Researchers from the Icahn School of Medicine at Mount Sinai, along with colleagues from around the globe, have identified the etiologies of primary lymphedema (characterized by tissue swelling), thoracic aortic aneurysm disease, and congenital deafness.
The researchers developed and used a database called Rareservoir, which contained rare variant genotypes and phenotypes of 77,539 people sequenced by the 100,000 Genomes Project (100KGP).
These findings may potentially lead to early detection and intervention for these rare diseases.
An estimated 10,000 rare diseases affect 1 in 20 people worldwide; fewer than half have known genetic causes. However, researchers at the Icahn School of Medicine at Mount Sinai—along with many collaborators from across the world—are making strides in discovering the genetic associations for certain diseases.
The team developed and employed a new computational approach and used it to discover the etiologies of three rare conditions:
Primary lymphedema (which is a group of genetic conditions marked by abnormal development of lymphatic vessels or failure of lymphatic function)
Thoracic aortic aneurysm disease
The approach analyzed large genetic datasets within these three disease groups, leading to a greater understanding of how the genes associated with these conditions function.
Building, and applying, the Rareservoir
The researchers describe their approach in a Nature Medicine article. First, they built a database called Rareservoir, which contained rare variant genotypes and phenotypes of 77,539 people sequenced by the 100,000 Genomes Project. This Project sequences and studies how genes impact health. The authors describe it as a “lightweight, flexible, and portable system for synthesizing the genetic and phenotypic data required to study rare disease cohorts with tens of thousands of participants.”
The team then employed the Bayesian genetic association method (or BeviMed) to look at the associations between genes and 269 rare diseases. BeviMed, say, authors of a review article in the Journal of Molecular Diagnostics, allows researchers to calculate the “probability of a particular hypothesis, either disease or carrier status, based on family information and/or genetic test results.”
Through these methods, the Nature Medicine researchers identified “241 known and 19 previously unidentified associations.” They validated associations with ERG, PMEPA1, and GPR156 by searching for pedigrees in other cohorts and using bioinformatic and experimental approaches.
What they found
With relevance to the three rare diseases, the authors found:
Primary lymphedema: Loss-of-function variants in the erythroblast transformation specific (ETS)–family transcription factor encoding gene ERG
Aortic disease: Truncating variants in the last exon of transforming growth factor-β regulator PMEPA1, leading to Loeys–Dietz syndrome (associated with aortic disease)
Recessive congenital hearing impairment: Loss-of-function variants in GPR156
The remaining 16 previously unidentified associations (from the 19 total) led to plausible hypotheses, the authors of the study said. Some of these associations include:
LRRC7, identified to be associated with intellectual disability
LRRC7-deficient mice exhibit a neurobehavioral phenotype
USP33, identified to be associated with early-onset hypertension
The authors noted that these remaining 16 findings will “require replication and validation before they can be considered causative genes.”
What these findings mean for future patients
Speaking with MDLinx, Ernest Turro, Ph.D., associate professor of Genetics and Genomics Sciences at the Icahn School of Medicine at Mount Sinai, and senior author of the Nature Medicine paper, explained how the findings regarding GPR156, PMEPA1, and ERG could lead to future potential clinical benefits.
Congenital hearing impairment
“The clinical benefit [in regards to GPR156] relates to detection of affected cases enabling enhanced surveillance and/or early intervention to prevent adverse outcomes,” Turro says. “Genetic diagnosis of GPR156-related hearing loss in at-risk families, or even in newborn screening programs, will enable early detection of profound hearing loss in early childhood when detection through conventional hearing tests is difficult.”
Early detection is key, since caring for deaf infants centers on preventing speech and language delay—allowing families to employ early interventions like focusing on visual communication or prepping for hearing aids or cochlear implant surgeries.
Thoracic aortic aneurysm disease
In the case of thoracic aortic aneurysm disease, Turro says the findings could also potentially lead to early detection and intervention. This could include “regular echocardiograms to detect the early formation of aortic aneurysm, thereby enabling corrective surgery to pre-empt life-threatening complications such as aortic dissection, or aneurysm rupture.”
Early diagnosis could mean that patients get the proper treatment they need, possibly beta blockers and angiotensin blockers to lower heart rate and blood pressure, Turro adds.
“Our discovery will enable further work to identify pathways and downstream signals that might be therapeutically targetable,” Turro says.
When it comes to potentially detecting aneurysms, Alexandra Kharazi, M.D., a cardiothoracic surgeon with Sharp in San Diego, California, says the study’s findings are significant.
“Currently, aortic aneurysms are often asymptomatic until they rupture, which can be life-threatening,” she says. “As an M.D., this study could impact my practice by potentially improving the accuracy of risk assessment for aortic aneurysms. In the future, it could also potentially lead to earlier detection of aortic aneurysms in high-risk patients, allowing for earlier intervention.”
Working together to save lives
These findings may change—and save—patients’ lives. As Turro says, “Identifying the genetic causes of a disease is often a first step in the path towards developing effective treatments. Patients with rare disorders often face a diagnostic odyssey lasting many years. Thanks to this work, certain patients will be able to obtain a definitive genetic diagnosis at last, providing closure and helping identify affected family members.”
Turro also emphasized the importance of physicians’ coming together with a shared goal. “We feel very fortunate to have worked with an outstanding group of collaborators across the globe, highlighting the importance of international cooperation in rare disease research.”