Lack of Genetic Diversity in Reference Groups Leads to Misdiagnoses

A new study has uncovered that a gene variant common in Oceanian communities was misclassified as a potential cause of heart disease, highlighting the risk of the current diversity gap in genomics research which can pose a greater risk for misdiagnosis of people from non-European ancestries.

Led by the Garvan Institute of Medical Research and published in the European Heart Journal, the researchers describe the cases of two individuals of Pacific Island ancestries who carry a genetic variant previously thought to be a likely cause for their inherited cardiomyopathy, which the team found to be common among healthy individuals from Oceanian regions.

Without greater inclusion of people of different ancestries, the benefits of genomics will continue to leave people of non-European descent behind, perpetuating existing gaps in healthcare.

Our study reaffirms the dangers of having a lack of genetic diversity in genomic reference groups and points to our urgent need to invest time and resources to ensure no community is left behind."

Jodie Ingles, Senior Author Associate Professor, Head of the Clinical Genomics Lab and Director of the Genomics and Inherited Disease Program at Garvan

Rare Gene Variant Found to be Common

Between the DNA of any two people, there are millions of letter differences, or genetic variants. These variants determine our looks, how our body functions, but they can also influence our risk of disease, including some of the most common – heart disease, diabetes and some cancers.

While scientific advances in genomics have been transformative for our ability to diagnose and treat disease, most genetic studies have focused on people of European descent.

In the current report, Associate Professor Ingles' team at the Garvan Institute investigated a genetic variant they found in two people with cardiomyopathies, who underwent research-based whole genome sequencing at a Sydney clinic. Cardiomyopathies are potentially fatal inherited heart conditions that make it harder for the heart to pump blood around the body, and affect up to one in 500 people.

The researchers found that the variant, in the cardiac troponin T gene, which plays a role in regulating heart muscle contractions, is extremely rare in large international population genomic databases.

"This meant that among seemingly healthy people, the variant is not often present. This can indicate it is the cause of an inherited disease, and indeed numerous clinical testing labs had already flagged this as a potential causative variant," explains Dr Alexandra Butters, first author of the study.

"We became suspicious about this variant being the cause of the patients' cardiomyopathy, and when we investigated this further with colleagues who had more genomic reference data of seemingly healthy individuals from various Oceanian regions (comprising Australasia, Melanesia, Micronesia and Polynesia), we found this variant to be really common – 3-4% of the population."

"This is far too common to be the cause of an inherited cardiomyopathy and indicates this is a benign genetic variant. We've since updated this in publicly available databases to avoid families getting incorrect genetic information," says Dr Butters.

When the researchers investigated the variant further, they found it to be also present in Neanderthal DNA, which speaks to how long this variant has been in the population and supports it as unlikely causing disease.

The Genomics Equity Gap

"The variant was listed as rare and potentially pathogenic because the datasets we use to understand common and rare genetic variation in healthy people contains predominantly data from people of European background," Dr Butters adds. "This means we don't necessarily know what is common and rare across historically under-represented ancestry groups, such as those from our regions. The danger of considering this as a cause of disease is that we could then incorrectly use it to tell family members they are or are not at risk of developing disease. That has potential for harm."

Associate Professor Ingles says: "The reality in the clinic today is that if I'm seeing a family of non-European ancestry, we are less likely to be able to make a genetic diagnosis following genetic testing, because we don't well understand what is truly rare genetic variation in these populations that have never historically been included in genomic research. This means those families miss out on the benefits of a genetic diagnosis, but also there is a chance of misclassification and potential harm."

"Our study underscores the critical need for large, diverse and openly accessible genomic reference databases to ensure we can accurately interpret variants and that we maximise the value of genetic testing."

Focus on Underrepresented Groups

A research program addressing the current gaps in genetic research at Garvan is OurDNA, led by the Centre for Population Genomics, a joint initiative of Garvan and the Murdoch Children's Research Institute in Melbourne. The team is enrolling people of ancestries that are underrepresented in the existing genomics databases, to establish the first Australian large-scale genomics resource to address the critical gap in genetic research representation for Australia's multicultural population.

"Australia is home to one of the most diverse populations in the world, but the representation of many Australian communities in global genetic research has been low," says Professor Daniel MacArthur, Director of the Centre for Population Genomics. "OurDNA has the potential to transform the way we diagnose and treat rare diseases for everyone."