Genomes Without Borders: Bridging Gaps in Health Equity

This May, New England Biolabs hosted Claudia Gonzaga-Jauregui, Ph.D., to speak on precision health equity in Mexico and Latin America, a focus of hers alongside genomic variation, especially concerning rare diseases. Genomic testing lies at the center of this health equity, which began to evolve significantly after the development of next-generation sequencing technology in 2005. However, this development alone was not enough to kickstart the use of molecular diagnosis.

“Until 2008 or so, most of the personal genomes that had been sequenced to date […] were individuals that were rich or famous or important figures, like Craig Venter or James Watson,” Dr. Gonzaga-Jauregui said in her seminar.

“The question remained whether genomic sequencing was actually going to be useful for diagnosing diseases, whether it was going to be a technology of commodity for the rich and famous, or it was actually going to impact healthcare.”

Then, in 2010, her Ph.D. advisor James Lupski and his co-authors published the first whole-genome sequencing (WGS) project to identify the molecular cause of a genetic disease. This proved that genetic diseases could be identified through WGS, which would allow for early intervention, access to personalized (precision) treatment and the development of public health policies. Instead of solely clinical diagnosis, which is reactive and treats already presenting symptoms, molecular diagnosis enables preventative, predictive care.

Unfortunately, genetic diagnosis through WGS is limited or absent in many countries, especially low- and middle-income countries (LMICs). Many factors act as barriers to genomic diagnostics in LMICs, such as the high cost, low availability, limited healthcare coverage and a deficit in specialized professionals and laboratories. Adding to this is a lack of awareness, both of genomic diagnosis and of rare genetic diseases. On the occasions when sequencing is done, it is often sourced outside of Latin America, with clinicians not receiving the complete results. Paired with the historical underrepresentation of genetic data in regions outside of Europe and the US, this lack of current genomic data makes it difficult for public health professionals to identify the genetic variants in Latin American populations, complicating efforts to bridge the health equity gap experienced by LMICs. This is where Dr. Gonzaga-Jauregui’s work comes in.

A cycle of lacking awareness, support, specialization, and availability lead to limited molecular diagnostic access in LMICs.

Molecular Diagnostics in Mexico

Currently, her work focuses on Mexico, such as with the Mexican Network for Rare Diseases (ReMexER), founded in 2020 to connect clinicians and researchers working on rare diseases, all of whom recognize the difficulties of molecular diagnosis for patients in the country.

“We have a project on genomics of rare and undiagnosed diseases in Mexico, so we provide exome sequencing — trio exome sequencing, most of the time, so mom, dad and affected child — for patients with suspected genetic disorders that cannot pay [for] these tests clinically, or many times they are sent out to other countries to get clinical testing,” she said in NEB podcast Lessons from Lab & Life™. “We offer free of charge, research-based exome sequencing for patients with genetic diseases to try precisely to enable that access [for] these patients that very clearly have genetic conditions but otherwise couldn’t afford to get genetic testing.”

Analysis and follow-ups are all done at the International Laboratory for Human Genome Research (LIIGH) in Mexico, where Dr. Gonzaga-Jauregui works. So far, they have found variants in disease-associated mutations in about 30% of the screened patients. Of these patients, 30% have novel variants, mutations associated with genetic conditions but with unknown specific effects. This is not unexpected, considering the lack of diverse genomics studies, such as genome-wide association studies. As of the time of writing, over 93% of these studies had European ancestry, and only 0.38% represented Hispanic or Latin American ancestry.

Studies like the Mexico City Prospective Study (MCPS) contribute to increasing representation. Released in 2023, the MCPS is currently the largest non-European ancestry population study, collecting 141,046 exomes and 9,950 whole genomes in the Coyoacán and Iztapalapa districts. The study identified 142 million genomic variants, 1.4 million of which were unique to the MCPS cohort. Dr. Gonzaga-Jauregui’s analyses of MCPS data have found that around 4.6% of the sequenced individuals carry a medically actionable variant.

“This is a resource for us to identify highly penetrant actionable variants in the Mexican population and also variants associated with other genetic conditions … This data has already been used by others to identify drug targets for diabetes and obesity and other conditions,” Dr. Gonzaga-Jauregui said.

