Tag: genetic screening

100,000 newborn babies will have their genomes sequenced in the UK. It could have big implications for child medicine | CNN

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CNN
 — 

The UK is set to begin sequencing the genomes of 100,000 newborn babies later this year. It will be the largest study of its kind, mapping the babies’ complete set of genetic instructions, with potentially profound implications for child medicine.

The £105 million ($126 million) Newborn Genomes Programme will screen for around 200 rare but treatable genetic conditions, with the aim of curtailing untold pain and anxiety for babies and their families, who sometimes struggle to receive a diagnosis through conventional testing. By accelerating the diagnostic process, earlier treatment of infants could prevent many severe conditions from ever developing.

The study would see roughly one in 12 newborn babies in England screened on a voluntary basis over two years. It will operate as an extension of current newborn testing, with the findings intended to inform policymakers, who could pave the way for sequencing to become more commonplace.

Nevertheless, the project has raised many longstanding ethical questions around genetics, consent, data privacy, and priorities within infant healthcare.

The health game-changers of the last 500 years

In the UK, like many other countries, newborn babies are screened for a number of treatable conditions through a small blood spot sample. Also known as the heel prick test, this method has been routine for over 50 years, and today covers nine conditions including sickle cell disease, cystic fibrosis and inherited metabolic diseases.

“The heel prick is long overdue to be obsolete,” argues Eric Topol, an American cardiologist and professor of molecular medicine at The Scripps Research Institute, who is not connected with the UK sequencing initiative. “It’s very limited and it takes weeks to get the answer. Sometimes, babies that have serious metabolic abnormalities, they’re already being harmed.”

Some conditions that are tested for have variations that may not register a positive result. The consequences can be life-altering.

One example is congenital hyperthyroidism, which impacts neurological development and growth and affects “one in 1,500 to 2,000 babies in the UK,” explains Krishna Chatterjee, professor of endocrinology at the University of Cambridge. It is the result of an absent or under-developed thyroid gland and can be treated with the hormone thyroxine, a cheap and routine medicine. But if treatment doesn’t begin “within the first six months of life, some of those deleterious neurodevelopmental consequences cannot be prevented or reversed.”

The Newborn Genomes Programme will test for one or more forms of congenital hypothyroidism that are not picked up by the heel prick test. “At a stroke, you can make a diagnosis, and that can be game changing – or life changing – for that child,” Chatterjee says.

The program is led by Genomics England, part of the UK Department of Health and Social Care. Along with its partners, it has carried out a variety of preparatory studies, including a large-scale public consultation. A feasibility study is currently underway to assess whether a heel prick, cheek swab or umbilical cord blood will be used for sampling, with the quality of the DNA sample determining the final choice.

Genomics England says that each of the 200 conditions that will be screened for has been selected because there is evidence it is caused by genetic variants; it has a debilitating effect; early or pre-symptomatic treatment has a life-improving impact; and treatment is available for all through the UK’s National Health Service (NHS).

Richard Scott, chief medical officer and deputy CEO at Genomics England, says the program aims to return screening results to families in two weeks, and estimates at least one in 200 babies will receive a diagnosis.

Contracts for sequencing are still to be confirmed, although one contender is American biotech company Illumina. Chief scientist David Bentley says the company has reduced the price of its sequencing 1,000-fold compared to its first genome 15 years ago, and can now sequence the whole human genome for $200.

Bentley argues that early diagnosis via genome sequencing is cost effective in the long term: “People get sick, they get tested using one test after another, and that cost mounts up. (Sequencing) the genome is much cheaper than a diagnostic odyssey.”

Illumina equipment in a sequencing laboratory. The cost of sequencing the human genome has fallen significantly in the last 15 years, says the company.

But while some barriers to genetic screening have fallen, many societal factors are still in play.

Feedback from a public consultation ahead of the UK project’s launch was generally positive, although some participants voiced concerns that religious views could affect uptake, and a few expressed skepticism and mistrust about current scientific developments in healthcare, according to a report on its findings.

Frances Flinter, emeritus professor of clinical genetics and Guy’s and St Thomas’ NHS Foundation Trust and a member of the Nuffield Council on Bioethics, described the program as a “step into the unknown” in a statement to Science Media Centre in December 2022, reacting to the launch of the program.

“We must not race to use this technology before both the science and ethics are ready,” she said at the time. “This research program could provide new and important evidence on both. We just hope the question of whether we should be doing this at all is still open.”

Genome sequencing has raised many philosophical and ethical questions. If you could have aspects of your medical future laid ahead of you, would you want that? What if you were predisposed to an incurable disease? Could that knowledge alone impact your quality of life?

“People don’t generally understand deterministic or fatalistic-type results versus probabilistic, so it does require real teaching of participants,” says Topol. In other words, just because someone has a genetic predisposition to a certain condition, it doesn’t guarantee that they will develop the disease.

