 1, 2002. Sharie Parks, PhD, a laboratory-based geneticist joined the group on September 1, 2002. Susan Ludwigsen, MA joined the group as a Research Associate in charge of bioinformatics in January 2002.
 
In March 2007, Dr. Hershberger moved to the University of Miami and the FDC Research Project moved with him. Dr. Li accompanied him and continues his work in the laboratory. Two new genetic counselors, Jason Cowan, MS and Ana Morales, MS, CGC, along with research assistant Yves Baptiste and laboratory technician Jorge Gonzalez were recruited to the program. In 2008, NIH funding renewal was obtained. That same year, Jill Siegfried, RN, MS, CGC, was recruited into the program as a genetic counselor. In 2009, Nadine Norton, PhD, joined the group as a laboratory scientist. Laura Hudson, MA, MPH, CCRC (certified clinical research coordinator) was hired as a regulatory specialist in 2008. See the Personnel page for more information on the current FDC Project Personnel.

Numerous other nurses and clinical and laboratory researchers have greatly aided this effort since 1993, and many have participated as coauthors in our publications.

What We've Accomplished (updated July 2009)

Publications.  Please see our Publications page for a list of our publications, research posters and platform presentations.

Gene Mapping in Our ‘Large’ FDC Families. In the 1990s, we selected approximately 10 large FDC families for comprehensive clinical and laboratory evaluation.  We defined ‘large’ as a family with a large enough number of affected subjects to provide adequate statistical power to undertake a full genome search to identify a novel FDC disease gene.  While we continue to evaluate all new family referrals for suitability for large family status, these very large families are quite infrequent.  We have maintained contact with subjects from large families because of their unique value to understanding its genetic heart disease.  We continue to actively seek genetic cause of DCM in some of thse families where cause has not been discovered.

Our ‘Small’ FDC Families.  We actively recruit and have constructed approximately 140 pedigrees from smaller FDC families (defined as having at least 2 members with DCM).  For these families, we have obtained medical documentation of disease and collected genetic material.  We feel that these families, although too small for gene mapping, may play an invaluable role as novel FDC genes are discovered and described.

Apparently Sporadic Families. We actively recruit families in which only one individual is known to have IDC, as evidence shows that genetics can play a role in disease causation, even in the absence of a family history. We currently have approximately 250 pedigrees with apparently sporadic IDC. Because DCM can be asymptomatic, participation of parents, children and siblings who have undergone screening is particularly essential in sporadic families to understanding the genetics of DCM.

Clinical data.  The clinical characteristics of our initial large (FDC-1, FDC-2, FDC-4) or very large (FDC-3) FDC kindreds have been published (Crispell et al., J Am Coll Cardiol 1999;34:837-847).  A follow-up account of FDC-1, substantiating the value of periodic rescreening of first-degree relatives of subjects with FDC, was also published (Crispell et al., J Am Coll Cardiol 2002;39:1503-1507).  We have also characterized numerous additional smaller to intermediate size FDC families, and have accumulated a great deal of experience with the screening and evaluation process related to this work.

Gene mutation identification.

            Lamin A/C.  We reported three families with lamin A/C mutations (Jakobs et al., J Cardiac Failure 2001;7:249-256; Hershberger et al., Am Heart J 2002 Dec;144(6):1081-6).  Following the initial report of LMNA mutations associated with FDC (Fatkin et al., NEJM 1999; 341:1515-24), we performed lamin A/C sequencing in our larger, linkage families (FDC-1 to FDC-16) to exclude lamin A/C mutations as a cause for FDC. We identified three kindreds with novel lamin A/C mutations detected by direct DNA analysis by Sanger dideoxynucleotide sequencing.  The clinical phenotype, including DCM, DCM with conduction system disease (CSD), CSD only, or no cardiovascular phenotype, as well as age, gender, and other pertinent features of their disease have also been comprehensively described (Jakobs et al., J Cardiac Failure 2001;7:249-256; Hershberger et al., Am Heart J 2002 Dec;144(6):1081-6). Following these results, we undertook LMNA genotyping in our 300+ cohort of DCM probands. We identified LMNA mutations in 19 probands (including the 3 previously reported) for an overall mutation frequency of 5.9%. Of these 18 mutations, 14 were observed from 184 confirmed or probable FDC (7.6%), and 4 from 135 (3.0%) possible FDC or apprently sporadic IDC index patients (Parks SB et al., Am Heart J 2008;156:161-9).

            Muscle LIM Protein.  We screened the coding region of MLP in 92 FDC index cases; one mutation was identified in a 46-year-old male with dilated cardiomyopathy (LVEF=25%), atrial fibrillation, and heart failure.  The DNA sequence variant (T to C at nucleotide 55, GenBank NM_003476) was predicted to substitute a highly conserved tryptophan at residue 4 with arginine (W4R).  The missense mutation resulted in a charge change at the affected region of MLP and was predicted to alter the protein structure.  This sequence variant was neither observed in other FDC index patients nor among 100 control chromosomes.  Our finding provided further evidence to support a recent report that mutations in MLP, though infrequent, may cause FDC.

            PSEN1 and PSEN2.   In 2005 we undertook a candidate gene study by sequencing PSEN1 and PSEN2 in DNA samples from 315 DCM probands. A novel PSEN1 mutation was found in 1 FDC family, and a single PSEN2 mutation was found in 2 unrelated FDC families. Calcium flux studies in cultured fibroblasts from family members harboring these mutations were consistent with aberrant presenilin function. Combined mutation frequencies in the cohort were 1%.

           Resequencing 6 DCM genes.   In 2006 with an RS&G Service award, 6 DCM genes were resequenced in 313 DNAs from our cohort at OHSU. The six genes included beta-myosin heavy chain (MYH7), cardiac troponin T (TNNT2), the cardiac sodium channel (SCN5A), titin-cap or telethonin (TCAP), LIM binding domain 3 (LDB3), and muscle LIM protein (CSRP3). The overall frequency of likely or possibly disease-causing mutations of those genes was 10.2%. Notably, the frequencies of mutations in patients categorized either with FDC or apprently sporadic IDC were similar (9.8% FDC vs 10.8% IDC).

Distant FDC Screening Trips:  We have completed greater than 20 distant screening trips, including locations in Oregon, Washington, Arizona, California, Illinois, Iowa, Indiana, Maryland, Michigan, Minnesota, Mississippi, Missouri, Nebraska, Oklahoma and Tennessee.  Our heartfelt thanks to the many gracious and wonderful physicians, nurses and office managers who have given us permission and assisted us in the use of their offices (exam rooms, echo and ECG equipment, and many other smaller items) in these weekend screening trips, and to the many fine echocardiographic technicians who have assisted with echo screening of these families.

Clinical Databases.  We recently underwent a major upgrade to our clinical databases with the addition of Progeny to our program.  We have algorithms for all data and materials that come into our program.  Unique and confidential identifiers have been designed for every subject in this project. 

Assurance for the Protection of Human Subjects in Research Studies.  We have been fully compliant will all regulations and guidelines from the NIH, the OHSU and University of Miami Institutional Review Boards for the Protection of Human Subjects involved in research protocols.