ARTICLE Translation of research discoveries to clinical care in arrhythmogenic right ventricular cardiomyopathy in Newfoundland and Labrador: Lessons for health policy in genetic disease Kathy Hodgkinson, PhD1,2, Elizabeth Dicks, PhD1, Sean Connors, MD, DPhil, FRCPC3, Terry-Lynn Young, PhD2, Patrick Parfrey, MD, FRCPC1, and Daryl Pullman, PhD4 Abstract: Arrhythmogenic right ventricular cardiomyopathy, a lethal ment of genetic disease because of the many lessons learned in autosomal dominant cause of sudden cardiac death in young people, is the decades during which the study has been in progress. prevalent in Newfoundland and Labrador (genetic subtype ARVD5). In ARVC is a biventricular cardiomyopathy characterized by the absence of implantable cardioverter defibrillator treatment, death fibro-fatty infiltration of the myocardium, which can lead to rates are extremely high. Research into arrhythmogenic right ventricular ventricular tachyarrhythmias and SCD. A positive ARVC diag- cardiomyopathy (ARVD5) began in the 1980s and the causative gene nosis depends on the number of clinical test abnormalities and mutation were discovered in 2008. The decades of research high- (major and/or minor criteria) exhibited by the individual.7 How- lighted major issues associated with the ethical management of genetic ever, clinical diagnosis is difficult and SCD may be the first information and the translation of research findings to clinical care. We presentation.5 Many of the criteria require tertiary level clinical describe these issues and the strategies used in managing them. Effec- testing, and the presence of ARVC pathology at autopsy in the tive knowledge transfer of the research information has resulted in absence of other abnormal clinical test results does not fulfill the systematic clinical and genetic screening coupled with genetic counsel- diagnostic criteria. The diagnostic utility of these criteria for ing and treatment for at-risk family members. Improved survival for diagnosis of ARVC, especially in the early stages, is poor. patients has been one clear result of this strategy. Optimal care of ARVC is almost always inherited as an autosomal dominant families where individuals are at-high risk of inheriting a disease with disorder. Clinical diagnostic difficulties are compounded by high morbidity and mortality requires the full integration of both genetic other factors common to all genetic disorders including variable research and clinical genetics programs. Although yet to be fully ef- expressivity (carriers may present with different signs and fected in our setting, our discussion highlights both the ethical necessity symptoms) and reduced penetrance (some carriers remain as well as some practical barriers in realizing this outcome. Genet Med asymptomatic). Hence, a genetic test able to provide a precise 2009:11(12):859–865. presymptomatic diagnosis unrelated to the utility of clinical Key Words: ARVC, research, consent process, clinical responsibility, testing obviates many of the diagnostic difficulties. ethics, duty to warn As early as the 1980s, individuals with ARVC in Newfound- land participated in research designed to elucidate etiology. The most recent study that began in 1997, aimed to define the natural enetic research into human disease provides information history and phenotypic expression of ARVC and to find the Gpertinent to an understanding of disease pathogenesis and gene responsible. Linkage to Chromosome 3 was published in can influence management strategies for that disease. Certain 19988 and a disease-associated founder haplotype (ARVD5)—a genetic conditions arise more frequently in Newfoundland and series of linked genetic markers surrounding the gene locus, Labrador due primarily to historic settlement patterns.1 Founder which are inherited together in affected individuals across gen- mutations are thus recognized for several autosomal dominant erations9—was recognized. In 2007, the local research team diseases,2–4 including arrhythmogenic right ventricular cardio- discovered the causative mutation in a novel gene TMEM43 myopathy (ARVC). ARVC in Newfoundland and Labrador is a within the disease-associated founder haplotype.6 To date, 17 cause of sudden cardiac death (SCD) because of lethal tachy- families have been identified with a founder mutation in arrhythmias5 caused primarily by a founder mutation in TMEM43 on Chromosome 3 (ARVD5). All subjects born at an TMEM43 (ARVD5).6 A long-standing research project on a priori 50% pedigree risk have been identified, all medical ARVC has changed both policy and procedure in the manage- records obtained (when available), and all relevant cardiac outcomes have been analyzed. This research demonstrated that this genetic subtype of From the 1Clinical Epidemiology