Introduction
During the last 4 decades, rapid progress in medical genetics and molecular medicine has revolutionized our approach for managing both communicable and non-communicable diseases. With better and effective control and prevention of communicable disorders, apparent rise in incidence and prevalence of a number of non-communicable diseases have attracted the attention of medical and public health professionals including the health planners and administrators.
Whilst communicable disorders remain significant in developing and less developed nations , collectively non-communicable disorders, particularly inherited/ genetic, contribute significantly to rising burden on mortality and morbidity in the developed world. Non-communicable disorders are wide ranging and multi-system including birth defects contributing to significant neonatal and infant mortality and morbidity. However, most non-communicable disorders of public health importance are late onset and remain a major cause for sustained morbidity and cause for early death. Major conditions in this category include obesity, diabetes mellitus, ischemic heart disease, stroke, common cancers (skin, lung, breast, colorectal and prostate), degenerative neurological diseases (motor neuron disease and multiple sclerosis) and neuropsychiatric diseases (dementia, bipolar depression, and schizophrenia). A number of genetic and genomic studies have provided strong evidence for genetic factors contributing to the causation and natural history of many non-communicable diseases. Whilst majority of the disorders are attributed to polygenic/ multifactorial inheritance with 50% or above heritability, a small but significant proportion is caused by high-risk Mendelian genetic conditions. Collectively are regarded familial with shared common life style and environmental factors.
The contribution of high-risk genetic heart conditions
A sizeable proportion, probably estimated to be about 10%, of all non-communicable diseases are accounted for high-risk genetic conditions with familial occurrence and recurrence following the Mendelian or monogenic inheritance pattern. Thus most non-communicable diseases are familial and inherited with a significant genetic or genomic component measured in terms of low, medium and high genetic risk.
Familial and inherited non-communicable disorders are now fast emerging as the global phenomenon. However, variation in the geographic and population-specific distribution remains unclear. In part this might reflect lack of awareness or insufficient numbers probably due to regional or country based epidemiology data surveillance system or strategic health policy focused on other common conditions, notably malnutrition, common infections, tuberculosis, human immunodeficiency virus (HIV) and other local health priorities. Thus available data might not indicate clearly incidence and prevalence of familial or inherited life-long disorders.
In the context of familial and inherited long-term conditions, many cardiovascular diseases deserve special consideration. These are collectively more prevalent and impose a huge burden on health resources with significant morbidity and young age mortality. In some conditions, risk for sudden unexplained death remains relatively high. Moreover, with increasing diagnostic and therapeutic avenues, most are amenable to specific diagnosis and targeted medical and surgical treatment. Most developed nations now enjoy benefits with improved survival rate and symptom free prolonged working long life contributing to positive socio-economic gains . Apart from complex polygenic inherited cardiovascular diseases (ischemic/coronary artery disease, hypertension, stroke), a number of high-risk cardiovascular genetic conditions are now managed by general or specialist clinical and health professionals, including primary care.
The high-risk cardiovascular genetic conditions include:
- structural developmental cardiac anomalies (e.g., ventricular septal defect, Fallott’s tetralogy, atrio-ventricular septal defect, truncus arteriosus etc.);
- cardiac muscle disease (e.g., hypertrophic and dilated cardiomyopathy);
- cardiac arrhythmic disease (e.g., long QT and Brugada syndromes);
- arterial and aortic vascular conditions (e.g., aortic/ arterial dilatation and aneurysm with dissection), and
- other multi-system genetic disorders with significant cardiovascular manifestations, for example familial hypercholesterolemia, Duchene/Becker muscular dystrophy, Marfan syndrome, Ehlers-Danlos syndrome, Fabry’s disease and systemic amyloidosis.
