Genomic dissection of inherited cardiomyopathies: identifying alleles, genes and mechanisms, for patient stratification. (360G-Wellcome-107469_Z_15_Z)

I propose three complementary work packages: WP1. I will pursue a focused and highly-powered gene discovery programme using whole exome sequencing in families. I will study children with severe and early onset genetic cardiomyopathies and their unaffected parents, to identify potentially causative variants according to a recessive or de novo disease model. This will identify genes and pathways causing dilated cardiomyopathy (DCM), and immediately benefit the families concerned. WP2. I will b uild on my recent work studying the clinical implications of genetic variation in Titin in DCM. First, I will use recently-generated sequencing data from >90,000 individuals, alongside new statistical approaches, to identify features that discriminate disease-causing variants from benign variants. Second, I will follow a cohort with DCM who have implantable cardioverted-defibrillators in situ, to determine whether Titin variants confer increased risk of ventricular arrhythmia, as our previous w ork suggested. WP3. I will perform focused in vitro studies of a subset of penetrant variants found above, to develop skills in molecular and cellular phenotyping and genome engineering. These mechanistic studies are critical for understanding disease pathogenesis, and for the application of genetic data not only for diagnosing and stratifying patients but for developing new therapeutic approaches.