Who We Are, Where We've Been and What We've Accomplished
Ray E. Hershberger, MD
Dr. Hershberger is a Professor of Medicine, a heart failure and transplant cardiologist, and a clinical and laboratory scientist who is the founder and Principal Investigator for the DCM (formerly, FDC) Research Project. He and his group continue their research efforts to discover and understand the genetics and genomics of human dilated cardiomyopathy and translate new knowledge into the practice of cardiovascular medicine. In his current position at The Ohio State University College of Medicine since 2012, he directs the Division of Human Genetics in the Department of Internal Medicine and is jointly appointed in the Cardiovascular Division. He devotes his outpatient clinical effort to cardiovascular genetics and also serves with the in-patient heart failure and cardiac transplantation service. Dr. Hershberger received his cardiovascular, heart failure and cardiac transplantation training at the University of Utah in Salt Lake City from 1985 – 1990, which also included a three-year laboratory-based research fellowship. In 1990 he joined the faculty of the Division of Cardiology at the Oregon Health & Science University (OHSU) in Portland, Oregon, as a heart failure and transplant cardiologist. Dr. Hershberger started the Familial Dilated Cardiomyopathy (FDC) Research Project in 1993 while at OHSU. He also directed the OHSU Heart Failure and Transplant Cardiology programs from 1993-2007. In 2007 Dr. Hershberger joined the Miller School of Medicine at the University of Miami in Miami, Florida, where he served as Associate Chief of the Division of Cardiology, Director of the Advanced Heart Failure Therapies Programs, and Director of Translational Cardiovascular Genetic Medicine. You may contact Dr. Hershberger via email at Ray.Hershberger@osumc.edu, his office phone number at 614-688-1388, or his direct line at 614-688-1305.
CLINICAL SCIENCE PERSONNEL
Ana Morales, MS, LGC
Licensed Genetic Counselor
Ana Morales is an Associate Professor of Medicine in the Division of Human Genetics at The Ohio State University and Co-Investigator with the DCM Research Project. Ana provides cardiovascular research studies in cardiovascular genomics, including the development of research proposals, writing manuscripts, and presenting at conferences. Her areas of focus include variant interpretation and the return of results and related genetic counseling issues. Her focused area of work is peripartum cardiomyopathy (PPCM) and the clinical genetic counseling aspects of this condition. Her work has resulted in publications addressing clinical genetics and psychosocial issues that are relevant to PPCM and DCM. She received her undergraduate degree in Biology from the University of Puerto Rico (Rio Piedras). In 2001, she completed her graduate degree in genetic counseling from Brandeis University, Waltham, MA. Employed as a genetic counselor first at Children’s Hospital in Boston, later in Puerto Rico and then at the University of Miami, Ana joined the DCM Research Project in 2007 as a Research Genetic Counselor. In 2011 she joined the Miller School of Medicine faculty of the University of Miami as an Instructor in the Department of Medicine. She has been a faculty member of The Ohio State University Division of Human Genetics in the Department of Internal Medicine since 2012.
Elizabeth Jordan, MMSc, LGC
Licensed Genetic Counselor
Elizabeth Jordan is an Assistant Professor of Medicine in the Division of Human Genetics at The Ohio State University and a Co-Investigator with the DCM Research Project. She received her undergraduate degree in Psychology and had additional focused coursework in human biology and genetics from Transylvania University in Lexington, Kentucky. Elizabeth completed her graduate training in Human Genetics and Genetic Counseling at Emory University in Atlanta, Georgia. Starting her career at the University of Louisville, Elizabeth’s background includes cardiovascular genetics, clinical cancer genetics, and general medical genetics in both pediatric and adult populations. In 2015, she joined the faculty at the University of Louisville School of Medicine as an Instructor in the Department of Pediatrics. Elizabeth joined the Division of Human Genetics at The Ohio State University and the DCM Research Project in the summer of 2017. She provides clinical genetic counseling in the Cardiovascular Genetics and Genomics Clinic and the Inherited Channelopathy Clinic at the Richard M. Ross Heart Hospital. Her areas of focus within the DCM Research project include variant interpretation, returning genetic results, and navigating related genetic counseling matters.