The remit and scope of GFHC include above inherited cardiovascular conditions (ICCs). Most ICCs can be diagnosed early with precision and managed by a combination of drugs and devices and surgical intervention . Advances in cardiovascular imaging combined with reliable properly validated biochemical and immunological biomarkers are routinely employed by cardiovascular and general physicians in the diagnosis and stratification of wide range of familial cardiovascular conditions. There are now several gene-molecule families etiologically associated with most monogenic/ Mendelian cardiovascular disorders. There are several next generation genome sequencing based diagnostic multi-gene panels available for confirmation of the disease causing specific gene mutation or pathogenic variants in major inherited cardiovascular conditions. Many genetic/genomic laboratories offer these services and have developed gene-disease specific genotype-phenotype databases. Most leading regional and teaching cardiovascular units in developed countries have multi-disciplinary teams (MDTs) managing patients and families with familial cardiovascular diseases. One of the important tasks of these dedicated MDTs includes advising and supporting the ‘at-risk’ healthy asymptomatic family members. Through systemic evaluation and genetic counseling processes, these anxious relatives are prepared and offered accurate predictive genetic testing. Those found to share the inherited specific gene mutation or the pathogenic variant are offered long term clinical surveillance (clinical examination, 12 lead electrocardiogram and ultrasound echocardiography), prophylactic medication (e.g., beta blockers), interventional cardiac (external or internal) devices (e.g. implantable cardioverter device- ICD) and in some cases by preventive surgical procedure.
Familial and inherited cardiovascular diseases are global and affect all irrespective of geographic and ethnic origin. It is a global phenomenon and requires a world wide high level strategic health approach. The whole group of conditions poses a major global challenge. The proposed Global Familial Heart Challenge (GFHC) is a new international initiative for raising awareness and developing regional and country specific health information, data resource and targeted specialist health service provision on ICCs.
Aim
To set up and develop the coordinated global network to deal with medical and health challenges of the familial / inherited heart disease.
Objectives
- To assist clinicians, health professionals, laboratory scientists and patient & family support groups to on the key health challenges of the familial and inherited heart disease- clinical diagnosis, laboratory genetic/genomic diagnosis, multi-disciplinary care and health surveillance, prevention and support.
- To develop a fully accessible clinically oriented database to include fully validated evidence-based information for clinical applications.
- To set up on-line access for the consumer (professionals, partners, patient and public) on qualified and validated information related to the key familial heart health challenges.
- To encourage and engage in applied research on management and treatment of familial/ inherited conditions in a cost-effective manner, including prevention; providing data for bio molecular research for a ’cure’.
- To strengthen the emphasis in public health to make sure that it encompasses some aspects of mapping genetic mutation and genomic variant patterns across various populations, and from this being able to provide some evidence to service providers regarding public health messages as opposed to individual case treatment.
Organizational Principles
The Global Familial Heart Challenge (GFHC) is a network of a number of clinical establishments, genetic/genomic laboratories, research centers and patient/ family support groups committed to caring and supporting patients and families affected with a familial/ inherited heart disease organized on the following principles:
- Each individual center, partner or professional of GFHC contributes on voluntary basis.
- GFHC does not have direct access to any patient clinical or research data or information.
- GFHC ensures that any information or data shared by the partner or participating organization is kept undisclosed as far as possible to avoid any breech of confidentiality or identity.
- GFHC supports the consumer- patient, family member, clinician, health professional, researcher or student engaged and/or committed to caring or supporting any one affected with a familial / inherited heart disease.
- GFHC functions through the consortium of several clinicians, health professionals, laboratory scientists, researchers and patient/ family support workers with these groups making recommendations for action on a participative and consultative basis
- The GFHC consortium is arranged on Regional and Country node basis to ensure that national regulatory and legal requirements are adhered to as well as all relevant social, cultural and religious norms are taken into account;
- Day-to-day administration will be under the supervision of the executive team selected from the consortium membership.
Administration
- The GFHC is administered by the core Executive team selected from the Consortium membership
- The GFHC has its own website page (www.Genomicmedicine.org/GFHC )
- The website has information on aims, objectives, consortium, membership, affiliations, consumer information and questionnaire.
- The GFHC will ensure working in parallel and partnership with already established databases network for ICCs, for example ClinGen, ClinVar (USA).
- The GFHC is financed through voluntary contributions and funding from leading professional and health organizations.
Partnership and Affiliations
- The GFHC works in close partnership with the Human Variome Project (HVP) through the International Scientific Advisory Committee (ISAC)
- It is anticipated that membership of the HVP/ ISAC will actively contribute to GFHC through discussions and advising based on the experience on similarly aimed projects like BRCA Challenge and Globin2020.
