Establishment of an Australian National Genetic Heart Disease Registry
Article Outline
- Abstract
- Introduction
- Aims of the Registry
- How the Registry Functions
- Registry to Date
- Conclusions
- Further Information
- Acknowledgements
- References
- Copyright
A National Genetic Heart Disease Registry has recently been established, with the aim to enrol every family in Australia with a genetically determined cardiomyopathy or primary arrhythmic disorder. The Registry seeks to further our understanding of the impact and burden of disease in this population; increase awareness and provide education to health professionals and families; and establish a large cardiac genetic cohort as a resource for approved research studies. The Registry is currently recruiting families with inherited cardiomyopathies (e.g. hypertrophic cardiomyopathy) and primary arrhythmogenic disorders (e.g. long QT syndrome), with scope to expand this in the future. Affected individuals, as well as their first-degree (at-risk) family members are eligible to enrol. Participants are currently being recruited from cardiac genetics clinics in approved recruitment sites and hope to expand to other Australian centres including general cardiology practice in the future. A significant focus of the Registry is to improve understanding and create awareness of inherited heart diseases, which includes ensuring families are aware of genetic testing options and current clinical screening recommendations for at-risk family members. A Registry Advisory Committee has been established under the NHMRC Guidelines, and includes a representative from each major recruitment centre. This committee approves all decisions relating to the Registry including approval of research studies. A National Genetic Heart Disease Registry will provide a valuable resource to further our knowledge of the clinical and genetic aspects of these diseases. Since most of the current data about the prevalence, natural history and outcomes of genetic heart diseases has emanated from the United States and Europe, characterising these Australian populations will be of significant benefit, allowing for more informed and specific health care planning and resource provision.
Keywords: Genetic heart disease, Registry, Families, Education, Research
Introduction
Genetic Registries have long been acknowledged as an important way of investigating less common conditions. Registries allow characterisation of such disease populations, including assessment of disease prevalence, burden and outcomes, as well as evaluation of interventions and current treatment options. International cardiac genetic disease registers have been in existence for many years, including the International LQTS Registry [1] and the International Registry for ARVC [2]. They continue to play an important role in furthering our understanding of inherited heart diseases by providing large cohorts to investigate natural history, prevalence and therapy evaluations [2], [3].
The genetic basis of many cardiac conditions has recently been identified, with at least 40 cardiac diseases currently known to have a genetic cause [4]. Common features of genetic heart diseases include significant clinical heterogeneity, with regards to both symptoms and outcomes. Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease, occurring in an estimated 1 in 500 individuals [5] and is the most common structural cause of sudden death in the young, including competitive athletes [6]. Approximately 30% of all sudden deaths occurring in those less than 35 years of age are listed as ‘undetermined’ where the heart appears normal at post mortem. It is thought that arrhythmogenic conditions such as long QT syndrome (LQTS) and catecholaminergic polymorphic VT (CPVT) are likely causes and thus has heralded the age of the molecular autopsy [7], [8]. Although the automatic implantable cardioverter-defibrillator (AICD) has revolutionised clinical management of patients who are at high risk of sudden death, identification of these remains a challenge across all inherited heart diseases [9], [10], [11]. Further understanding of the clinical, genetic and environmental factors that influence disease phenotype is likely to shed light on this complex issue.
Obtaining a genetic diagnosis in families is not a straightforward matter. Genetic testing for inherited heart diseases is readily available in most cases either commercially or as part of research, though interpretation of the results can be problematic. These diseases are genetically heterogeneous, meaning most families harbour their own unique family-specific mutation. Initial gene screening of a proband will identify a causative gene mutation in approximately 30–75% of families depending on the disease in question [12]. This means a significant number of families undergo genetic testing with no mutation identified, leading to an indeterminate result. Potential explanations include the possibility of gene mutations existing in as yet undiscovered genes or inability to detect the mutation in the genes screened with current technology. The majority of inherited heart conditions are autosomal dominantly inherited, being the result of single gene mutations. To further complicate matters, it is now emerging that in a proportion of cases multiple gene mutations are present. This has been reported in HCM, LQTS and Brugada syndrome (BrS) with multiple mutation carriers also being more likely to develop severe disease [13], [14], [15]. This finding has significant consequences for cardiac genetic counselling, including creating more complex inheritance risks and the need for all common genes to be included in initial gene screening panels. This is best done in the setting of a specialised cardiac genetic clinic [12].
