“100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care—Preliminary Report”, 2021-11-11 (; similar):
Background: The U.K. 100,000 Genomes Project is in the process of investigating the role of whole 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.
Method: We conducted a pilot study involving 4,660 participants from 2,183 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 40–55%. 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. Cohort-wide burden testing across 57,000 genomes enabled the discovery of 3 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.
Conclusion: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases.
…However, South Asian ancestry was statistically-significantly more common among pediatric probands than among adult probands (16% vs. 4%, p < 0.001); our results indicated potential consanguinity in 43% of the 93 pediatric South Asian probands and in 1% of the other 478 pediatric probands (Table 1).
…Health Care Outcomes after Diagnosis: The findings from our approach ended long diagnostic odysseys for some participants and their families (the median duration of such an odyssey was 75 months, and the median number of hospital visits was 68) (Table S1), and we speculate that they will mitigate NHS resource costs (the combined cost for 183,273 episodes of hospital care among the affected participants was £87 million [$122 million]) (Table S3). In addition, 134 of the 533 genetic diagnoses (25%) were reported by clinicians to be of immediate clinical actionability—only 11 (0.2%) were described as having no benefit. As of now, the remainder of the diagnoses are of unknown usefulness. The benefits in terms of health care included 4 diagnoses that led to a suggested change in medication, 26 that led to suggested additional surveillance of the proband or relatives, 13 that allowed for clinical trial eligibility, 59 that informed future reproductive choices, and 32 that had other benefits (Table S9).
In several specific probands, diagnoses have had important clinical actionability. In a 36-year-old man with suspected choroideremia, we detected a novel CHM promoter variant causing loss of gene expression,27 a diagnosis that enabled eligibility for a gene-replacement trial. A male neonate proband presented with severe infection and transient neurologic symptoms immediately after birth and died at 4 months of age with no diagnosis but with health care costs of ~£80,000 ($112,000) (Table S10). A diagnosis of transcobalamin II deficiency due to a homozygous frameshift in TCN2 was made from this study, which enabled predictive testing to be offered to the younger brother within 1 week after birth. The younger child, who received a positive result, received weekly hydroxocobalamin injections to prevent metabolic decompensation.
A 10-year-old girl was admitted to the intensive care unit with life-threatening chicken pox. She had undergone a diagnostic odyssey over a period of 7 years at a total cost of £356,571 ($499,199) across 307 secondary care episodes (Table S11). We were able to diagnose CTPS1 deficiency due to a homozygous, known pathogenic splice acceptor variant. A diagnosis enabled a curative bone marrow transplantation (cost of £70,000 [$98,000]), and predictive testing in her siblings showed no additional family members to be at risk.
One proband had waited until his 6th decade of life for a genomic diagnosis of an INF2 mutation causing focal segmental glomerulosclerosis. His father, brother, and uncle had all died from kidney failure. He had received 2 kidney transplants, had transmitted the condition to his daughter, and was concerned about whether his 15-year-old granddaughter, who was under surveillance, was at risk. After he received his genetic diagnosis, the granddaughter was tested, found to be negative, and discharged from regular medical surveillance.
…Discussion: Our findings show a substantial increase in yield of genomic diagnoses made in patients with the use of genome sequencing across a broad spectrum of rare disease. The enhanced diagnostic benefit was observed regardless of whether participants had undergone previous genetic testing (diagnostic yields were 31% among those who had undergone testing and 33% among those who had not). In 25% of those who received a genetic diagnosis, there was immediate clinical actionability…The findings from our pilot study support the case for genome sequencing in the diagnosis of certain specific rare diseases in the new NHS National Genomic Test Directory.37 In patients with specific disorders, such as intellectual disability, genome sequencing is now the first-line test in the NHS (Table S12).
With a new National Genomic Medicine Service, the NHS in England is in the process of sequencing 500,000 whole genomes in rare disease and cancer in health care. We hope that our findings will assist other health systems in considering the role of genome sequencing in the care of patients with rare diseases.