Unit, Memorial University; 2Discipline of Genetics, Memorial University; 3Division of Cardiology, Memorial Univer- ARVC is lethal, with a median age to death in men of 41 years sity; and 4Division of Community Health and Humanities, Memorial Uni- compared with 71 years in women.5 Despite the sex influence, versity, St. John’s, Newfoundland, Canada. the disease follows a classic autosomal dominant mode of Daryl Pullman, Department of Medical Ethics, Division of Community inheritance with clear male-to-male transmission (Fig. 1). Our Health and Humanities, Memorial University of Newfoundland, St. John’s, study determined that the disease was 100% penetrant (as NL, Canada A1B 3V6. E-mail: [email protected]. defined by clinical sign or symptom) in both sexes (by age 63 The first two authors contributed equally to this manuscript. years and 76 years in men and women, respectively), and heart 6 Disclosure: The authors declare no conflict of interest. failure was a later manifestation in survivors of SCD. Between 1998 and 2007, before the identification of the causative muta- Submitted for publication May 13, 2009. tion, presymptomatic diagnosis of carriers was possible by Accepted for publication September 18, 2009. utilizing “research generated” haplotype analysis. This allowed DOI: 10.1097/GIM.0b013e3181c20bb3 for prophylactic use of implantable cardioverter defibrillators Genetics IN Medicine • Volume 11, Number 12, December 2009 859 Hodgkinson et al. Genetics IN Medicine • Volume 11, Number 12, December 2009 Fig. 1. An ARVC family pedigree showing autosomal dominant inheritance. Squares ϭ males, Circles ϭ females, Blacked in symbol ϭ ARVD5 (positive diagnosis based on SCD under 50 years, cardioversion for ventricular tachycardia or ventricular fibrillation under 50 years, obligate carrier status, and/or the presence of the TMEM43 S358L mutation). Oblique stroke through symbol ϭ dead, WT ϭ wild type for TMEM43, Question mark (?) ϭ remain at an a-priori 50% risk, Arrow ϭ proband. (ICD). A subsequent analysis indicated that the ICD signifi- The ethical management of genetic information and cantly improved survival of men in this population.5 the translation of research findings to clinical care The significant morbidity and mortality exhibited by this disease, the high penetrance, and the high risk to relatives led to Lesson 1: The need for a centralized biobank to a number of challenging issues with regard to the management preserve valuable samples over time of these patients, their families, and the data generated both Following the publication in 1980 of results that linked through research and clinical means. Issues included: (i) the hypertrophic cardiomyopathy with specific human lymphocyte ethical management of genetic information and the translation antigen types,10 researchers in Newfoundland were interested in of research findings to clinical care; (ii) the process of technol- exploring the relationship between ARVC and human lympho- ogy transfer from the research laboratory to the clinical labora- cyte antigen. The recognition of a large ARVC family led to the tory; and (iii) the optimal management of genetic data whether treatment of an affected male in Ontario,11 followed by the first generated through research or clinically. In what follows we high- description of the ARVC family by the research team in 1988.12 light key events in the history of the research, discuss lessons Genetic studies involving large groups of people, in which learned from the experience, and outline some continuing chal- accurate phenotyping and the creation of a comprehensive fam- lenges in the on-going clinical management of these families. ily pedigree are central to success, are slow, and cumbersome This article highlights some aspects of the journey taken by by nature. The data ultimately derived are priceless. The initial the researchers, clinicians, ethicists, and policy makers who samples were seen as resources related exclusively to one have worked on ARVD5 in Newfoundland during the past two research project designed to answer one research question. decades. Figure 2 catalogues some of the key events and the Archiving was not available or desired at the time of the initial lessons learned during the search for the causative mutation for study, nor was it common practice to initiate contact with ARVC in Newfoundland and Labrador, and the on-going man- clinical genetics services. agement of patients and families during that time. We believe Collected blood samples from this initial research were our experiences will prove instructive for all genetic research stored until space limitations resulted in their destruction in the dealing with genetic conditions with high morbidity and mor- early 1990s. By the time the subsequent study that