Further research is required to better understand why such variability exists in the clinical expression of these diseases, as well as to improve the utility of genetic tests, in particular increasing mutation detection rates. In Australia, genetic testing for inherited cardiac diseases is not presently government subsidised, limiting the access of families to a genetic diagnosis. In addition, selection bias is always an issue when recruiting from a single tertiary referral centre and can potentially lead to skewed results. A National Genetic Heart Disease Registry will provide the patient cohorts required to answer many of these questions, with the elimination of selection bias, helping ensure that Australian research groups remain on the forefront of cardiac genetic research.
Aims of the Registry
The National Genetic Heart Disease Registry aims to:
An ongoing focus of the Registry will be to advocate for government funding of cardiac genetic testing in Australia, with the aim of establishing fair access to these services for all families suffering from inherited heart diseases. Additionally, a long-term goal of the Registry is to create a DNA bank for the storage of DNA samples from every person enrolled in the Registry.
How the Registry Functions
The success of the National Genetic Heart Disease Registry hinges on the good communication and collaborations already existing between major cardiac genetic centres, general cardiologists, clinical genetics units and the families with disease. An overview of how the Registry will function is summarised in Fig. 1. Some of the key aspects of this are summarised below.
Figure 1.
Overview of how the National Genetic Heart Disease Registry will function. (A) At enrolment, clinical and genetic data are collected and stored in the Registry database. (B) The Registry may periodically make contact with a registrant to update data, provide educational material and advise of research programs. (C) Regular interaction between cardiologists, clinical genetics units, general practitioners (GP) and patient support groups is necessary. (D) Research groups are able to use the cohort following Registry Advisory Committee and local HREC approval, and the Registry will approach eligible participants on the group's behalf.
Participant Recruitment
Eligible participants include individuals with a diagnosis of a genetic heart disease, as well as their first-degree (at-risk) relatives. Individuals of any age can register, and the genetic heart diseases included are listed in Table 1. These include the inherited cardiomyopathies (HCM, familial dilated cardiomyopathy [FDC], arrhythmogenic right ventricular cardiomyopathy [ARVC], left ventricular noncompaction [LVNC] and familial restrictive cardiomyopathy [RCM]) and the primary arrhythmogenic disorders (LQTS, CPVT, BrS and idiopathic ventricular fibrillation [IVF]). The inclusion of these specific diseases reflects the experience of the centres where the Registry will initially recruit. There is scope to expand the Registry to include other inherited heart diseases in the future, including Marfan's syndrome and familial hypercholesterolaemia.
Table 1. Cardiac Genetic Diseases Included in the Registry
| Inherited cardiomyopathies | Hypertrophic cardiomyopathy |
| Familial dilated cardiomyopathya | |
| Arrhythmogenic right ventricular cardiomyopathy | |
| Left ventricular noncompactionb | |
| Familial restrictive cardiomyopathya | |
| Primary arrhythmogenic disorders | Long QT syndrome |
| Catecholaminergic polymorphic ventricular tachycardia | |
| Brugada syndrome | |
| Idiopathic ventricular fibrillation | |
aIndividuals with dilated or restrictive cardiomyopathy must be known to have familial disease based on having: (1) at least one other affected family member, or (2) a genetic diagnosis. |
bIndividuals with left ventricular noncompaction must either have: (1) at least one other affected family member, or (2) isolated clinical expression, i.e. not part of a syndromic condition, or (3) a genetic diagnosis. |
Individuals will, in the first instance, be recruited from participating Registry recruitment centres. Generally this will be a specialised cardiac genetic clinic, incorporating a cardiologist, clinical geneticist and/or genetic counsellor. However, this will hopefully extend to other centres including general cardiology practice in the future. Any health professional (including cardiologists and general practitioners) can contact the Registry Coordinator to enquire about patient enrolment. Further family members will be recruited through the proband, with participant information sheets and consent forms to be passed along within the family. Additionally, a one-page advertisement has been approved by a local human research ethics committee (HREC) for wide circulation in support group newsletters, websites, etc. and individuals are asked to contact the Registry Coordinator for more information.