Laiken Peterson, MS, LGC
Licensed Genetic Counselor
Laiken Peterson is an Assistant Professor of Medicine in the Division of Human Genetics at The Ohio State University and a Co-Investigator with the DCM Research Project. She graduated from the University of Wisconsin-Eau Claire in 2017 with a Bachelor’s degree in Biology and minors in Chemistry and Psychology. She then went on to pursue her Master’s degree in Genetic Counseling at The Ohio State University. Upon graduation in the spring of 2019, she joined the Division of Human Genetics and the DCM Research Project at The Ohio State University. Within the DCM Research Project, Laiken’s duties include variant interpretation, returning genetic results, and navigating related genetic counseling matters. In addition to her research duties, she provides clinical genetic counseling to patients and their families in the Cardiovascular Genetics and Genomics Clinic at the Richard M. Ross Heart Hospital.
Esther Barlow, BS
Clinical Research Manager
Esther Barlow serves as the Clinical Research Manager for the DCM Precision Medicine Study. She joined the Study in 2016 and provides overall management of our clinical research operations and personnel, including The Ohio State University clinical research coordinator group and support staff. Esther’s role includes the training of personnel at new study sites, as well as managing all aspects of patient and family member recruitment and enrollment activities. Esther came to us with more than 10 years of experience in helping manage a large clinical trials group, with a focus area in the training of Clinical Research Coordinators. She earned her bachelor’s degree in biology and is Association of Clinical Research Professionals (ACRP) certified. You may contact Esther via email at Esther.Barlow@osumc.edu or her office phone number at 614-688-9815.
Alisa Blazek, PhD
Research Administration Scientist
Alisa Blazek joined the DCM Research Project in January 2019 as a Research Administration Scientist. Prior to joining the DCM team, she was a Principal Research Scientist at Battelle Memorial Institute where she managed large scientific research programs comprised of multidisciplinary teams of biologists and data and physical scientists. Alisa earned her M.A. in Exercise Science and her PhD in Molecular, Cellular, and Developmental Biology with a focus on molecular mediators of exercise responses from The Ohio State University. Alisa performed human clinical exercise studies and assessments during her graduate research at Ohio State. As a member of the DCM Research Project, Alisa assists Dr. Hershberger and the entire project team with the overall operation of the team, including administration, process improvement, finances, and scientific and programmatic development. Alisa can be contacted by email at Alisa.Blazek@osumc.edu or by calling 614-685-9007.
Abraham Lucey, MA
Research Outreach Coordinator
Abraham Lucey is a Research Outreach Coordinator with the DCM Precision Medicine Study. He joined the study in 2017 and supports the Clinical Research Manager and study team with study management processes. He also assists with recruitment and enrollment activities at sites and The Ohio State University. Abraham earned his master’s degree in International Relations. You may contact Abraham via email at Abraham.Lucey@osumc.edu or his office phone number at 614-685-9089.
Hayley Curran, BS
Clinical Research Coordinator
Hayley Curran is a Clinical Research Coordinator with the DCM Precision Medicine Study. She joined the Research Project in 2017 and supports the Clinical Research Manager with study management processes. Hayley earned her bachelor’s degree in Health Sciences with a minor in Neuroscience. You may contact Hayley via email at Hayley.Curran@osumc.edu or her office phone number at 614-366-3083.
Erika Bello-Pardo, BS
Clinical Research Coordinator
Erika Bello-Pardo is a Clinical Research Coordinator with the DCM Precision Medicine Study. She joined the study in 2018 and supports the Clinical Research Manager and study team with study management processes. She also assists with recruitment and enrollment activities at sites and The Ohio State University, particularly with patients of Hispanic ethnicity. Erika earned her bachelor’s degree in Biological Sciences from Florida International University and is currently working towards a Master of Arts in Bioethics at The Ohio State University. You may contact Erika via email at Erika.Bello-Pardo@osumc.edu or her office phone number at 614-293-7038.
Laura Sullivan, BA
Clinical Research Assistant
Laura Sullivan is a Clinical Research Assistant with the DCM Precision Medicine Study. She joined the study in 2019 and supports the Clinical Research Manager and Coordinators with study management processes. Laura earned her bachelor’s degree in Biology with a minor in Evolution, Ecology, and Organismal Biology. You may contact Laura via email at Laura.Sullivan2@osumc.edu or her office phone number at 614-293-8968.
