June 25, 2024

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Will DNA sequencing for every newborn become a reality in future?

Will DNA sequencing for every newborn become a reality in future?

Will DNA sequencing for every newborn become a reality in future?  Science: DNA sequencing for every newborn will be the future direction of development! 

In basic biology research, and in many application fields, such as diagnosis, biotechnology, forensic biology, and biosystems, knowledge of DNA sequence has become an indispensable knowledge.

The rapid sequencing speed with modern DNA sequencing technology has helped to sequence complete DNA sequences, or multiple types of genome sequencing and life species.

According to surveys, 5% to 7% of people are born with rare diseases. Newborn sequencing can screen out these genetic diseases and enable early treatment of newborns.

In 2016, a girl named Cora Stetson was born in Boston. Within 48 hours of her birth, hospital staff took a drop of blood from her heel to test for rare genetic diseases-a test that all newborns in the United States need to do. Since Cora’s parents also agreed to let her participate in a study, a researcher also took blood for more tests, which searched for about 1,500 disease genes in her genome.

Facts have proved that genetic information is crucial. Although standard tests found that Cora had a disease caused by a B vitamin processing enzyme called biotinase, subsequent tests were negative and her pediatrician concluded that Cora did not have the disease.

But genomic testing showed that she did have a mild genetic mutation that caused a biotinase deficiency, but this mutation may still cause “decreased vision and learning difficulties,” said Cora’s mother and drama educator Lauren Stetson. Cora is now taking biotin every day and is a kindergartener who is “energetic, crazy and lively”.

Cora’s case illustrates the prospect of sequencing the entire genome of newborns: discovering a large amount of genetic information can identify babies in need of treatment and improve their health in the future.

Richard Scott, chief medical manager of Genomics England (a government-funded company), said: “5% to 7% of people are born with a rare disease.

If it can be found, many people can be treated early in life.” Genome sequencing may Will help with this. “The cost has dropped so much that we are now at a tipping point-it would be wrong not to do this.”

The researcher published his paper on “Science” on September 23, titled “Sequencing every newborn’s genome to detect diseases faces ethical and practical obstacles, but the United Kingdom is pushing ahead with a major test”

Will DNA sequencing for every newborn become a reality in future?  

Genomics England hopes to test babies in a pilot research project involving up to 200,000 babies. Although it was originally designed to detect genes for rare diseases in children, it also stores genomic data for later use to help predict drug susceptibility and the risk of adult diseases (such as cancer) in the future. Some American researchers are also eager to include whole-genome sequencing in newborn screening. The motivation is to find babies who can benefit from an increasing number of gene therapies, which are often targeted at fatal childhood diseases such as Sanfilippo syndrome, a metabolic disorder that can cause brain damage.

But this British plan has an advantage: the UK’s national healthcare system already uses whole genomes in clinical care. In the United States, there may still be a long way to go to sequence the genome of every newborn. Even if the technology is low-cost, a nationwide newborn genome screening may require complex infrastructure and hundreds of millions of dollars. Some companies have begun selling newborn tests that can sequence multiple genes or entire genomes, at a cost of between a few hundred to a few thousand dollars. But these tests may only benefit relatively wealthy families.

In every country, ethical and practical issues abound, including which disease genes are tested and whether testing should be performed by default. In fact, a research team funded by the National Institutes of Health (NIH) warned in a 2018 report that, so far, “whole-genome sequencing of all newborn babies is not supported”. The report pointed out that the health effects of many mutations are unknown, and many genetic diseases are still untreatable. American disease advocacy organizations and clinical geneticists did not focus on performing whole-genome sequencing, but focused on accelerating the existing slow national system of newborn screening.

Barbara Koenig, a co-author of the 2018 report and a bioethicist at the University of California, San Francisco, said that as costs fall, newborn genome sequencing may become attractive, but it is not easy. “The genome is much more complicated than it seems.”

The idea of ​​the newborn genome can be traced back at least to the first draft of the human genome published in 2001. In a television interview broadcast that year, Francis Collin, then director of the National Human Genome Research Institute, predicted that it would be “feasible” to obtain an “analysis report” from the DNA sequence of infants within 20 years. In 2010, NIH held a seminar and planned four pilot projects to explore the sequencing of the newborn’s genome.

Will DNA sequencing for every newborn become a reality in future?  

Currently at Rady Children’s Hospital-San Diego, a project led by Stephen Kingsmore has achieved some success: sequencing critically ill newborns to determine if they have genetic diseases. For example, in October 2020, a couple brought a 5-week-old baby boy to the Rady emergency room. A computed tomography scan showed abnormalities in the brain. Kingsmore’s research team then discovered a serious vitamin B metabolism disorder mutation in the baby’s genome. Soon, the boy began to drink formula milk with added vitamins, and he is now in good health. Kingsmore’s research team reported in The New England Journal of Medicine on June 3 that this situation may explain the death of his sister when he was an infant nine years ago.

