Investigating the causes of mutation-negative hypertrophic cardiomyopathy: Role of cryptic RNA mis-splicing in myosin binding protein C (MYBPC3)

Hypertrophic cardiomyopathy (HCM) is defined as left ventricular hypertrophy in the absence of abnormal loading conditions. It is the commonest genetic heart disease and a major cause of sudden cardiac death and heart failure.

It is usually inherited as an autosomal dominant genetic trait but the yield of genetic testing is less than 60%, even in patients with a family history.

Furthermore, when the causal genotype is known, phenotype associations remain poorly defined and currently have limited clinical actionability.

These gaps in knowledge expose individuals and families to uncertainty about diagnosis and their future health and limit opportunities for disease modifying therapeutic discovery.

The aim of this project is to explore the importance of previously understudied RNA mis-splicing non-coding and exonic genetic variation in myosin binding protein C (MYBPC3).

Our preliminary quantitative analysis of sequencing variants in HCM has identified a number of cryptic RNA mis-splicing variants in this gene.

We seek to confirm these findings in 2,000 HCM patients previously screened for mutations in established HCM genes and will test the functional impact of selected MYBPC3 variants by characterisation of cardiomyocytes differentiated in vitro from patient derived induced pluripotent stem cells and CRISPR/Cas9-edited isogenic controls.