Nevertheless, sequencing newborn babies has made some of those questions more acute.

“One of the tenets of genomics and genomics testing is the importance of maintaining people’s autonomy to make their own decisions,” says Scott, highlighting the optional nature of the program.

“We’ve been quite cautious,” he stresses. “All of the conditions that we’re looking for are ones where we think we can make a really substantial impact on those children’s lives.”

Parents-to-be will be invited to participate in the program at their 20-week scan, and confirm their decision after the child’s birth.

“These will be parents, most of whom won’t have any history of a genetic condition, or any reason to worry about one. So it will be an additional challenge for them to appreciate what the value might be for their family,” says Amanda Pichini, clinical lead for genetic counseling at Genomics England.

Part of Pichini’s remit is to ensure equal access to the program and to produce representative data. While diversity comes in many forms, she says – including economic background and rural versus urban location – enlisting ethnically diverse participants is one objective.

“(There) has been a lack of data from other ethnic groups around the world, compared to Caucasians,” says Bentley. “As a result, the diagnostic rates for people from those backgrounds is lower. There are more variants from those backgrounds that we don’t know anything about – we can’t interpret them.”

If genomics is to serve humanity equally, genome data needs to reflect all of it. Data diversity “isn’t an issue that any one country can solve,” says Pichini.

Other countries are also pursuing sequencing programs and reference genomes – a set of genes assembled by scientists to represent a population, for the purpose of comparison. Australia is investing over $500 million AUS (around $333 million) into its genome program; the “All of Us” program is engaged in a five-year mission to sequence 1 million genomes in the US; and in the Middle East, the United Arab Emirates is seeking its own reference genome to investigate genetic diseases disproportionately affecting people in the region, where Illumina’s recently opened Dubai office will add local sequencing capacity.

Richard Scott of Genomics England says he hopes findings from the UK will be useful to other countries’ health systems, especially those not in “a strong position to develop the evidence and to support their decisions as well.”

Sequenced genomes will enter a secure databank using the same model as the National Genomic Research Library, in which they are deidentified and assigned a reference number.

Researchers from the NHS, universities and pharmaceutical companies can apply for access to the National Genomic Research Library (in some cases for a fee), with applications approved by an independent committee that includes participants who have provided samples. There are plenty of restrictions: data cannot be accessed for insurance or marketing purposes, for example.

“We think it’s really important to be transparent about that,” says Pichini. “Often, drugs and diagnostics and therapeutics can’t be developed in the NHS on (its) own. We need to have those partnerships.”

When each child turns 16, they will make their own decision on whether their genomic data should remain in the system. It hasn’t yet been decided if participants can request further investigation of their genome – beyond the scope of newborn screening – at a later date, says Scott.

After the two-year sampling window closes, a cost-benefit analysis of the program will begin, developing evidence for the UK National Screening Committee which advises the government and NHS on screening policies. It’s a process that could take some time.

Chatterjee suggests an entire lifetime might be needed to measure the economic savings that would come from early diagnosis of certain diseases, citing the costs of special needs schooling for children and support for adults living with certain rare genetic conditions: “How does that balance against the technical cost of making a diagnosis and then treatment?”

“I’m quite certain that this cost-benefit equation will balance,” Chatterjee adds.

Multiple interviewees for this article viewed genome sequencing as an extension of current testing, though stopped short of suggesting it could become standard practice for all newborn babies. Even Topol, a staunch advocate for genomics, does not believe it will become universal. “I don’t think you can mandate something like this,” he says. “We’re going to have an anti-genomic community, let’s face it.”

Members of the medical community have expressed a variety of concerns about the program’s approach and scope.

In comments released last December, Angus Clarke, clinical professor at the Institute of Cancer and Genetics at Cardiff University, queried if the program’s whole genome sequencing was driven by a wish to collect more genomic data, rather than improve newborn screening. Louise Fish, chief executive of the Genetic Alliance UK charity, questioned whether following other European nations that are expanding the number of conditions tested through existing bloodspot screening may have “just as great an ability to improve the lives of babies and their families.”

If genome sequencing becomes the norm, it remains to be seen how it will dovetail with precision medicine in the form of gene therapy, including gene editing. While the cost of sequencing a genome has plummeted, some gene therapies can cost millions of dollars per patient.

But for hundreds of babies not yet born in England, diagnosis of rare conditions that have routine treatments will be facilitated by the Newborn Genomes Programme.

“So much of medicine today is given in later life, and saves people for a few months or years,” says Bentley. “It’s so good to see more opportunity here to make a difference through screening and prevention during the early stages of life.

“It is investing maximally in the long-term future as a society, by screening all young people and increasing their chances of survival through genetics so they can realize their enormous potential.”

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Should We Be Testing Everyone’s DNA?

