Whole genome sequencing and analysis to identify new disease genes for hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy is a common and medically important inherited heart muscle disease. Genetic analysis using classical genetic approaches revealed that mutations in myofilament genes cause this condition in about 60% of affected families; this knowledge has led to major impacts on clinical care, including direct use of genetic testing. Our understanding of the pathways by which these mutations cause the condition has led to clinical trials of new medical therapies that are looking very promising. However, mutations in these genes are not found in around one half of affected individuals and families. New high-throughput sequencing approaches now make it possible for the first time to try to identify the remaining disease genes and we are embarking on a large-scale collaborative programme to sequence the whole genome in many hundreds of individuals.

This project will use bioinformatic and potentially functional genomic analysis to identify novel disease genes and their downstream consequences. Our group has an established track record in this area and will be able to deploy the necessary techniques to make important new discoveries (reviewed in Watkins et al. 2011; see also Carballo et al. 2009, Marston et al. 2009). This is likely to include statistical genetic analysis (in collaboration with Prof Martin Farrall) and potentially biochemical analysis of mutant proteins (in collaboration with Prof Charles Redwood), and/or creation and phenotyping of gene targeted models (in collaboration with Prof Houman Ashrafian (e.g. see Oliveira et al 2012, Ashrafian et al. 2012)).