Genetic modifiers of hypertrophic cardiomyopathy in the Old Order Amish

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disorder and the most frequent cause for sudden cardiac death in the young. Characteristic features are thickening and scarring of the heart muscle which can result in abnormal heart rhythms and heart failure. In over 50% of cases a genetic cause can be identified and several hundred different mutations have been shown to cause the condition. However, even amongst family members who carry the same mutation, extensive variation in how severely the individuals are affected exists. Some members of the family might have a very thickened heart muscle or die suddenly and others might have no signs or symptoms. The mechanisms leading to the thickening of the heart muscle are not very well understood and even less is known about why there is such variation in severity. However experts in the field agree that this variation is most likely caused by a combination of environmental and additional genetic factors.
The Old Order Amish population in North-eastern Ohio are a rural, genetically isolated population descended from a limited number of founders who emigrated from Europe in the 18th century. We have established a close relationship with the Amish community through a long running project (Windows of Hope) to investigate inherited diseases which occur within the community. As part of this project we previously investigated 10 Amish infants with a severe form of HCM. We discovered that the disease was caused by mutation of both copies of a gene known to be involved in HCM (MYBPC3) and that carriers of a single copy of this mutation have 'typical' signs of the adult form of the disease. Unfortunately this mutation is common in the Amish community and represents the largest collection of individuals with the same HCM mutation known. (. Recently we undertook detailed studies of relatives of the infants with severe HCM who carry one copy of the mutation. We observed that these individuals show the typical variability in severity seen in HCM. We intend to investigate a total of 200-250 gene carriers and assess them with a comprehensive cardiological evaluation including ECG, ECHO scan and 24 hour ECG monitoring. This will be the largest familial cohort sharing the same HCM causing mutation ever described. We will then perform detailed genetic testing of their DNA with the newest technology in genome analysis that is available. We intend to find additional variations or changes in the DNA of people who carry the MYBPC3 mutation which predispose them to developing severe disease, or which protect them from developing severe disease despite the fact that they carry the causative mutation. The Amish population is particularly suited for this sort of research as they have a 'homogenous' genetic background, which means their DNA differs much less than individuals of the general population and also because they have such similar life-styles which means there is less environmental influence. We will then go on and see whether these genetic modifiers that we discover in the Amish population are also present in an unrelated cohort of patients with HCM, that have been seen at either St George's or the Brompton Hospital. This will further validate our results and test whether our findings are applicable in the general population. The identification of genetic modifiers would greatly contribute to our understanding of the different disease processes in HCM and might translate into novel approaches for prevention and therapy of patients affected by HCM.

Hypertrophic cardiomyopathy (HCM) is the commonest inherited cardiovascular disorder and cause of sudden cardiac death in the young. Characteristic features include unexplained ventricular hypertrophy, myocyte disarray and interstitial fibrosis and several hundred causative mutations mainly in genes encoding sarcomeric proteins have been identified. Significant variation in phenotypic expression exists even amongst carriers of the same mutation within one family. Although the mechanisms underlying this phenomenon are poorly understood, they are likely to involve genetic modifiers. We have previously described a cohort of 10 infants in the Amish community in Ohio affected by severe HCM which were found to be homozygous for a splice site mutation (c.3330+2T>G) in MYBPC3. Our investigation of heterozygous gene carriers indicates that 11/41 (27%) had an intraventricular septal thickness in diastole (IVSd) over 15 mm and 3/41 (7%) had an IVSd over 20 mm, compared to none in the control group. The Amish are a founder population with a very homogenous life-style, complete genealogical records and large families and therefore constitute an ideal human model for modifier studies. We intend to recruit an additional 200 gene carriers who can all be interlinked through an extensive pedigree and evaluate them with ECG, ECHO and ambulatory monitoring which will result in the phenotypic description of the largest familiar cohort to date sharing the same HCM mutation. With a combined strategy of whole exome sequence analysis and a genome wide association study we will then identify genetic modifiers of the phenotype. This will improve our understanding of the pathophysiological mechanisms involved in the disease process and potentially identify novel targets for the development of treatment strategies to influence the natural history of HCM. Putative modifiers will then be investigated in a replication cohort of 340 unrelated genotyped HCM patients.

Our research findings will have an impact on the following people and areas:
1. The Amish community
We are offering free genetic testing for the MYBPC3 mutation (which will be corroborated in a CLIA approved laboratory) and a comprehensive basic cardiological assessment to relatives of affected family members. Many Amish people have no health insurance and do not seek medical attention from doctors or hospitals. In the last 11 years the members of the Windows of Hope project have established a solid relationship with the Amish community which has resulted in mutual respect and trust. This allows us to identify carriers of the HCM mutation who would normally be undetected and recommend to those family members that they should formally be assessed in a Cardiology clinic. Appropriate treatment can then ensue. We will also provide genetic counselling and education on inherited cardiac conditions.
2. Patients affected by hypertrophic cardiomyopathy
Currently the mechanisms leading to the expression of the highly variable phenotype in HCM are poorly understood. Our study might improve our understanding which could have an impact on patients with HCM in the following areas:
a) Genetic modifiers for severity of HCM might be used as part of the risk stratification in HCM when determining who might benefit from an internal defibrillator. More patients at risk might receive this life saving treatment and fewer devices might be implanted in patients that are less at risk. This could save lives and at the same time improve cost effectiveness (5-10 years).
b) Better understanding of the mechanisms leading to hypertrophy, the development of atrial and ventricular tachyarrhythmias and identification of risk factors for heart failure and sudden cardiac death will improve our care for patients with HCM in general. Appropriate treatment might be initiated at an earlier stage before the occurrence of complications (eg embolic stroke after atrial fibrillation developed) and more accurate estimation of prognosis and disease progression might be possible (within 5 years).
c) Improved knowledge about the mechanisms involved in the disease process will also contribute to the identification of novel treatment strategies that will benefit patients in the future by targeting specific pathways and altering the natural history of disease rather than just alleviating symptoms like current treatments do (5-10 years).
3. Academic peers
The phenotypic decription of the largest HCM cohort to date and identification of genetic modifiers in HCM will offer unique insights into the pathophysiological mechanisms of the disease process and be the basis of many future research projects (see section Academic Beneficiaries).
4. Government bodies
A better understanding of the mechanisms leading to the different pathologies in HCM and the identification of genetic modifiers will help government bodies to produce valid and informed recommendations and guidelines on risk stratification and treatment of HCM (5-10 years).
5. General population
Improved risk stratification and earlier initiation of therapy which changes the natural course of disease and results in less morbidity and mortality will reduce healthcare costs for patients with HCM. The money saved can be spent in other areas and therefore the wider community will benefit as well.
5. Colleagues and collaborators
Conducting this collaborative and interdisciplinary research study will provide learning opportunities for everyone involved. This will enhance the understanding of other specialties and strengthen future collaborations.
6. Myself
I will gain a large asset of generic research skills, a solid understanding of how genomic technologies may be applied to address a research question and expertise in hypertrophic cardiomyopathy and inherited cardiac disorders. These will all be invaluable assets for future research projects and my career as an academic cardiologist.