Using a new computational approach developed to analyze large genetic data sets from rare disease cohorts, researchers at the Icahn School of Medicine at Mount Sinai have discovered previously unknown genetic causes of three rare diseases: primary lymphedema (characterized by tissue swelling), thoracic aortic aneurysm disease and congenital deafness, reports Europa Press.
The work, published in the journal nature medicinehas been carried out in collaboration with colleagues at the University of Bristol (UK), the Catholic University of Louvain (Belgium), the University of Tokyo, the University of Maryland, Imperial College London and other centers around the world.
Rare diseases affect approximately 1 in 20 people, but only a minority of patients receive a genetic diagnosis. Less than half of the 10,000 registered rare diseases have a known genetic cause, despite the fact that this is known to be the origin of 80% of them. That is to say, that the explanation for their development lies in “an error” in the genome transmitted by their parents. The remaining 20% are acquired due to infectious or autoimmune reasons.
The genomic sequencing of large cohorts of patients with rare diseases offers a way to discover genetic causes that remain unknown. However, large genetic data sets are unwieldy, slowing down research considerably, say the scientists.
“Although rare diseases are rare individually, collectively they are quite common. It is important for our understanding of human biology and for the development of diagnostics and therapies that the remaining causes are found,” explains study lead author Ernest Turro, Associate Professor of Genetics and Genomic Sciences at Icahn Mount Sinai.
“Many people with a rare disease struggle for many years to obtain a genetic diagnosis -keep going-. By developing and applying statistical methods and computational approaches to find new causes of rare diseases, we hope to expand understanding of the underlying causes of these diseases, speed up time to diagnosis for patients, and pave the way for the development of treatments”.
The researchers studied a collection of 269 classes of rare diseases using data from 77,539 participants in the 100,000 Genomes Project, one of the largest datasets of patients with rare diseases phenotyped and sequenced with whole genomes. They identified 260 associations between genes and classes of rare diseases, including 19 associations previously absent from the literature. Through an international academic collaboration, the authors validated the three most plausible novel associations by identifying additional cases in other countries and using experimental and bioinformatics approaches.
“We hope that our computational framework will help accelerate the discovery of the remaining unknown etiologies of rare diseases in general. For now, we hope that a genetic diagnosis can be reached for selected families with primary lymphedema, thoracic aortic aneurysm, and unexplained deafness.” said Daniel Greene, a postdoctoral fellow at Icahn Mount Sinai and lead author of the study. “We also plan apply our methods in novel ways and on other data sets, with the goal of further unraveling the genetic causes of rare diseases.”
A better understanding of the functions of the genes involved in these and other disorders could pave the way for the development of treatments for these and other minority pathologies. Knowing the molecular causes of rare diseases, that is, the genetic mutations present in the people who suffer from them, is key to the development of innovative therapies such as gene therapy, which consists of correcting a genetic problem by introducing a healthy copy of the defective gene.