This article has been updated to clarify that the variant is now classified as benign in ClinVar.
NEW YORK – A genetic variant thought to potentially cause inherited cardiomyopathies may actually have no disease relation after a research team at Australia's Garvan Institute of Medical Research found it to be common among Oceanian populations and rather well evolutionarily conserved.
In the study published this week in the European Heart Journal, two individuals diagnosed with cardiomyopathies and whose ancestors came from Oceania (a region composed of the Australian continent and the Pacific Islands) underwent research-based whole-genome sequencing, which revealed that each had a variant in the cardiac troponin T (TNNT2) gene, called TNNT2 c.571-1G > A (rs483352835). The two individuals were then told that this was likely to be the cause of their potentially fatal inherited cardiomyopathy.
Researchers at the Garvan Institute studying the genetics of cardiomyopathies, however, felt skeptical. "It is a seemingly rare variant in a gene with robust gene-disease association for inherited cardiomyopathies, especially hypertrophic cardiomyopathy," Jodie Ingles, director of the Genomics and Inherited Disease Program at Garvan and the study's corresponding author, said via email.
The allele frequency of rs483352835, or the rate at which it appears in a given population, amounts to only a fraction of a percent in people of European and Asian ancestries whose data is stored in several genomic databases, including gnomAD, All of Us, and the UK Biobank. These sources, however, have a known bias towards people of European ancestry, whereas, as Ingles explained, Australia features "fairly unique Pacific and Indigenous populations which are virtually absent from any genomic reference data or genomic research studies."
Because of this, Ingles, who is also a practicing cardiac genetic counselor, said that she always asks for ancestry of patients for whom she interprets genetic results. "It is really important to know whether this person is from an ancestry group that is represented in genomic data," she said.
By scanning across databases and enlisting the help of the Pacific Islands Rheumatic Heart Disease Genetics Network and other researchers, Ingles and her team estimated an allele frequency of roughly between 4 and 9 percent among people of Polynesian ancestry and 3.5 percent across a wider group that included people of Melanesian and South Asian ancestries.
"I think we can have a false sense of security from the extremely vast datasets that are available, such as gnomAD v4," Ingles said. "This variant is rare in those datasets, and yet we think present in [roughly] 4 percent of those with Oceanian ancestry."
Yusuf Henriques, founder and CEO of bioinformatics company IndyGeneUS AI, called Ingles' work "a fascinating study with important implications for medical genetics," and called the fragmentation of genomic data across institutions, countries, and proprietary systems, a "persistent issue" in genomic research. "This fragmentation makes it difficult to identify population-specific genetic variations, increasing the risk of misclassification," Henriques said.
One of IndyGeneUS' key efforts is to help advance African genomics. Last year, the Delaware-based company partnered with South Africa's Aurum Institute to sequence up to 3 million human samples in an effort to study infectious and noncommunicable diseases, which will be stored at a biorepository in Johannesburg.
Because the indigenous peoples of Australia and Papua New Guinea derive slightly over 3 percent of their DNA from Neanderthal ancestry, Ingles and her team also examined data available on those ancient genomes for evidence of the variant's evolutionary conservation. They found it in two Neanderthal genomes but in no Denisovan genomes, suggesting that it may have arisen some 130 to 145 thousand years ago, after Neanderthals diverged from modern humans.
To the Garvan researchers, this degree of evolutionary conservation provided more evidence against the variant's likely pathogenicity.
The value of diversity in study populations has been highlighted numerous times over the years, ranging from clinical trial participants to the cell lines used in basic research. Studies repeatedly uncover previously unknown disease-associated variants in non-European populations, underscoring the need for diversity as a means of ensuring equitable access to the benefits of genomic research.
"I think what is really important to highlight though, is that this is not a matter of waving our hands and saying we need more ancestral diversity," Ingles said. "To do it properly is a really challenging problem. None of our research frameworks, ethics, funding agencies, etc. appropriately enable the type of deep community engagement needed to properly do this. And then for Indigenous communities where there have been previous mistakes made, this community engagement will take as long as it is required to."
In fact, efforts are underway to build trust with such communities and ensure that they are not barred from receiving the benefits of genomic research. The Canadian Precision Diagnosis Study and Silent Genomes Project, for example, both seek to leverage whole-genome sequencing to improve indigenous Canadians' access to precision medicine.
Ingles' work supports another such genetic diversity effort called OurDNA, which is led by the Centre for Population Genomics, a joint initiative of the Garvan Institute and the Murdoch Children's Research Institute in Melbourne. OurDNA is now actively recruiting people in Australia's Filipino and Vietnamese communities, and will soon begin recruiting members of the Sudanese and Lebanese communities as well as the Oceanic Samoan, Fijian and Tongan communities.
Other efforts to improve the diversity of genomic datasets include Link23, an effort supported by Genomics England and Data Science for Health Equity. This initiative aims to foster global collaboration in genomic health equity and providing researchers with analytical tools to do so.
Based on their findings, ClinVar recently classified rs483352835 as a benign variant.
IndyGeneUS AI's Henriques said that Ingles' study underscores the necessity of diverse genomic databases for both scientific accuracy and clinical applications, and that the misclassification of the TNNT2 variant provides a clear example of how Eurocentric genomic research can lead to misdiagnoses in non-European populations.
"A key question arising from this study is how widespread similar misclassifications are across other conditions due to the lack of representation in genomic databases," Henriques said. "How many other 'pathogenic' variants might actually be benign within certain populations?"
Ingles and her team wrote in their study that although addressing existing barriers to research participation and achieving ancestral diversity will require significant effort and resources, the work is essential for ensuring that all people benefit from genomic medicine equitably.
"It’s kind of mind blowing that a variant so obviously benign could be almost absent in the datasets we currently use to define rarity," Ingles said.