Genomic profiling of Cardiomyopathy in Malaysia

Inherited cardiomyopathy is one of the most common causes of heart failure. The most common forms are Hypertrophic Cardiomyopathy or HCM, which affects 1 in 500 of the population, and dilated cardiomyopathy or DCM, which affects 1 in 2500. Individuals with cardiomyopathy may not be aware of the condition until they develop complications. To date, there is no cure for these diseases and patients are mainly treated symptomatically. Most of systematic genetic studies of HCM and DCM have focused on North American or Western European patient populations. This planned work will extend initial findings that some predominant mutations reported in Caucasians are absent in the Malaysian population and provide a comprehensive analysis of the genetic profiles of Malaysian cardiomyopathy patients. We hope the study will identify significant variants in the Malaysian population and provide valuable information to improve the clinical aspects of cardiomyopathy, including early diagnosis, prognosis and genetic counselling for affected families, in Malaysia. Overall, it will lead to improvement of the welfare of the population of Malaysia by improving the diagnosis and clinical management of cardiomyopathy in Malaysia with lasting benefits for patients and their families.

Familial cardiomyopathy (CMP) is one of the most common causes of heart failure with a prevalence of 1 in 500 (hypertrophic cardiomyopathy, HCM) and 1 in 2,500 (dilated cardiomyopathy, DCM). Individuals with CMP may not be aware of the condition until they develop complications. To date, there is no cure for CMP and patients are mainly treated symptomatically. Therefore, the study of genetic predisposition and its functional impact on CMP pathogenesis is essential for disease diagnosis and management. The bulk of systematic studies have focused on North American or Western European patient populations. This planned work will provide a comprehensive analysis of the genomic profiling of Malaysian cardiomyopathy patients using the clinical and genetic expertise of the University of Malaya combined with the genomic and functional experience at the University of Oxford. A total of 300 patients will be recruited from the University Malaya Medical Centre (UMMC) and the Malaysian National Heart Institute (IJN). We will use whole-genome sequencing analysis and evaluate the impact of the major mutations on disease development via an in-silico approach. WGS data will be analysed using a bespoke bioinformatic pipeline tuned to synchronise variant calling with existing CMP variant databases; novel variants will be interpreted in the context of the ACMG guidelines. The distribution of mutations will be analyzed for association with the clinical manifestations. The structure-function properties of the selected novel variants will be evaluated in vitro to gain insight into disease mechanisms. We hope the study will identify significant variants in the Malaysian population and provide valuable information to improve the clinical aspects of cardiomyopathy, including early diagnosis, prognosis and genetic counselling for affected families, in Malaysia.

Who might benefit benefit from this research?

Top of the list is Malaysian cardiomyopathy patients, as so little is known at present regarding the genetic architecture of their disease. Then cardiomyopathy patients worldwide, this disease is highly heterogeneous in terms of pathogenic genes and variants and the steady accumulation of variant data can allow clinicians to improve the quality and confidence in their prognostic advice when interpreting previously unreported variants in known pathogenic genes. Finally, all those who have their genomes sequenced (not least the 5 million genomes planned by Genomics England), in whom variants in cardiomyopathy genes will be found "incidentally", it is only by having extensive databases of variants linked to cardiac health records that we can make sense of this data in a timely manner.

How might they benefit from this research?

Documenting pathogenic genes and variants in Malaysian cardiomyopathy patients can befit individuals by improving prognosis by periodic clinical surveillance with early treatment (drugs, pacemakers, implantable cardioverter defibrillators) to avoid life-threatening abnormal heart rhythms and ward off heart failure. Cascade screening programs can be implemented to bring comparable benefits to blood relatives of cardiomyopathy patients. There is the potential for similar benefits for cardiomyopathy patients worldwide as well as all those struggling with "incidental findings".