Data Collection
The Registry collects information about demographics, medical history, family history, use of medical services (e.g. how often a patient sees their cardiologist), results from cardiac investigations (such as echocardiogram reports) and results of any genetic testing carried out (Table 2). All collected data are securely stored and entered on to a centralised Registry database. Hard copy data are stored at the site from which the registrant was recruited. DNA samples are not collected in the first stage of establishment of the Registry, but this remains a long-term goal of the Registry.
Table 2. Data Collected by the Registry
| Category | Examples of Data Collected |
|---|---|
| Sociodemographic | Date of birth, gender, ethnicity, country of birth, height and weight |
| Clinical history | Clinical diagnosis, age at diagnosis, sudden cardiac death event, other serious medical conditions, symptoms, medications |
| Interventions | Details of interventions, including AICD indications, device details, adverse events and appropriate shocks |
| Use of medical services | Details of individuals use of services, including cardiology consults, cardiac investigations and clinical genetics consults. |
| Cardiac investigations | Document results of echocardiograms, electrocardiograms, cardiac MRI, exercise stress tests, etc. |
| Genetics | Status of genetic testing in the family, details of any genetic diagnosis in the individual |
| Family history | Family history of sudden death, family history of disease, de-identified pedigree included |
Registry Advisory Committee
The Registry Advisory Committee is a requirement outlined by the National Health and Medical Research Council (NHMRC) Guidelines for Genetic Registers and Associated Genetic Material [16]. The governance structure is shown in Fig. 2. The purpose of the advisory committee is to approve how the Registry will function and how Registry data are to be used, including approval of external research groups who apply to use the cohort in the future. The advisory committee includes a representative from every major recruitment site and a patient representative.
Figure 2.
Governance Structure of the National Genetic Heart Disease Registry. The Registry Advisory Committee oversees all major decisions relating to the Registry. The Registry Coordinator reports to the Advisory Committee and coordinates the day-to-day functioning of the Registry. Sites currently recruiting are RPAH and RBWH. Both Melbourne sites are expected to begin recruiting in 2008. Additional recruitment sites are anticipated in the future. Abbreviations: RPAH
=Royal Prince Alfred Hospital, Sydney; RBWH=Royal Brisbane and Women's Hospital, Brisbane; RCH VIC=Royal Children's Hospital, Melbourne; RMH=Royal Melbourne Hospital, Melbourne.
Use of the Registry for Improving Patient Care and Education
As those involved in the Registry have qualifications and experience in cardiac genetics, it will not only be a tool for further understanding these diseases, but also provide information, education and support to families living with inherited heart conditions. This will include a twice yearly newsletter posted to all registrants, a patient website where disease information sheets can be accessed (www.registry.centenary.org.au), and contact details of local Registry investigators.
Use of the Registry by External Research Groups
The Registry cohort will be available to external research groups. This will involve an application to the Registry Advisory Committee and local HREC approval of the project. Upon approval, the Registry will contact those participants who consented to be approached for research programs, provide them with information about the study and the investigators contact details should they wish to participate.
Registry to Date
The Registry has currently enrolled approximately 150 families from NSW and Queensland since May 2007, representing initial recruitment only. This is expected to rise dramatically in 2008 as more attention will be focused on recruitment rather than establishing Registry methods and guidelines, and it is anticipated that over 1000 participants will enrol within the next 5 years. An online Registry website will provide information to families, health professionals and research groups. Finally, Registry guidelines that dictate how the Registry is to operate have been created and approved by the Registry Advisory Committee.
Conclusions
The establishment of a National Genetic Heart Disease Registry will provide a valuable resource to families, health professionals and research groups alike. The Registry aims to provide accurate and up-to-date information about these diseases, with a strong focus on ensuring at-risk family members are aware of current clinical screening recommendations. This large patient cohort will assist researchers address many of the unanswered questions surrounding cardiac genetic diseases, with the ultimate goal of improved treatment options and patient care.
Further Information
If you have patients who are eligible to enrol or would like to enquire about becoming a Registry recruitment site, please contact the Registry Coordinator, Ms Jodie Ingles (Tel.: +61 7 3636 3244 Email: j.ingles@centenary.org.au) (www.registry.centenary.org.au).
Acknowledgements
JI is the recipient of a University Postgraduate Award, University of Sydney. CS is the recipient of a co-funded NHMRC and National Heart Foundation of Australia Practitioner Fellowship.
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PII: S1443-9506(08)00812-3
doi:10.1016/j.hlc.2008.05.603
© 2008 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved.
