The 100,000 Genomes Project has advanced the development of rare-disease diagnosis, highlighting the situation that genome sequencing is applied for diagnosis with an increased diagnostic yield.
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.
Diagnostic yields could be various in terms of different family structures, but it's noticed that family trios (both parents and the rare-disease affected child) and families with larger pedigrees have the highest diagnostic yields. In detail, the diagnostic yields of disorders with a monogenic cause were much higher than those of disorders with a complex cause. And for patients with intellectual disability, hearing disorders, and vision disorders, diagnostic yields are ranging from 40 to 55%.
It's noticed that the diagnostic yield in this project was 6% for tumor syndromes, which is inspiring as cancer, another genomic disease, is the UK's single biggest killer. Over 350,000 people are diagnosed every year. In the 100,000 Genomes Project, researchers sequenced DNA from tumor and healthy cells, and then compare the two sequences, uncovering the exact genomic changes causing an individual's cancer. With whole-genome sequencing results, diagnosis and treatment choices in caring for cancer patients could be more precise, especially when it comes to avoiding unnecessary treatments and toxic side effects.
This study indicated some diagnostic answers and even necessary clinical actions to patients and families who had not been diagnosed for over 75 months. For instance, a 36-year-old male who is a suspected choroideremia carrier became eligible for a gene-replacement trial after the diagnosis. This study also provided a life-saving opportunity to a male neonate proband's younger brother by predictive testing. Moreover, a ten-year-old girl with severe chickenpox, whose illness had not been diagnosed for 7 years, was admitted to an intensive care unit due to a CTPS1 deficiency diagnosed in this study, which fortunately brings her a curative bone marrow transplant.
In conclusion, the 100,000 Genomes Project piloting on rare-disease diagnosis in health care highlights the situation that genome sequencing is applied for diagnosing some specific rare diseases and has shown an increased diagnostic yield. This study and similar projects are expected to assist in caring for rare-disease patients with whole-genome sequencing.
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