100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care — Preliminary Report, 2021, Smedley et al.

https://www.nejm.org/doi/full/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.)
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Guardian article:
Whole genome sequencing could save NHS millions of pounds, study suggests
Genomics England and NHS England findings highlight benefits of using WGS to help detect rare diseases:
https://www.theguardian.com/science...ld-save-nhs-millions-of-pounds-study-suggests

 

Hundreds of patients in gene study given rare disease diagnosis

"A 10-year-old girl with a rare, unknown condition also received a diagnosis through the study which meant she was able to have a bone marrow transplant. She had been admitted to intensive care multiple times and visited hospital on more than 300 occasions.

Testing of her siblings revealed no other family members were at risk."

https://www.bbc.co.uk/news/health-59235573

Another example of how dangerous FND/MUS/etc are as a 'diagnosis'.

 

It looks like in this study, they only recruited patients in whom a rare disease was already suspected by clinicians. The paper writes:

"we recruited participants who had been identified by health care professionals and researchers as having rare diseases (across a broad range of categories) that had not been diagnosed after receipt of usual care in the NHS, which included either no diagnostic tests (because none were available) or approved diagnostic tests that did not include genome sequencing"
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It would be interesting if experts in rare diseases looked at a sample of ME/CFS patients to see how many patients with rare disease they can pick out of the ME/CFS cohort...

 

Isn't that what the NIH effectively did with their inter-mural study?