Spencer King Harris, BS
Clinical Research Assistant
Spencer King Harris is a Clinical Research Assistant with the DCM Precision Medicine Study. He joined the study in 2019 and supports the Clinical Research Manager and Coordinators with recruitment, enrollment, and other study processes. Spencer earned his bachelor’s degree in Molecular Genetics from The Ohio State University in 2017. He then moved to Beijing, China where he worked in the pharmaceutical sector learning about Quality Assurance processes. He later traveled to London, England where he worked in the Electronic Medical Records field for the Great Ormond’s Street Children’s Hospital. You may contact Spencer via email at Spencer.Harris@osumc.edu or his office phone number at 614-293-8950.
Tomohiko Ai, MD, PhD
Tomohiko Ai joined the DCM Research Project as a Research Specialist in 2018 to assist the project team with variant adjudication. In addition to his work with the DCM Project, Dr. Ai is an Adjunct Assistant Professor of Cardiology at the Indiana University School of Medicine and an Adjunct Associate Professor of Emergency Medicine at the Tokyo Medical and Dental University. Specializing in cardiology, molecular biology and clinical pathology, Dr. Ai earned his MD from Osaka Medical College and his PhD from Kyoto University in Japan. You may contact Dr. Ai via email at Tomohiko.Ai@osumc.edu .
Julia Pinsonneault, PhD
Julia Pinsonneault joined the DCM Research Project as the Scientific Editor in 2018. She provides scientific writing, editing, organization, and other services to contribute to the development and production of scientific abstracts, publications, and presentations. Julia also helps with data analysis. Prior to joining the DCM team, she was a research scientist for 13 years in pharmacogenomics, a regulatory coordinator in the Clinical Trials Office, and a freelance editor. Julia earned her PhD in Molecular Biophysics and Biochemistry with a focus on molecular genetics from Yale University. You may contact Julia via email at Julia.Pinsonneault@osumc.edu or at her office phone number at 614-293-7453.
Jenni Chichka, MA
Project Manager and Media Coordinator
Jenni Chichka is a Project Manager and Media Coordinator for the DCM Research Project. She joined the team in 2018 and assists with external communications and coordination of media activities, as well as internal project operations. Along with having more than more than 10 years of experience in project management at Ohio State University, Jenni also has a background in non-profit communications. She received her bachelor’s degree in journalism and her master’s degree in high education administration. You may contact Jenni via email at email@example.com or at her office phone number at 614-366-6267.
INFORMATICS AND COMPUTATIONAL PERSONNEL
Daniel D. Kinnamon, PhD
Research Assistant Professor
Director of Human Genetics Research Informatics
Dan Kinnamon is a Research Assistant Professor and Director of Human Genetics Research Informatics in the Division of Human Genetics at The Ohio State University and a Co-Investigator with the DCM Research Project. He has several years of experience collaborating on the design and analysis of biomedical studies and expertise in data management, software development, and high-performance computing. Dan provides direction for statistical and informatics aspects of the DCM Research Project at all stages of the research process. He played a key role in the design of the DCM Precision Medicine Study and continues to be involved in the oversight of daily operations. He also led the design and implementation of an entirely new informatics infrastructure for the DCM Precision Medicine Study that is housed within the Division of Human Genetics Data Management Platform at the Ohio Supercomputer Center. The Human Genetics Research Informatics Core team that Dan manages maintains and expands this infrastructure on an ongoing basis to meet the operational and scientific needs of study staff. Dan received a bachelor’s degree in Economics and Latin American Studies in 2002 and a master’s degree in Statistics in 2003, both from Stanford University. After working as a biostatistician at Children’s Hospital Boston and the University of Miami, he completed a PhD in Human Genetics and Genomics at the University of Miami in 2013. He joined The Ohio State University Division of Human Genetics in the Department of Internal Medicine later that year.
Carl Starkey, PhD
Senior Research Analytics Specialist
Carl Starkey is a Senior Research Analytics Specialist in the Human Genetics Research Informatics Core. He joined the DCM Precision Medicine Study in 2016. He is responsible for writing workflows, investigating novel applications of software for genetics research, and curating clinical and genomic data in the Division of Human Genetics Data Management Platform. As the study matures, he will participate in the statistical analysis of the study’s findings utilizing knowledge and experience from his physics education and research. He holds a PhD in physics from the University of Toledo. Carl can be contacted via phone 614-685-9059 or email Carl.Starkey@osumc.edu.
Ferry Oriyo, MS
Research Analytics Specialist
Ferry Oriyo is a Research Analytics Specialist in the Human Genetics Research Informatics Core. She joined the DCM Precision Medicine Study in 2016. With over a decade of experience in clinical research application development and management, Ferry designs informatics tools and solutions for the study. She holds a master’s degree in Health Information Management and Systems from The Ohio State University.You may contact Ferry via email at Ferry.Oriyo@osumc.edu or phone: 614-293-9135.