In June of this year, Kingsmore reported at an online conference on gene therapy hosted by NIH that in 23 studies conducted by him and other research groups in the past decade, 1839 severely ill children, 36% of them (mostly infants) were children The genetic diagnosis was obtained through genome sequencing. The results of the study of 533 patients (29% of the total) triggered changes in medical care and saved the lives of some babies.

As a result of this, several countries, including Australia and the United Kingdom, are routinely including the genome sequencing of critically ill newborns. California and Michigan have approved the addition of this test to the Medicaid program. Diana Bianchi, director of the National Institute of Child Health and Human Development in the United States, said at the meeting that genome sequencing “is becoming a new form of treatment for critically ill newborns.”

Other NIH pilot studies have used genome sequencing as a tool for screening all babies (health and disease) and compared it with standard newborn screening. The project started in the United States in the 1960s to screen for phenylketonuria (PKU), a metabolic disorder that causes intellectual disability unless the baby eats a special diet. States now mainly use biochemical tests to screen for PKU and about 30 to 70 other treatable diseases. Whole-genome sequencing can find those single-gene diseases and hundreds of diseases that currently have no biochemical tests, such as neonatal diabetes, hemophilia, and a kidney disease called cystinopathy.

But this technology is not foolproof. NIH-funded research and related studies have found that when the entire genome or protein-coding DNA is sequenced, 12% or more of the cases found in newborn screening are missed. This is because sequencing missed some genetic changes, and analysts may ignore other changes, even those genetic changes related to neonatal diseases that have not been proven to be harmful. But the study also shows that if these two methods are combined, it may be very effective, because sequencing can confirm an ambiguous biochemical test result, just like Cora.

Cora is one of a pilot project called BabySeq, which emphasizes another complexity of newborn sequencing: there are mutations that may never affect health. A research team led by Robert Green of Harvard University’s Brigham and Women’s Hospital (Brigham and Women’s Hospital) studied disease mutations in approximately 1,500 genes in 127 healthy babies and 32 sick babies. Approximately 8% of healthy babies and 9% of all babies have mutations in childhood genetic diseases. This data is very alarming. 88% of babies are carriers of genetic diseases. This discovery may make parents feel uneasy. Even if their baby has only one copy of the gene mutated, it takes two copies of the gene to get sick.

Among the 10 healthy babies who carried the disease gene, only Cora’s later clinical test results showed that she had the disease and should be treated. Seven other people have heart disease risk genes, and some babies who have slightly abnormal results in heart function tests will be subject to health monitoring. But many people with these mutations have never experienced symptoms.

Despite the uncertainty, according to the survey results published in JAMA Pediatrics in August, the parents of babies in the BabySeq pilot project, including 15 families with infants at risk of illness, did not experience serious problems because of the results. Anxiety or breakdown of family relationships. “Many parents would rather know about these risk factors than be ignorant of them,” Green said.

However, this finding also brought a warning: only 7% of the parents invited to participate in the BabySeq project accepted the invitation, and like Cora’s parents, most of them were well-educated whites.

To understand the broader population’s response to newborn sequencing, NIH is funding the BabySeq2 project, which will recruit 500 ethnically and socioeconomically diverse families in Boston, New York City, and Birmingham, Alabama.

In the United Kingdom, whole-genome sequencing has been used in routine medical care, and the public has begun to participate in newborn sequencing. This summer, Genomics England and the British National Screening Council announced the results of consultations with 130 different members of the public.

If the parents agree, and the parents only get test results for those childhood diseases that are treatable or preventable, then they support newborn sequencing.

Genomics England intends to follow these principles in its large pilot project, which can screen for up to 600 genetic diseases that can cause early childhood symptoms. If there is no cure, all of these diseases will be treated, which may include vitamin B6-dependent epilepsy and diamond blackfarn anemia (a red blood cell disease).

Scott said that planners hope to recruit up to 200,000 newborns within a few years, which is a significant proportion of the 600,000 births in the United States each year.

The pilot project was supported by Genetic Alliance UK. Policy director Nick Meade said that these organizations believe that whole-genome sequencing is a way to speed up the current screening program in the UK, which only detects nine diseases.

However, as David Curtis, a psychiatric geneticist at University College London, put it, for critics, “there are a lot of ethical and cost issues.” He is worried that discovering some variants that do not make babies sick will lead to unnecessary testing and family anxiety.

