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Whole-Genome Sequencing Shines for Rare Disease Diagnosis in 100K Genomes Pilot Study

NEW YORK – A UK-led team has shared findings from the pilot stage of the 100,000 Genomes Project, demonstrating that whole-genome sequencing can aid in diagnosing a significant subset of the rare disease cases it considered.

"Our findings show that deployment of this comprehensive and efficient genomic test at the first signs of symptoms can improve diagnostic rates," senior and corresponding author Mark Caulfield, a Queen Mary University of London researcher who was previously affiliated with Genomics England, said in a statement. "This study has paved the way for clinical implementation of whole-genome sequencing as part of the [National Health Service (NHS)] Genomic Medicine Service."

In a paper published in the New England Journal of Medicine on Thursday, researchers from Genomics England, NHS England, Queen Mary University of London, and elsewhere presented findings for 4,660 participants from rare disease-affected families, including 2,183 rare disease patients, who had their genomes sequenced for the pilot stage of the 100,000 Genomes Project. The group included some patients and families who had spent years searching for genetic explanations for 161 conditions marked by a wide range of clinical features and phenotypes.

The genome sequencing was done using Illumina short-read sequencing, and clinical genetics teams and technology from Congenica and Fabric Genomics contributed to the phenotype-based variant prioritization steps used to find the most promising genetic variants. Investigators at Illumina, Congenica, and Fabric Genomics co-authored the study.

With the help of electronic health record data, whole-genome sequencing, and automated methods for prioritizing suspicious variants, the team successfully diagnosed one-quarter of the cases, uncovering new and known pathogenic or likely pathogenic mutations, including culprits in protein-coding parts of the genome and in noncoding regions missed by exome sequencing.

"A large proportion of the diagnoses we discovered were found outside the coding region and would not have been detected by existing approaches," co-lead author Damian Smedley at Queen Mary University of London said in a statement. "This study makes the case for healthcare systems worldwide to adopt whole-genome sequencing as the genetic test of choice for rare disease patients."

The diagnostic yield was particularly high for patients with hearing or vision, metabolic, neurological, or intellectual disability symptoms. There, the researchers reached diagnoses for between 40 percent and 55 percent of patients. They noted diagnoses were more common when sequence data for parent-child trios or large families was available. Diagnostic rates were also relatively high for conditions stemming from single gene changes but came in at just 6 percent or so for patients with tumor syndromes.

Within a group of 533 newly diagnosed patients, the team saw immediate treatment or clinical management changes for 134 individuals.

Along with these and other benefits to patients, the investigators suggested that the ability to reach a diagnosis with genomic approaches could provide long-term cost advantages for health systems, by providing opportunities to offer more targeted, effective treatments and curbing the use of expensive treatments that do not provide benefits to the patients.

"The findings from our approach ended long diagnostic odysseys for some participants and their families … and we speculate that they will mitigate NHS resource costs," the authors wrote, noting that hospital costs came in at $122 million for the care provided to patients en route to a diagnosis.

The investigators outlined a handful of situations where both patient benefits and health system savings were evident, including the case of a 10-year-old girl diagnosed with homozygous splice acceptor changes affecting levels of the immune system gene CTPS1.

Over seven years, she visited the hospital or secondary care sites more than 300 times at a cost of almost $499,200, they explained, starting with treatment for severe chicken pox in the intensive care unit. After her genomics-based diagnosis, the child received a curative bone marrow transplant that came with a relatively modest price tag of $98,000.

The team noted that additional diagnoses might be possible with the inclusion of long-read sequence data and phased genomes. Even so, they said the current findings suggest that short-read genome sequencing alone can significantly boost rare disease diagnoses.

"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," the authors noted, adding that "[w]e hope that our findings will assist other health systems in considering the role of genome sequencing in the care of patients with rare diseases."