Jonathan Mead, BS
Research Analytics Specialist
Jonathan Mead is a Research Analytics Specialist in the Division of Human Genetics. He joined the DCM Precision Medicine Study in 2017. He supports the informatics efforts of the Division of Human Genetics Research Informatics Core by managing data, developing software tools for clinical personnel, and maintaining study database infrastructure. He also assists with in the bio-statistical analyses involved in the DCM Research Project. Jonathan earned his bachelor’s degree in biomedical engineering, with a minor in biology. You may contact Jonathan via email at Jonathan.Mead@osumc.edu or his office phone number at 614-685-8967.
Stephen Ashley, BS
Research Analytics Specialist
Stephen Ashley is a Research Analytics Specialist in the Division of Human Genetics Data Management Platform. He joined the DCM Precision Medicine Study in 2018 and supports the Human Genetics Research Informatics Core, assisting with developing and maintaining informatics tools for the clinical team. He earned a bachelor’s degree in Biology from Florida State University. You may contact via email at Stephen at Stephen.Ashley@osumc.edu or his office phone number at 614-293-4117.
Allison McMurray, BS
Allison McMurray is a Support Analyst for the Human Genetics Research Informatics Core. She joined the DCM Precision Medicine Study in 2018, and provides end-user support and query and reporting assistance. She has a bachelor’s degrees in Neuroscience and Psychology from The Ohio State University. You may contact Allison via email at Allison.McMurray@osumc.edu or her office phone at 614-293-7035.
How the Dilated Cardiomyopathy Research Project started and has progressed
Why is our group studying dilated cardiomyopathy (DCM)? Dr. Hershberger chose this area of research following the 1992 report that 20% of cases of DCM of unknown cause (idiopathic DCM, IDC) could be shown to be familial with the clinical screening of family members. This evidence indicated a genetic cause for DCM.
Since then, our goal has been to identify the genetic causes of DCM in order to understand DCM cause, how DCM progresses, and to devise new prevention and treatment strategies for cardiomyopathy and heart failure.
It is our sincere hope that the information gained from studying individuals and families with DCM will lead to prevention, earlier diagnosis, and better interventions.
In 1993, Ray Hershberger, MD started the Familial Dilated Cardiomyopathy (FDC) Research Project at Oregon Health & Science University. At that time none of the genetic basis of DCM had been discovered. The goals of the study were to discover the genes and their variants causing DCM and to translate these discoveries into the practice of cardiovascular medicine. At that time, our research was focused on large families with multiple affected individuals, which are ideal for linkage and gene mapping studies.
Since 1993, Dr. Hershberger has recruited all personnel and has directed all aspects of the research effort. Our research team is composed of clinicians and scientists in cardiology and genetics.
In 1995, Mike Litt, PhD was recruited to the FDC research project because of his expertise in linkage analysis and gene mapping.
In 1996, a small grant supported genotyping for preliminary data for the first National Institutes of Health (NIH) submission. An NIH grant was prepared and submitted in 1996 and resubmitted in 1997.
In 1998, first funding from the National Heart, Lung and Blood Institute (NHLBI grant number HL 58626) of the NIH was activated in May 1998. Shortly following, Petra Jakobs, PhD, joined the laboratory effort.
In late 1998, Emily Burkett, MS, CGC (certified genetic counselor) joined the project to assist with the rapid expansion of FDC large and small families.
In 2000, we obtained a single capillary-based genotyping instrument to facilitate genotyping activities.
In 2001, Jessica Kushner, MS, CGC, another talented genetic counselor, joined the study.
In 2002 and 2008, NIH research funding was renewed. This funding has provided the core support for all of our research activities. Around this time, the project expanded to accept participants with non-familial DCM, and by 2005, Dr. Hershberger and his team had enrolled more than 300 families. Sharie Parks, PhD, a laboratory-based geneticist joined the group on September 1, 2002. Susan Ludwigsen, MA joined the group as a Research Associate to assist with bioinformatics in January 2002. In 2003 we acquired a 16 capillary-based instrument to expedite genotyping and gene sequencing in our laboratory. With this investment, our families underwent research genetic testing for single genes. NIH support through the NHLBI-funded Resequencing and Genotyping Service enabled sequencing of our cohort for small gene panels.
