Dr Chai-Ann Ng in the Institute's Innovation Centre

Star Scientist - Dr Chai-Ann Ng

Providing answers to families with inherited heart disorders

10 July 2024

Despite great advances in genome sequencing technologies, people living with genetic heart arrhythmia conditions are often left in the dark about the specific cause of their disease.

This can be distressing for patients as well as family members who may also have inherited the mutation but are left in the dark

Dr Chai-Ann Ng is hoping to change that by providing families with answers so that anyone at risk can be treated and monitored appropriately.

It’s complex work involving the screening of thousands of genetic variants in the Institute’s Innovation Centre.

You’ve recently helped develop a new test that may help families with the condition Congenital Long QT – can you tell us more about it?

Dr Chai-Ann Ng

Long QT Syndrome is a heart rhythm disorder that can cause sudden cardiac death and generally affects people who are otherwise fit and healthy. It’s relatively rare – around one in 2000 Australians will have this condition.

When someone is diagnosed with long QT syndrome, a genetic test will be recommended to try to identify the specific cause. For some patients, a genetic variant will be found that we can be certain is the cause of the disease. For others, a variant is found that we are confident is benign. But for the majority, a variant will be identified for which we do not have enough evidence to establish whether it is benign or pathogenic but instead is classified as a variant of uncertain significance (a VUS). A VUS result is often distressing for patients as it can lead to diagnostic delays and prevent family screening.

My team, which is led by Professor Jamie Vandenberg, thought it was vital that we develop faster and more accurate ways to functionally characterise variants and minimise the number of variants that remain classified as VUS.

How does this new long QT genetic test work?

The traditional way of characterizing the function of ion channel gene variants is to use an electrical technique called voltage-clamp electrophysiology. This is a difficult and labour-intensive technology. What we have done, is developed a high throughput automated patch clamp assay (an investigative procedure), using the Institute’s Innovation Centre’s SyncroPatch machine. Rather than taking a few weeks-months to characterize each mutant, we can now study up to 10 variants a day. This assay provides functional evidence to support classifying a variant as either pathogenic or benign. But we still need to then pass that data back to genetic counsellors who can integrate our data with the clinical data before making a final determination as to whether the variant can be called pathogenic or benign.

What patients will benefit from this test from your team?

We perform functional testing for patients that have VUS in genes known to cause inherited arrhythmia syndrome, such as Long QT and Brugada Syndrome. Clinicians or clinical testing services in Australia that look after these patients will reach out to me if they identify a VUS in a cardiac ion channel gene. I am also collaborating with Invitae Corporation to perform a large-scale reclassification of VUS in ion channel genes by incorporating variant-specific functional data with their clinical datasets which has the potential to provide updated genetic diagnosis for hundreds of patients.

Are there some genetic variations that are more dangerous than others?

Recently, we have shown in a large multinational cohort of more than 1000 long QT syndrome patients that genetic variants which cause up to 90% loss of function are associated with a more than 10-fold greater risk of major cardiac events (arrhythmia, sudden death) compared to patients who have variants that cause only moderate loss of function (<50% loss of function). We are now collaborating with researchers from the Vanderbilt University Medical Center in the US to integrate our variant-specific functional data with clinical data to see if we can develop individualised risk calculators and thereby help tailor monitoring, medication, and treatment accordingly.

Dr Chai-Ann Ng with Professor Jamie Vandenberg

Where did your fascination with science start and where it’s headed?

I was born just outside of Kuala Lumpur in Malaysia, and during my high school education I chose the science stream and subsequently enrolled in a Bachelor of Chemistry at La Trobe University in Melbourne. When I arrived in Melbourne, in 2000, I remember thinking that it was warm just like Malaysia. I joined the Victor Chang Cardiac Research Institute in 2009. During my first decade working at the Institute, we didn’t have all the technology that we have now, which limited the clinical impact of our research. It was back in 2016 at a Gordon Research Conference on ion channels, that I was first introduced to automated patch clamp electrophysiology – the SyncroPatch 384PE, which can perform 384 voltage clamp experiments in parallel. The first SyncroPatch in the southern hemisphere was later installed at the Institute’s Innovation Centre in 2018 and I used it to establish the world-first functional genomics assay for inherited arrhythmia syndromes in 2020. Since then, I have been determined to try and help as many patients as possible and in 2022, we were fortunate to receive a large Genomics Health Future Missions grant to enable us to establish clinical-grade functional assays for a wide range of inherited arrhythmia syndromes, as well as inherited epilepsy syndromes, familial hemiplegic migraine, episodic ataxia type 2, cystic fibrosis, and polycystic kidney disease. I am very excited and looking forward to establishing the Institute as the functional testing centre in Australia for channelopathies.

You’ve clearly made Sydney your home, what do you do outside of work?

I have two very active children – Jayden and Megan who are turning 11 and eight. So, it’s kids’ stuff outside of work like any other family. They both like to go to the beach very much and Sydney has plenty of beautiful beaches to explore.

Acknowledgement of Country

The Victor Chang Cardiac Research Institute acknowledges Traditional Owners of Country throughout Australia and recognises the continuing connection to lands, waters and communities. We pay our respect to Aboriginal and Torres Strait Islander cultures; and to Elders past and present.

Victor Chang Cardiac Research Institute - The Home of Heart Research for 30 Years