100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report.
Document Type
Article
Publication Date
11-11-2021
Publication Title
The New England journal of medicine
Keywords
JGM, Adolescent, Adult, Child, Child, Preschool, Family Characteristics, Female, Genetic Variation, Genome, Human, Humans, Male, Middle Aged, Pilot Projects, Polymerase Chain Reaction, Rare Diseases, Sensitivity and Specificity, State Medicine, United Kingdom, Whole Genome Sequencing, Young Adult
JAX Source
N Engl J Med 2021 Nov 11; 385(20):1868-1880
Volume
385
Issue
20
First Page
1868
Last Page
1880
ISSN
1533-4406
PMID
34758253
DOI
https://doi.org/10.1056/nejmoa2035790
Abstract
BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection.
METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis.
RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives.
CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.).
Recommended Citation
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100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report. N Engl J Med 2021 Nov 11; 385(20):1868-1880