He also worried that the cost of neonatal genomics testing would be approximately US$900 per baby, or US$540 million per year, which is too high for the potential return, and pointed out that newborns cannot agree to store their genomes in Genomics England.

Get the place. “In 18 years, will that kid be happy that someone takes his genome sequence and saves it in the database?” Curtis asked.

Advocates of genome-wide screening agree that there are many uncertainties that need to be resolved, including whether to provide parents with mutations that may not cause disease, and whether to detect incurable diseases such as Fragile X syndrome that cause intellectual disability.

A parent told the British Counseling Center that he was very happy that his son did not know that he had Duchenne muscular dystrophy before the onset of symptoms. They had a happy and carefree four years.

However, Tiina Urv of the National Center for Advance Translational Science said that basically everyone who attended the NIH’s June gene therapy conference “recognized that whole-genome sequencing (for all babies) is the future. They discussed some stories.

For example, a San Diego couple took a seemingly healthy baby home from the hospital in June 2019, and then received a call: Standard newborn screening found that Fitz Kettler lacked a normal immune system.

Fitz was recommended to Kingsmore His genome sequencing team found that he was suffering from severe combined immunodeficiency (SCID), a rare disease that could kill him within a year.

Fortunately, San Francisco researchers are testing a gene therapy for SCID. Fitz participated in the experiment and received a transplant of his own bone marrow cells to correct the mutation through genetic modification.

His mother, Christina Eagle-Kettler, said at the June meeting that his family is still quarantining him to prevent him from contracting COVID-19, but he now has functioning immune cells and is growing vigorously. She said that early diagnosis through sequencing is the key. “I can’t imagine not helping other similar families with early diagnosis.”

However, there are practical obstacles to adopting neonatal sequencing in the United States. First, it takes several years to add a new disease to the current screening program, and then it takes more time to transfer this disease to the state screening list, which makes it possible to screen by adding hundreds of genome sequencing The outlook for the disease is bleak.

Cynthia Powell, a clinical geneticist at the University of North Carolina at Chapel Hill, is the chair of the committee overseeing the national list. She said that the committee is looking for ways to expedite action, for example, a way to increase a class of diseases immediately.

Some researchers are also concerned that the addition of genome sequencing to US newborn screening may rebound existing plans. Newborn screening is basically mandatory, just like vaccinations for children (parents generally do not choose not to vaccinate).

Koenig said the goal of preventing severe childhood diseases in the entire population is “very important.” Powell said adding genes that are not always disease-causing or lacking a clear and effective treatment, and storing the baby’s entire genome, may make parents abandon the project. “I think this may endanger the entire newborn screening system and even fail to screen for diseases like PKU. I think we have to be very careful,” she said.

Marc Williams, a clinical geneticist at the Geisinger Health System, said that the United States still lacks infrastructure for universal newborn sequencing, such as a recognized place to store the genome data of 3.7 million babies born each year.

State laboratories that now perform newborn screening may not be able to interpret the entire genome. According to Melissa Wasserstein, a clinical geneticist at the Albert Einstein School of Medicine, the process “will have to be super smooth.”

In contrast, in the UK, most of the infrastructure is already in place. Thanks to the “100,000 Genome Project”, a study that used sequencing to diagnose or treat patients with rare diseases in the past decade, the UK already has a research database and seven laboratories that provide whole-genome testing.

The U.S. healthcare system also needs to provide genetic counseling and possible treatments for families that get terrifying sequencing results. Powell said: “Our health care system has been unable to withstand the conditions required for standard newborn screening tests.”

Currently, American researchers are advancing demonstration projects. For example, starting next year, researchers plan to use a DNA test that only sequence specific genes with parental consent to perform 100 or more genes on up to 20,000 newborns in North Carolina. Disease screening.

Wasserstein led a study called ScreenPlus, which will test 175,000 babies born in hospitals in multi-ethnic communities in New York City over a period of more than 5 years for 14 serious diseases that are not included in the standard screening list. . One of the goals is to observe whether the estimated 20 to 40 babies with these diseases are healthier than babies who are later diagnosed.

The project will also seek parents’ opinions on newborn screening, including the use of whole-genome sequencing. Wasserstein said that this investment is “hopefully understanding how to launch whole-genome sequencing of newborns in a sensitive way.”

Lauren Stetson said that she knew the risks were high. She said that the sequencing of the newborn’s genome is “important” because it can deliver life-changing messages that are important to some people.

But she warned that after the newborn is sequenced, the treatment must be available. When she and her husband learned of Kola’s genetic results, they were immediately introduced to a genetic counselor and an expert in biotinase deficiency. “The doctors have prepared all the information for us. This gives our world hope again,” she said. If newborn sequencing “becomes a very common thing, it needs a system to support it.”



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