In March 2007, the project moved to the University of Miami (UM). Two genetic counselors, Jason Cowan, MS, and Ana Morales, MS, LGC were recruited to the program.
In 2008, Jill Siegfried, RN, MS, CGC, was recruited into the program as a genetic counselor. Laura Hudson, MA, MPH, CCRC (certified clinical research coordinator) was hired as a regulatory specialist.
In 2008, NIH research funding was renewed.
In 2009, Nadine Norton, PhD, joined the group as a laboratory scientist. Research continued on selected genes, which eventually expanded to exome sequencing and zebrafish functional studies. By 2009, over 400 families had enrolled; however, it became clear that a much larger number of families would be required for progress.
In 2009, Dr. Hershberger began developing the DCM Consortium.
By 2010, Dr. Hershberger had recruited 5 institutions external to the University of Miami to the DCM Consortium.
In 2011, a $10 Million NIH proposal focused on gene discovery leveraging exome sequencing was nearly funded.
In 2012, Dr. Hershberger was recruited by The Ohio State University (OSU)/Wexner Medical Center in Columbus, Ohio, as Director of the Division of Human Genetics within the Department of Medicine. Dr. Hershberger and Ana Morales, MS, CGC, moved the FDC Research Project to OSU.
In 2013, the Familial Dilated Cardiomyopathy (FDC) Research Project became the Dilated Cardiomyopathy (DCM) Research Project to better communicate that we welcome individuals with DCM with or without a family history. In late 2012 Dr. Hershberger restarted communications with the NIH’s National Heart Lung and Blood Institute (NHLBI) regarding funding a large definitive family-based DCM study, which evolved into the now funded Precision Medicine study. The Discovery study work progressed with several hundred individuals undergoing exome sequencing.
In 2013, Dr. Hershberger began expanding the DCM Consortium to prepare for the Precision Medicine study. Three of the sites from the 2011 application continued in the Consortium at OSU. A larger number of families necessitated adding additional sites to the Consortium. Because of a scientific decision to enroll equal numbers of DCM patients and families of European and African ancestry, sites with fitting enrollment demographics were prioritized. Communications with NHLBI program personnel continued throughout 2013. Dr. Hershberger and Ana Morales traveled to initiate clinical sites for pilot phase enrollments.
In 2014, following a conference call to NHLBI leadership on June 2, 2014, permission was received to provide a letter of request to seek approval to submit the Precision Medicine study. A request was prepared and transmitted on July 1, 2014, to the Director of the Division of Cardiovascular Sciences at NHLBI, and permission to apply was received on August 8, 2014. The Precision Medicine study, research application, in the process since 2013, was completed and submitted for an October 5, 2014, NIH deadline. The application was greatly strengthened with extensive supporting documentation from collaborators at clinical sites and other co-investigators.
In 2015, the Precision Medicine study application was scored at an outstanding level. We were informed that the NHLBI would fully support our study. A National Human Genome Research Institute supplement was requested and received to add Hispanic ethnicity to the study. First funding was received in 2015.
As of 2016, the Discovery study has enrolled more than 700 families in our research, and over 400 participants have been exome sequenced. The Precision Medicine study commenced enrollment in June 2016, and enrollment continues to date.
In 2016, the Precision Medicine study was activated for enrollment at OSU on June 7. Other sites were activated later in 2016. It became clear that additional enrollment capacity would be needed, and the Consortium undertook expansion to 25-30 clinical sites.
As of 2017, more than 25 sites have joined the DCM Consortium. Enrollment and related activities for the Precision Medicine study continue. Development of the pilot phase for the Discovery study, in preparation for an NIH application, is underway.
Since 1993 numerous other nurses and clinical and laboratory personnel not mentioned above have provided invaluable assistance with the DCM Project at OHSU, UM, and OSU. Many of these individuals have participated as coauthors in our publications. We also recognize the hundreds of families who have participated in our research, and scores of physicians, nurses and genetic counselors who have referred patients and families to us. Thank you!
What We've Accomplished
Please see our Publications page for a full citation of our publications
BAG3. In 2011, we identified rare variants in BAG3 (BCL2-associated athanogene 3) as causative of DCM by using comprehensive genomic approaches (Norton et al., Am J of Human Genetics 2011; 88:273-282). Applying both genome-wide copy number and whole-exome sequencing analysis in a large FDC pedigree with autosomal dominant transmission, we identified 428 single point variants, 51 insertion deletions and 440 copy number variants > 1 kb. Of these, a 8733 bp deletion in BAG3 was found in seven affected family members. The deletion was absent in 355 controls. Knockdown of bag3 in a zebrafish model recapitulated DCM and heart failure. Sequencing of coding regions in 311 additional unrelated probands identified one frameshift, two nonsense, and four missense rare variants absent in 355 control DNAs, four of which were familial and segregated with disease.
