NEW YORK – An international consortium led by researchers at the Icahn School of Medicine at Mount Sinai in New York has uncovered the genetic causes of three rare conditions — primary lymphedema, thoracic aortic aneurysm disease, and congenital deafness — using a new method to analyze data from the UK 100,000 Genomes Project.
An immediate implication of the findings is that patients with those diseases may now obtain a confirmatory diagnosis, Ernest Turro, associate professor of genetics and genomic sciences at Icahn Mount Sinai and corresponding author of the study, told GenomeWeb. "The tests may also help identify potentially other affected relatives and families," he said.
Collectively, rare diseases affect roughly one in 20 people, but fewer than half of the approximately 10,000 cataloged rare diseases have a known genetic etiology, the authors noted.
For their study, published in Nature Medicine on Friday, Turro and colleagues analyzed a collection of 269 rare disease classes using data from 77,539 participants in the UK 100,000 Genomes Project (100KGP), one of the largest datasets of rare disease patients and their unaffected relatives with phenotypes and whole-genome-sequencing data.
According to the researchers, the reduction in costs of whole-genome sequencing over the last decade has greatly facilitated the collection of more data on patients with rare diseases. However, working with big datasets has proved to be a challenge. By developing a compact relational database called the "Rareservoir," the authors were able to reduce the data size and analyze the data efficiently. "This really was one of the main innovations from the point of view of this analysis," Turro said.
Researchers then used a Bayesian genetic association method called BeviMed, identifying 260 associations between genes and rare disease classes, including 241 previously known ones and 19 new ones.
Out of these 19 new associations, the researchers were able to validate three, with the ERG, PMEPA1 and GPR156 genes, by identifying additional cases in other countries. While ERG was linked to primary lymphedema, variants in PMEPA1 and GPR156 resulted in Loeys-Dietz syndrome and congenital hearing loss, respectively.
"The finding about the congenital hearing loss gene has major implications for newborn screening," said Turro. "Conventional hearing tests can be quite difficult, but with the genetic test, interventions can begin early to prevent speech or language delays."
Turro also said that the findings on primary lymphedema and Loeys-Dietz syndrome would help in diagnosing more people on a timely basis.
For the remaining 16 new associations, he and his team identified what they called "plausible hypotheses" that will "require replication and validation before they can be considered causative genes."
With regards to the limitations of the study, the authors said that approximately 82 percent of the data from the 100KGP were from people of European ancestry — corresponding to the makeup of the population in England and Wales — constraining the ability to identify causative variants specific to other ancestry groups.
Additionally, they noted that 28 of the rare disease patient sets had fewer than five probands, highlighting the need to enroll more individuals with ultra-rare diseases, and that they only looked at single-nucleotide variants and indels in coding genes, ignoring structural variants and variants in regulatory regions or noncoding genes.
They also said that the study focused on monogenic models of rare disorders, even though the genetic etiologies of certain rare diseases may be polygenic. "These limitations point toward multiple promising avenues of future research to uncover the remaining unknown genetic determinants of rare diseases," the authors concluded.