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100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care — Preliminary Report
- Source :
- Mumford, A D 2021, ' 100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care-Preliminary Report ', New England Journal of Medicine, vol. 385, no. 20, pp. 1868-1880 . https://doi.org/10.1056/NEJMoa2035790
- Publication Year :
- 2021
- Publisher :
- Massachusetts Medical Society, 2021.
-
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.).
- Subjects :
- Adult
Male
Proband
medicine.medical_specialty
Adolescent
Pilot Projects
Genomics
Polymerase Chain Reaction
Genome
State Medicine
Young Adult
03 medical and health sciences
0302 clinical medicine
Health care
Human Phenotype Ontology
Humans
Medicine
Child
Exome sequencing
030304 developmental biology
Family Characteristics
0303 health sciences
Whole Genome Sequencing
Genome, Human
business.industry
Genetic Variation
Rare Diseases/diagnosis
General Medicine
Middle Aged
United Kingdom
3. Good health
Child, Preschool
Family medicine
Medical genetics
Female
business
Bristol
030217 neurology & neurosurgery
Rare disease
Subjects
Details
- ISSN :
- 15334406 and 00284793
- Volume :
- 385
- Database :
- OpenAIRE
- Journal :
- New England Journal of Medicine
- Accession number :
- edsair.doi.dedup.....07e7a9cb72d07e6534b79e777083f769
- Full Text :
- https://doi.org/10.1056/nejmoa2035790