- The GFHC is affiliated with a number of national Institutes, Professional Organizations and Patient/ Family Support groups who are able to become partners/members of GFHC
Functions and Roles of GFHC
The GHFC will be service –oriented, aiming to fill the gap in many parts of the world for information related to an ICC or familial heart disease-
- Clinical phenotype
- Clinical Diagnosis – medical, biochemical and imaging
- Medical and surgical management including drugs, devices, interventions and preventive options
- Clinical genetic information- gene(s) and molecule(s), gene-specific variants, genomic variation (single nucleotide polymorphism, copy number variation).
- Research level information- for example ICC related gene-specific mutations, genomic variants, comparative genomics, epigenomics, metabolomics, pharmacogenomics etc.
The individual consumer, a researcher, patient or clinician, can approach GFHC with a specific enquiry or service. The consumer provides information and relevant professional input in relation to the question or service. The Executive team then, through an expert or the working group reviews the individual enquiry. The executive team may reply direct or refer to a participating center or a specific professional to deal with the specific enquiry or question. Enquiries on clinical care matters, health management and support, are referred to the lead executive for the Regional/ Country node.
Data analysis and Audit
Data and information developed by GFHC would be regularly reviewed and audited in conjunction with participating organizations and affiliated partners . The GFHC will utilize experience and information from similarly aimed and databases networks. For example, the colorectal and gastrointestinal cancer group, INSIGHT, has been very successful in its aims and objectives that largely echo the purpose and remit of the GFHC.
Executive plan
The GFHC is a major new initiative and will require carefully coordinated and planned approach. It is likely the project shall commence in 2017 subject to hosting and financial arrangements. It is envisaged that the whole project will take minimum 5 years.
The following time scale is proposed-
2017-2018: Consultations with proposed partners and participating regional and country node organizations; refinement of GHFC goals and objectives; determining of decision making structures and governance of GFHC; agreement of project scope and resourcing needs; review of current data base arrangements; development of plan to take things forward; identification of key national and international partners
Project applications for fund raising including grants from regional and international agencies
2019-2020:
- Setting up GFHC central base working with the host centre
- The executive team commences working
- Disease specific team working developed
- Ethical, legal and confidentiality policy of GFHC
2020-2022:
- Disease specific epidemiological Data/Information collection
- Genetic/ genomic mutation/ variant database for global access and use
- Familial/ Inherited cardiovascular phenotype ontology database
- Mechanisms and policy for consumers accessing and using GFHC resources
Annual Review/ Report
Progress and all activities of GFHC will be regularly reviewed on annual basis. All partners and participating organizations will receive the annual report. It is also envisaged that GFHC shall report progress and preliminary outcomes at designated international conference or relevant meetings, for example Biennial Human Variome Project conference, annual meeting of the Global Alliance for Genomics and Health (GA4GH) and major international human genetic/ genomic societies’ meetings.
Partners and Participating Organizations
The GFHC is a global effort hosted by the Institute of Medical Genetics, Cardiff University School of Medicine, Cardiff University, UK
Partners
Human Variome Project through the International Scientific Advisory Committee
Global Alliance for Genomics and Health (G4GH)
World Health Organization (WHO)
Participating organizations
The following organizations will be approached to ascertain their level of involvement and participation . Association and partnership will be variable with the GFHC. This might range from virtual professional recognition to joint regional and country-specific individually financed and managed projects on clearly defined objectives. Preliminary and informal discussions with some of these groups are encouraging with positive feedback.
The GFHC proposes to approach the following professional groups and organizations-
- Asia-Pacific Human Genetic Society
- Australasia Human Genetics Society
- Society for Indian Academy of Medical Genetics
- South African Human Genetics Society
- European Human Genetics Society
- British Cardiovascular Society
- Association for Inherited Cardiac Conditions
- British Heart Foundation
- ClinGen/ ClinVar
Regional/ National Accredited Genetic/ Genomic laboratories:
- Academic Medical Center, Amsterdam/ Prof. Arthur Wilde
- Center for Medical Genetics, University of Gent, Belgium/ Prof. Anne de Piepe & Dr. Julie de Becker
- Department of Medical Genetics, University of Antwerp, Belgium/ Prof. Bart Loeys
- Health-n-Code, Center for Cardiovascular Genomics, La Coruna, Spain/ Prof. Lorenza Montserrat
- Department of Cardiology, Post Graduate Institute for Medical Education & Research, Chandigarh, India/ Prof. Ajay Bahl