Rare diseases, as the European Union defined, are conditions that affect fewer than 1 out of 2000 people, which are also known as orphan diseases as the pharmaceutical industry previously was not interested in developing treatments for them due to possibly less profitability and higher investment. However, approximately 10,000 rare diseases are increasingly challenging worldwide health and affecting 6% of the population in Western societies.
Though causes for rare diseases are various, more than 80% of them are related to genetic changes in genes or chromosomes. Nevertheless, just a few rare diseases can be tracked from a diagnosed person, and more children with a rare disease die before they were 5 years old. This circumstance has not changed until the application of the next-generation sequencing (NGS) in the past 10 years that impressively improved the diagnosis rates of rare diseases. But major patients still were unable to accept a molecular diagnosis but only standard diagnostic testing. To address diagnostic insufficiency, the 100,000 Genomes Project was launched by the U.K. government in 2013 to put whole-genome sequencing (WGS) into practical studies of rare diseases, cancers, and infections.
To evaluate the impact of WGS application on the genetic diagnosis of rare diseases in the National Health Service (NHS) in the United Kingdom, the 100,000 Genomes Project started a pilot study, in which people who have been professionally identified as rare-disease patients while not yet received any genomic diagnosis are determined as eligible participants. Researchers recruited 4660 participants (including 2183 probands and 2477 family members) from 2183 families with 161 disorders covered, including common neurologic conditions, ophthalmologic conditions, and tumor syndromes. Meanwhile, they collected previous testing data of in probands if any, including single-gene tests, karyotyping, single-nucleotide polymorphism arrays, next-generation sequencing panels, and exome sequencing bioinformatics.
Researchers undertook detailed clinical phenotyping on probands of recruited families, and collected electronic health records for further computational analyses. After accumulating data on clinical features, performing genome sequencing, applying automated variant prioritization, and identifying novel pathogenic variants, researchers have observed an obviously increased diagnostic yield across a broad spectrum of rare diseases.