Using a new computational approach developed to analyse large genetic datasets from rare disease cohorts, researchers at the Icahn School of Medicine at Mount Sinai and colleagues including the University of Bristol, have discovered previously unknown genetic causes of three rare conditions: primary lymphedema (characterised by tissue swelling), thoracic aortic aneurysm disease, and congenital deafness.
The work was done in collaboration with colleagues at KU Leuven, Belgium; the University of Tokyo; the University of Maryland; Imperial College London, and others from around the world.
An enhanced understanding of the functions of the genes involved in these and other disorders could pave the way for the development of treatments. The findings are published today [16 March] in the online issue of Nature Medicine.
Rare diseases affect approximately 1 in 20 people, but only a minority of patients receive a genetic diagnosis. Fewer than half of the 10,000 recorded rare diseases have a known genetic cause. Genome sequencing of large cohorts of rare disease patients provides a route toward discovering the genetic causes that remain unknown. However, large genetic datasets are challenging to work with, slowing down research significantly, said the investigators.
The investigators studied a collection of 269 rare disease classes using data from 77,539 participants in the 100,000 Genomes Project, one of the largest datasets of phenotyped and whole-genome-sequenced rare disease patients. The researchers identified 260 associations between genes and rare disease classes, 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 through experimental and bioinformatic approaches.