PSEN1 and PSEN2. In 2005 we undertook a candidate gene study by sequencing PSEN1 and PSEN2 in DNA samples from 315 DCM probands (Li et al, AM J of Human Genetics 2006;1030-39). 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%.
SELECTED OTHER GENE SEQUENCING STUDIES
Exome sequencing in large FDC families. Our initial focus in the 1990s was large FDC families (meaning several affected subjects in one extended family), extremely helpful at linkage analysis and gene mapping for novel gene discovery. Recent developments in sequencing technology have now made it possible to sequence all genes that encode proteins simultaneously, termed exome sequencing. We used both linkage analysis and exome sequencing of 48 individuals with DCM from 17 families to analyze TTN truncating mutations (Norton, et al, Circ Cardiovasc Genetics 2013;6:144-53). We identified six TTN truncating variants in 7 families. By linkage analysis the TTN region fell under the second highest genome-wide multipoint linkage peak (MLOD 1.59). Two additional novel truncating TTN variants did not segregate with DCM. We also found that while the average number of missense variants per individual was ~23, the average number of TTN truncating variants was 0.014 per individual. These data suggest that TTN truncating variants contribute to DCM cause. However, the two families with non-segregating TTN mutations illustrate the challenge of determining the role of TTN in DCM.
BAG3. In 2011, we conducted exome sequencing in 68 individuals from 22 of our largest FDC families. We discovered BAG3, noted above, and others still in progress. We also developed an exome variant calling pipeline and conducted zebrafish-based functional studies.
LMNA. In 2001 we sequenced LMNA our larger, linkage families (FDC-1 to FDC-16) to exclude lamin A/C mutations as a cause for FDC and identified three families with novel LMNA mutations (Jakobs et al., J Cardiac Failure 2001;7:249-256; Hershberger et al., Am Heart J 2002; 144:1081-6). We also sequenced LMNA in our 300+ cohort of DCM probands and identified 18 mutations in 19 probands (including the 3 previously reported) for an overall mutation frequency of 5.9%. (Parks SB et al., Am Heart J 2008;156:161-9).).
Resequencing 11 DCM genes. With an RS&G Service award, 11 DCM genes were resequenced in 312 DNAs from our cohort at OHSU in two studies. The 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) in the first study. Myosin-binding protein C (MYBPC3), alpha-myosin heavy chain (MYH6), tropomyosin (TPM1), cardiac troponin C (TNNC1), and cardiac troponin I (TNNI3) were sequenced in the second study. Variants were classified as likely or possibly disease-causing in approximately 10%. Notably, the frequencies of mutations in patients categorized either with FDC or apparently sporadic IDC were similar. Overall, mutations in these 11 genes were identified in approximately 27% of DCM probands.
RBM20. In 2010, 312 DCM probands were evaluated for nucleotide alterations in exons 6 through 9 of RBM20. We found six unique RBM20 rare variants in 1.9%. Four mutations, two of which were novel (R634W and R636C) and two previously identified (R634Q and R636H), were identified in a hotspot in exon 6. Two other novel variants (V535I in exon 6 and R716Q in exon 9) were outside of this hotspot. We also observed that RBM20 mutations are associated with advanced disease.
‘Small’ FDC Families. We actively recruit 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. With exome sequencing these small FDC families now also 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. 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 some of our initial very large FDC kindreds have been published (Crispell et al., J Am Coll Cardiol 1999; 34:837-847<). A follow-up account of one of these families substantiated the value of periodic rescreening of first-degree relatives of subjects with FDC (Crispell et al., J Am Coll Cardiol 2002; 39:1503-1507). We have also characterized numerous additional smaller to intermediate size FDC families (Kushner et al., J Cardiac Failure 2006;12:422-29), and have accumulated a great deal of experience with the screening evaluation process related to this work. We also notify participants when relevant research results are available and provide assistance during the confirmatory testing process (Siegfried et al., J Genetic Counseling 2013; 22:164-74).
Offsite Screening Trips. We have completed greater than 25 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.