Research into DCM at the Institute

Professor Fatkin’s research is primarily focused on understanding the genetics behind inherited cardiomyopathies like DCM.

When Professor Fatkin started researching DCM more than two decades ago, genetics analysis was in its infancy, time consuming, and involved a lot of guesswork as to which genes to study.

“Back in those days, there was no such thing as genetic testing for DCM because we were still at the stage of discovering what the important genes were,” says Prof Fatkin.

To investigate this question, Professor Fatkin and her team began studying Australian families where multiple members of the family had DCM, suggesting an inherited gene defect might be at play.

The aim was to start identifying the genes involved in DCM so they could understand how DCM develops at the molecular level, identify young family members at risk of developing DCM in the future, and potentially develop targeted therapies to slow down or reverse disease progression.

Professor Fatkin says: “Over the years, we have worked with many families affected by DCM. For example, we have undertaken several trips to see families in rural areas where there is limited access to screening tests to check heart function. We take our portable echo machine and spend a few days echoing grandmas and babies and everybody in between to check their hearts for signs of the reduced pumping action of the heart muscle that is associated with DCM.”

Discovering the link between DCM and mutations in the TTN gene

After years of sequencing and genetic analysis, in 2015 Professor Fatkin and her team were part of a breakthrough global, collaborative study of 5,267 patients led by Harvard Medical School, Imperial College London and Singapore’s National Heart Centre that confirmed that mutations in the TTN gene that truncate, or shorten, the key heart protein called ‘titin’ are an important cause of DCM.

“We now know that this is most common type of genetic mutation associated with DCM - about one in every five families we are studying has a truncating TTN variant,” says Professor Fatkin.

“The sequencing technology has advanced so much that we can now look at a person’s entire genetic makeup in a single test, aka whole-genome sequencing, rather than painstakingly sequencing one gene at a time.”

Uncovering the benefits of whole genome sequencing over standard genetic testing

In 2018, scientists at the Victor Chang Cardiac Research Institute and the Garvan Institute of Medical Research through their collaborative National Cardiogenomics Program, published a study that looked at the entire genetic make-up of 42 patients with DCM to analyse the benefits of whole genome sequencing vs standard testing.

The study found that whole genome sequencing, which looks at a person’s entire DNA sequence, was more sensitive and more comprehensive than traditional testing.

Whole genome sequencing was found to be able to identify the genetic causes of more cases of DCM than a standard clinical test, which only looked at a restricted set of heart disease genes.

“We've got results in all sorts of genes that we can now give back to our patients.”

Understanding the role of DMD gene variants in DCM

In 2023, Professor Fatkin and her team published a study on the link between DMD gene variants and DCM. The study showed that DMD gene variants are an infrequent but important cause of DCM, particularly in young males.

DMD-associated DCM is an X-linked disease, which means it is caused by a mutation in a gene on the X chromosome. X-linked diseases tend to affect males. In females - who have XX chromosomes, compared to males who have XY chromosomes - having a second normal copy of the gene means they are usually unaffected by the disease or only mildly affected.

The team’s work highlighted the importance of appropriate genetic testing strategies to distinguish DMD-associated DCM from types of DCM that are inherited in an autosomal dominant pattern, where the gene with the mutation is located on a non-sex chromosome.

“Accurate identification of DMD-associated DCM is essential to ensure appropriate treatment and genetics testing to detect at-risk family members,” says Professor Fatkin.

“This is of particular importance as we know that DMD-associated DCM is associated with severe disease, including high rates of heart failure, heart transplantation and ventricular arrhythmia.”

Exploring how genetics, other illnesses and lifestyle factors impact DCM severity

Professor Fatkin and her team are currently studying how the unique combinations of genetic background, other illnesses and lifestyle factors can increase the severity of DCM in individuals who have TTN gene variants.

“There’s a big range in how these variants affect different people - some people present with heart failure in their twenties and thirties and other people are pretty healthy until later in life,” says Professor Fatkin.

“Now we are trying to understand whether some of these environmental and lifestyle factors – like alcohol intake, obesity, diabetes, certain chemotherapy drugs etc - have additive effects to the gene variant.

“We now realise that looking at the whole person and their individual context is really important to understanding how gene mutations combine with other factors to affect heart function.”

What impact has Professor Fatkin’s research had on people with DCM?

Genetic testing for inherited cardiomyopathies is now routinely performed in cardiac genetic clinics around the world – changing the outlook for those with this potentially deadly disease by ensuring disease-causing rare genetic variants are identified early.

“With advances in knowledge and advances in sequencing, we can fill in the gaps and give families practical recommendations,” says Professor Fatkin.

While treatments that reverse the effects of the underlying gene mutation are not currently available for most families, Professor Fatkin says early identification of family members who carry a harmful gene change means clinicians can now treat and monitor the patient – including medication, lifestyle changes and regular echocardiograms – before symptoms appear.

Professor Fatkin says: “Prior to genetics most people just waited until they had symptoms and then went to the doctor and had heart failure therapy. Now we can test the younger generations to see who’s at risk, identify early changes in heart muscle function, and start early treatment.

“We can talk to each person and work out what is contributing to their risk in terms of their lifestyle. We can also do pregnancy monitoring – as we know the risks of cardiomyopathy can increase during late pregnancy and soon after giving birth. Then there’s the psychosocial side – it can help relieve some of the anxiety associated with DCM when we can tell people which gene mutation is at fault.

“We can also tailor advice to the specific gene mutations. For example, there are some genes such as the LMNA gene that are often associated with rapid disease progression so we might err on the side of caution and choose early implantation of a defibrillator or early heart transplantation rather than just waiting till people’s health deteriorates.”

In the future, gene therapy may enable the gene mutation itself to be fixed to prevent DCM.

Key Collaborators and Funders of this research

Professor Fatkin and her team in the Institute’s Inherited Heart Disease laboratory have worked on DCM research with the Institute’s Deputy Director and Head of the Cardiac Electrophysiology laboratory Professor Jamie Vandenberg and a strong network of national and international research collaborators, including the St Vincent’s Hospital cardiology department, the Garvan Institute of Medical Research, major cardiomyopathy centres across Australia, and Harvard Medical School.

Key funders of Prof Fatkin’s DCM work include the Medical Research Future Fund (MRFF), NSW Health and the National Health and Medical Research Council (NHMRC).