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Author: Liz Zee
Guide: In basic biological research, and in many application fields, such as diagnosis, biotechnology, forensic medicine In science and biological systems, 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 after she was born, 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.
It turns out that genetic information is crucial. Although standard tests found that Cora had a disease caused by a B vitamin processing enzyme called biotinase, follow-up tests were negative and her pediatrician concluded that Cora did not have the disease. But genomic tests 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". The case of
Cora illustrates the prospect of sequencing the entire genome of a newborn: discovering a large amount of genetic information can identify a baby in need of treatment and improve its health in the future. Genomics England (a government-funded company) Chief Medical Manager Richard Scott 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 help with this. "The cost has dropped so much that we are now at a tipping point-it would be wrong not to do so. "
researchers published their paper on " Science " on September 23, the article is 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
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 will also store genomic data for later use. To help predict drug sensitivity 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 those who can benefit from the increasing number of gene therapies. Of infants, these therapies are often for fatal childhood diseases, such as Sanfilippo syndrome, which is a metabolic disorder of that can cause brain damage .
But this British plan has one advantage: British national medical care The health care system is already using whole genomes in clinical care. In the United States, there may be a long way to go to sequence the genome of each newborn. Even if the technology is low-cost, a nationwide screening of the newborn’s genome is still possible. It 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 cost relative Wealthy families benefit.
Moral and practical problems abound in every country.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 "does not support whole-genome sequencing of all newborn babies." 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.
2018 report co-author, University of California, San Francisco bioethicist Barbara Koenig said that as costs fall, newborn genome sequencing may become attractive, but it is not easy. "The genome is much more complicated than it looks."
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.
is currently at Rady Children’s Hospital-San Diego. The project led by Stephen Kingsmore has achieved some success: the critically ill newborns are sequenced 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 subsequently discovered a serious vitamin B metabolism disorder mutation in the baby's genome. Soon, the boy began to drink formula milk with added vitamins. He is now in good health. Kingsmore’s research team reported in The New England Journal of Medicine on June 3,This situation may explain why his sister died when she was a baby 9 years ago.
In June of this year, Kingsmore reported at the NIH-sponsored Gene Therapy Online Conference that in 23 studies conducted by him and other research groups in the past ten years, 1839 severely ill children, 36% of them (mostly infants) Of children got the genetic diagnosis 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 result, several countries including Australia and the United Kingdom are routinely including the genome sequencing of severely ill newborns. California and Michigan have approved the addition of this test to medical assistance intend. Diana Bianchi, director of the National Institute of Child Health and Human Development of the United States, said at the meeting that genome sequencing "is becoming a new form of treatment for critically ill newborns."
NIH's other 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 monogenic diseases and hundreds of diseases that are currently not biochemically tested, 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 might ignore other changes.Even those genetic changes associated with neonatal diseases 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: has mutations that may never affect health. A research team led by Robert Green of the Harvard University 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 with disease genes, 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.
Although there are uncertainties, 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, were not affected by the results. Severe anxiety or breakdown of family relationships. "Many parents would rather know about these risk factors than 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 neonatal 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 is 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 psychiatry geneticist David Curtis of University College London (University College London) puts it, for critics, "there are a lot of moral 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.
whole-genome screening advocates agree thatThere are many uncertain factors for to resolve, including whether to provide parents with mutations that may not cause disease, and whether to detect incurable diseases such as , fragile X syndrome, and 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 June Gene Therapy Conference “recognized that whole-genome sequencing (for all babies) is the future direction. They discussed Some stories, such as a pair of San Diego couple who took a seemingly healthy baby home from the hospital in June 2019, and then received a call: Standard newborn screening found that Fitz Kettler lacks a normal immune system. Fitz was recommended to Kingsmore's genome sequencing team, and it turned out that he was suffering from severe combined immunodeficiency (SCID), a rare disease that may kill him within a year.
Fortunately, the San Francisco study The staff is testing a gene therapy for SCID. Fitz participated in the trial and received his own transplantation of bone marrow cells, through genetic modification to correct the mutation. His mother Christina Eagle-Kettler in The June meeting said 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 will take several years to add a new disease to the current screening program.Subsequent transfer of this disease to the state's screening list requires more time, which dims the prospect of adding hundreds of genome sequencing to detect diseases. University of North Carolina (University of North Carolina) Chapel Hill clinical geneticist Cynthia Powell is the chair of the committee responsible for overseeing the national list. She said that the committee is looking for ways to expedite action, for example, a way to immediately increase a class of diseases.
Some researchers are also concerned that the addition of genome sequencing to newborn screening in the United States 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 Geisinger Health System (Geisinger Health System), said that The United States still lacks the infrastructure for universal newborn sequencing, such as a recognized place to store the 3.7 million babies born each year. Genomic data. 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, US 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 tests on up to 20,000 newborns in North Carolina. Screening for multiple genetic diseases. 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 newborn genome sequencing 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 a biotinase deficiency expert. "The doctors have prepared all the information for us. This gives our world hope again," she said. If neonatal sequencing "becomes a very common thing, it needs a system to support it."
Reference:
https://www.science.org/content/article/sequence-every-newborn-s-dna -despite-obstacles-uk-pushes-ahead
Note: This article aims to introduce the progress of medical research and cannot be used as a reference for treatment options. If you need health guidance, please go to a regular hospital.
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