Genetics of cardiomyopathy

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Genes are instructions to make the building blocks of the cells that make up the human body. Novel technologies can read these instructions quickly and cheaply. These technologies are used in healthcare to identify genetic variants. These can be thought of like “spelling mistakes” which cause inheritable conditions by producing faulty building blocks. However, telling the difference between these spelling mistakes and normal variation in genes can be difficult. Therefore, many genetic variants are classed as ‘variant of unknown significance’ (VUS), which means we don’t know whether it is causing a disease or part of normal genetic variation.

A protein called Filamin C is a building block of muscle cells, including specialised muscle cells in the heart. Genetic variants in filamin C can cause inherited dysfunction of the heart muscle, known as cardiomyopathies. In some cases, they weaken the pumping function of the heart muscle so much that heart transplantation is required. In other cases, they can cause abnormal heart rhythms which can be life-threatening and even result in sudden cardiac death. Two families have been identified, where relatives carry the same genetic variant (M82K) in filamin C. In both families, weak heart muscles are observed in affected individuals; in one family there were also several sudden cardiac deaths. As this variant is currently classed as VUS, we cannot use this genetic information to tell relatives if they are at risk.

This project is led by Professor Katja Gehmlich and her team at the University of Birmingham, working closely with clinician scientists at the University of Glasgow, who are involved in the care of some patients with the genetic change. The project will use heart samples to see what goes wrong at a molecular level in the presence of this genetic variant. It is thought that filamin C will form lumps and change the composition of the muscle.

To test this, the team will create a ‘disease in a dish’ system, using a new technology to generate beating human heart cells in the laboratory, which carry the genetic variant. They will then analyse whether these cells also have weaker pumping function, what is causing it and whether their electrical function is affected.

Finally, they will test medications we think might be beneficial in this ‘disease in a dish model’ to get an idea which drugs might help to treat the patients in future.

If this method is successful, it will provide a template for the future for testing other genetic variants that contribute to issues with the heart muscle. It is also hoped that this project will provide the scientific evidence needed to re-classify the M82K genetic variant from a VUS to a known ‘disease-causing’ variant. This will allow other family members to be tested, so they know if they are at risk of heart problems in future. Awareness of genetic heart issues allows for people to access the best preventative care, to reduce the risk of serious complications and improve peace of mind.