NEJM: The fastest ever!

Genome sequencing allows scientists to see a person's complete DNA sequence makeup, which contains information on everything from eye color to genetic diseases
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Therefore, genome sequencing is crucial for diagnosing diseases in patients that involve DNA—once doctors know a specific genetic mutation, they can plan treatment accordingly

The weeks it takes to sequence a patient's genome and return the results are considered quick by most doctors
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So, can it be further reduced to days or even hours?

On January 12, 2022, Stanford University researchers published an article titled: Ultrarapid Nanopore Genome Sequencing in a Critical Care Setting in the New England Journal of Medicine (NEJM)
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A research team has developed a new ultra-fast genome sequencing method for diagnosing rare genetic diseases that takes an average of 8 hours, unprecedented in standard clinical care
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Rapid diagnosis means patients spend less time in the intensive care unit, need fewer tests, recover faster and spend less on care

breaking new records

The research team recruited 12 patients and sequenced their genomes.
Five of them obtained a genetic diagnosis from the sequencing information (this is because the cause of the disease in other people has nothing to do with the gene), and it took an average of 8 hours.
The diagnosis rate 42%
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12% higher than the average diagnostic rate for diagnosing mysterious unknown diseases by sequencing

Not all diseases are genetically linked, which may be why some patients go undiagnosed after their sequencing information is returned, the researchers said
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In one case, a patient's genome was sequenced in just 5 hours and 2 minutes, setting a Guinness World Record for the fastest DNA sequencing technology

Professor Euan Ashley said: "This is an amazing time, an incredible thing has been achieved and we are approaching a new frontier
.
"

The researchers then analyzed the patient's sequencing data for a total of 7 hours and 18 minutes.
The previous record was 14 hours by the Rady Children's Institute
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That said, Stanford cut the time to half

Stanford scientists plan to provide less than 10 hours of rehabilitation for patients in the intensive care unit at Stanford University Hospital and Stanford University's Lucille Packard Children's Hospital, with other hospitals over time.
service
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quick! Faster! even faster!

To achieve faster sequencing speeds, the research team needed new hardware
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So the research team contacted Oxford Nanopore Technologies, the pioneer of nanopore gene sequencing technology, and they built a machine consisting of 48 sequencing units, called flow cells

The idea at the time was to use all flow cells to sequence a person's genome at the same time
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Quantitative change brings qualitative change.

Prof.
Euan Ashley said that sequencing data was not being processed fast enough, so data pipelines and storage systems had to be completely rethought and improved
.

Workflow for Ultrafast Nanopore Genome Sequencing

Fortunately, his graduate student Sneha Goenka has found a way to feed data directly into a cloud storage system, where computing power can be amplified enough to sift through the data in real time
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Algorithms then scan the input DNA sequence and restore the genetic code to identify genetic mutations that may lead to disease

Suffice to say, from start to finish, the research team was looking for ways to speed up the sequencing of patient genomes
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Now, the team is optimizing its system to reduce time even further
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Professor Euan Ashley is excited about the future of this technology: "I think we can cut the time in half again, and if we can do that, we'll have answers before the hospital rounds are over
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It's a creative leap
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"

long read sequencing

Perhaps the most important feature of this new diagnostic method, which can quickly find suspicious DNA fragments, is that it uses a method called long-read sequencing
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Traditional genome sequencing techniques cut the genome into small pieces, read the DNA sequence of each piece, and finally stitch the entire genome together using the standard human genome as a reference
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But this method doesn't always capture the full extent of our genome, and the information it provides sometimes ignores genetic variants that point to a diagnosis
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In contrast, long-read sequencing preserves long stretches of DNA consisting of tens of thousands of base pairs, providing scientists with more detail to search for sequence errors
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Professor Euan Ashley said that long-read sequencing makes it easier to find genetic mutations on large fragments of the genome
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In fact, in the absence of long-read sequencing, some mutations are nearly impossible to detect, which is one of the main reasons we take this approach
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Previously, long-read sequencing had disadvantages such as low accuracy and high price
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Only recently has Oxford Nanopore succeeded in increasing the accuracy of long-read sequencing high enough for disease diagnosis
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It is reported that this study is the first to demonstrate the feasibility of such long-read sequencing as the main means of medical diagnosis
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save patient's life

The new ultra-fast nanopore genome sequencing developed by the research team is not only at the technical level, but also towards clinical application
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A typical case is a 13-year-old boy from Oregon, USA, Matthew Kunzman
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About a year ago, the boy always had a cough and high fever.
At first, his parents thought it was the flu or a new crown infection.
However, his symptoms became more and more serious.
Test results also showed that these symptoms were caused by myocarditis.

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Myocarditis is a severe inflammation of the heart that makes it difficult for the heart organ to pump blood to the rest of the body
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Examinations at the local hospital revealed dire conditions - his heart was rapidly failing, and doctors advised immediate flight to Stanford Hospital for treatment
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A day after arriving at Stanford Hospital, his condition deteriorated and he was left on life support
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Professor Euan Ashley said: "There are two reasons why a healthy child suddenly develops this type of heart failure: one is myocarditis, usually triggered by a virus or other physical stress; the other is a genetic cause, a gene related to heart function caused by mutation
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Diagnosing the specific cause is critical to his treatment
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Myocarditis is usually reversible, and with treatment, the heart can return to normal, but if his condition is genetic, the only solution at the moment is a heart transplant
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The research team approached his parents, explained the rapid sequencing study to them, and asked them if they would like to participate in the study
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With permission from his parents, researchers used a few milliliters of his blood to sequence the ultrafast nanopore genome, and hours later, the sequencing data showed that his condition was due to a genetic mutation
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With this information, the little boy was immediately placed on the heart transplant list
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21 days later, he had a new heart transplant, and today, about a year later, he is recovering well and is living a healthy and happy life
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Ultrafast nanopore genome sequencing enables diagnosis in hours

In another case, a 3-month-old infant presented to the Stanford Hospital emergency department with an unexplained seizure
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The research team performed ultra-fast nanopore genome sequencing on the patient's genome, and in just over 8 hours, the team had the answer -- the baby's epilepsy was caused by a mutation in the CSNK2B gene
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If the research team had relied only on standard tests at the time, it would have been difficult to make a diagnosis in a short period of time
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While further testing will likely lead to the correct diagnosis for the patient, this will require waiting in the dark for weeks
.

All in all, this ultra-fast nanopore genome sequencing technology can diagnose a patient's genetic cause in about 8 hours, setting a Guinness World Record for the fastest DNA sequencing technology, and setting the record for rare genetic disease diagnosis.
" game changer"
.

Professor Euan Ashley said: " Traditional standard tests screen patients' blood for disease-related markers, but they scan only a few well-documented genes
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This new technology can scan a patient's entire genome for Any and all genetic variants, even if the gene was discovered the day before
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"

After the publication of this study, more scientists began to pour into this field.
Perhaps in the near future, genetic diagnosis will be like nucleic acid testing.
Get the fastest and most suitable treatment
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Original source:

John E.
Gorzynski, et al.
Ultrarapid Nanopore Genome Sequencing in a Critical Care Setting .
NEJM, January 12, 2022.
DOI: 10.
1056/NEJMc2112090.