Among these other conditions is cancer — 112 variants were identified in the study that affect all but six of the 28 genes associated with medically actionable hereditary cancer. Of these, only 87 variants have been previously reported. Paired with the many unique variants found, this study highlights the importance of diverse, representative genomic research.

“We’re still finding new pathogenic or likely pathogenic variants that are unique to the dataset in Mexico City Prospective,” she said. “This correlates with an increased risk for breast, ovarian and colorectal cancer in the cohort, which is similar to what we see in the epidemiological data for cancer in Mexico.”

ReMexER highlights time until diagnosis and prevalence of rare diseases, most of which are genetic. Ancestry bias and unknown gene variants contribute to treatment difficulties.

Precision Health Outside of Mexico

Dr. Gonzaga-Jauregui also works to raise awareness about precision health inequity both globally and in Latin America. In 2021, the World Health Organization (WHO) implemented its Science Council, which held workshops on genomics and equity as their first theme, one of which Dr. Gonzaga-Jauregi participated in. This council released a report on supporting genomics public health access, recommending the promotion of genomics use, collaboration to promote national and regional programs and the promotion of ethical and equitable information sharing and standards.

Without region-specific programs, association markers are less transferable between populations, increasing disparity and reducing specificity for rare and actionable variants. Dr. Gonzaga-Jauregui points to the 70 genes deemed medically actionable by the American College of Medical Genetics (ACMG), last updated in 2021. Although these serve as a valuable baseline for population studies, gene variants and their frequencies vary across specific populations. This can be seen in populations outside of Latin America as well, such as the Amish community in Lancaster County, Pennsylvania. Here, Dr. Gonzaga-Jauregui notes a smaller range of variants but higher frequencies, with some variants present in up to 14% of the population — markedly higher than the 2% – 4% frequency estimated for other population studies, such as the UK Biobank.

“We cannot say, like, ‘Every [population] will have two percent, any population will have two percent,” she said. “It is really important to understand the sociodemographic history of the different populations to really assess the impact of this type of variation. So, each population will be unique, and their catalogue and frequencies of these variants will be also unique, which is the reason to do this type of study in other underrepresented populations.”

Additionally, Dr. Gonzaga-Jauregui works on increasing awareness specifically for rare diseases. Part of this is the Collaborative for Rare Diseases in the Caribbean and Latin America (CEPCAL). CEPCAL is a regional initiative operating through eight working groups, ranging from legislation to access to research networks. One of these groups encourages the development of molecular diagnostics reference centers in Latin America to spread out sequencing capacity throughout the region without being too fragmented. This allows for sequencing data to remain in the area so that it can contribute to public health for Latin American populations.

“We understand that it’s unrealistic to expect that each country in Latin America — that there will be 33 genome centers in the 33 different countries to do this type of analysis and large-scale sequencing,” she said.

“One strategy that we’re taking with this collaborative is to find partners that may be interested in supporting the piloting of reference centers in Latin America where we can bring samples from the countries around [them].”

Another group in CEPCAL centers education and outreach, which ReMexER also emphasizes. ReMexER hosts a symposium on International Rare Disease Day (Feb. 28) and offers training and education to fill the resource gap caused by the lack of information available in Spanish. CEPCAL also has a group focusing on the representation of vulnerable populations in Latin America.

“The Latin America and Caribbean region has a very high proportion of Indigenous populations, so, based on this prevalence, of the 50 million Indigenous people in the region, we estimate that about three to four million people will have a rare disease that are of Indigenous communities,” she said. “This is also relevant because these are generally populations or communities that are underserved. They have little access to healthcare and, many times, high impact of rare genetic conditions because of the sociodemographic history of these communities.”

It is no small task to improve the state of genomic testing availability in Mexico, let alone in Latin America as a whole, but Dr. Gonzaga-Jauregui is committed to contributing to the body of genomic research in Mexico. She believes in the power that genomics can have on health equity, which can be seen through her public engagement work and her encouragement of collaboration and understanding of internationally shared challenges.

“Human genomics has the potential to reduce the equity gap in different countries; however, it also has the potential to broaden it if we don’t, as a community — as a scientific community, as a society — make efforts in making genomics available to everyone.”