Contributed Commentary by Gary J. Latham
July 26, 2021 | During the second convention of the Medical Committee for Human Rights in 1966, the Rev. Dr. Martin Luther King stated, “Of all the forms of inequality, injustice in health is the most shocking and the most inhuman.” Yet more than 50 years later, disparities accessing accurate, actionable results from genetic tests continue to challenge patients and the diagnostic community. To achieve more equitable healthcare for all participants and to build confidence in genetic testing, we must address this challenge with today’s tools and a contemporary resolve. There has never been a better time to carry out this imperative; our technologies and information are unrivaled in history, and the appreciation of our responsibility is only deepening.
The sources of health disparities are complex, and diagnostic testing is just one waystation on what is often an exhausting trek for many patients and their families. We know that testing has outsized value in guiding and managing patient care, and thus is similarly vital in providing uniform, high-quality results across different populations. For example, whether a person gets a reliable test result may be a function of the test provenance: Was it designed to target genetic variants for the disorder of interest while also considering that person’s ancestry and its impact? Many tests routinely used by labs to identify rare diseases or determine carrier risk were designed from public genetic databases built with information primarily from people of European descent. Today’s genetic tests are highly effective for these populations, but may not be nearly as useful across other ancestral groups.
To put some numbers around this, a 2009 study analyzing the representation of different ancestries in genome-wide association studies (GWAS) found that only 4% of samples were taken from people of non-European lineage. As of June 2021, the GWAS diversity monitor shows about 12% participation from non-Europeans. Although that’s progress, it is not nearly enough to even out the accessibility of genetic testing and precision medicine more broadly. Fortunately, there is reason to believe things are improving.
A Real-World Example
Let’s consider the example of genetic testing for cystic fibrosis (CF). There are two groups of people who need CF testing: patients with the condition and people interested in finding out whether they are carriers who might have a child with the disease. For both groups, testing involves identifying pathogenic variants in the CFTR gene.
One of the best known and most powerful resources for making connections between genotype and phenotype in CF is the CFTR2 database. This resource curates data from nearly 90,000 patients and categorizes more than 350 disease-causing mutations. However, 95% of people represented in the database are of European descent.
CF is one of the only diseases for which universal carrier screening is recommended, regardless of a prospective parent’s ancestry. That means that targeted genetic tests designed from the CFTR2 database — the most common information source for CF genetic tests — are most accurate for people of European ancestry, and less accurate for everyone else.
The advent of large-scale sequencing studies for a broad range of ancestries is now giving us a more detailed view into the prevalence of CF mutations in non-European populations. Thanks to publicly available data released from recent studies, we finally have critical information to complement sources such as the CFTR2 database.
We can use this information to create a much more globally diverse genetic testing panel. Such a panel would cover the most common variants in CFTR2 as well as those identified in studies more representative of the general population. One of these studies sequenced the CFTR gene in samples from more than 115,000 individuals in the US; the demographic makeup was about 56% Caucasian with more than 10% each for individuals of African, Latin American, and Asian descent. Another resource is gnomAD, which includes data from a dozen different ancestries. The end result would be a panel that has far greater reach for patients of various ancestries.
The CF example is not unique. By broadening our data sources to design more comprehensive tests, we can address a wide variety of diseases for which genetic testing is recommended. We don’t need to wait for a new set of technologies. We just need to access the right information and use it to develop tests that can better serve heterogeneous populations.
Moving forward, a fundamental design principle for genetic tests should be that they are pan-ancestry and cover a much broader range of genes and mutations. In fact, there are already indications from professional genetics and genomics organizations that CFTR panels should cover 90% or more of CF-causing mutations across all major ancestral groups.
We have made remarkable progress in understanding the genetic basis for many diseases, and then translating that understanding to diagnostic testing. But we must continue to heed the call to action from the Rev. Dr. King so many years ago. The reality is that we have to make a concentrated and deliberate effort to be more inclusive because the kind of change that is needed will not happen organically. Our aim in healthcare should always be to treat every body, not just some bodies.
Dr. Gary J. Latham is the Chief Scientific Officer at Asuragen, a Bio-Techne brand. The opinions expressed here are his own and not necessarily those of the organization. He can be reached at Gary.Latham@bio-techne.com.