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Kelly Kashmer credits genetic testing with saving her life.

In 2014, during a routine medical appointment, a physician’s assistant began asking questions about her relatives and their experiences with cancer. As she mentally climbed her family tree, she recalled her grandmother on her mother’s side, and an aunt, had both been diagnosed with cancer. The details were fuzzy. (She’d later learn that both had died of ovarian cancer.) An aunt on her father’s side, too. But, she reasoned, they were all older than 60 when they were diagnosed. Kashmer was young – only 31 – and busy.

The PA recommended genetic testing for variations known to be linked to hereditary breast and ovarian cancers. A mutation in a BRCA gene increases a woman’s lifetime risk of breast cancer fivefold, and cancer treatment, in general, is more successful during the earliest stages. Kashmer, who was focused on raising her two smart and spirited daughters, ages 1 and 3, didn’t know anything about mutations, risk, and screening.

“Really, I’d never heard anything other than being in the Target line and seeing an article about Angelina Jolie,” says Kashmer, who lives in Fort Mill, SC. In 2013, the actress, whose own mother had died of breast cancer, announced she had tested positive for a pathogenic BRCA mutation and undergone a double mastectomy and reconstruction.

Kashmer consented, unaware that insurance wouldn’t cover the test. She would later be charged $5,000. “If my insurance company had told me that, I would have said, ‘Don’t run it,’” she says now. She didn’t think much about it at the time: As she left, she threw away the informational pamphlets the PA had given her about genetic risks.

Two weeks later, she learned that she’d tested positive for a mutation in the BRCA2 gene. Two weeks after that, after having what was supposed to be baseline imaging – an MRI and mammogram – she was diagnosed with stage II, triple-negative breast cancer. “I was very active, very healthy, and our lives just got turned upside down,” she says. “I definitely got thrown into the middle of this.” 

In hindsight, she regards that genetic test as a warning and a blessing in disguise: Without it, she wouldn’t have had imaging or been diagnosed, or been able to act on the diagnosis, as unwelcome as it was. Her experience raises an interesting question: What if everyone had access to screening, not just for breast cancer but for any treatable disease?

Right now, genetic testing isn’t usually used as a front-line tool in medicine. It may be offered with other screening tools when a person’s family history suggests an increased inherited risk of disease, or after they’ve received a diagnosis. Those data can guide treatment decisions for people with some cardiac diseases. Tumor sequencing has become routine in cancer care because some targeted treatments are linked to particular mutations. 

It’s not routinely offered in primary care practice, but some researchers, geneticists, and providers say maybe it should be. Genetic testing, in the future, could be a universal screening tool. As sequencing becomes less expensive and research unearths connections between variations and risk, genetic screening could support a kind of “precision public health” approach to medicine, one that allows anyone – not just those with a diagnosis or with access to tests – to benefit from the tools of precision medicine.

Using precise molecular information to help the population sounds like a contradiction. “Precision public health does seem almost oxymoronic when you look at the terms,” says Laura Milko, PhD, a public health genetics researcher at the University of North Carolina at Chapel Hill’s Department of Genetics. But she and other proponents say genetic testing for harmful mutations with associated interventions – if appropriately combined with other screening tools – suggests an effective way to reach a greater share of the population at risk. 

Since 2014, when Kashmer was diagnosed with breast cancer, the cost of genetic testing has fallen to a few hundred dollars, rather than a few thousand. And unlike the case 9 years ago, some insurance plans now cover testing that is recommended by a doctor, though policies vary by company and by state. (And they don’t cover elective, private testing.) These changes have helped increase awareness and access, and advocates argue that widespread use of genetic testing would make it more likely that people who are at risk and don’t know it could take preventive action.

“In order for precision health to be equitable for everybody, it needs to be available to everybody,” Milko says. Even though the cost of sequencing has fallen, “what’s happening now is that ‘healthy, wealthy’ folks are able to access things like genetic testing.” That’s partly because of the cost of the test, which is still at least hundreds of dollars, and partly because of disparities in access to high-quality care. People in some ethnic or racial groups, or with low socioeconomic status, get genetic testing at disproportionately lower rates than wealthy, white patients, which means those at high risk because of inherited genes are less likely to find out. Population-based DNA testing points to a way to remedy disparities in screening rates among people from diverse racial, ethnic, or socioeconomic groups.

At the same time, there’s a wide gulf between the potential and putting the testing into practice. No recommended guidelines or accepted standards exist for population DNA screening programs. Privacy and ethical concerns abound about personal genetic data, and insurance companies lack a systematic way to reimburse costs for the tests.

But the payoff for navigating those challenges, says Milko, would be a boon to public health and a potential decrease in diagnoses of many diseases. “The promise is that it would allow us to screen people pre-symptomatically, ideally implemented in such a way that everyone would have access to it,” she says. But “ideally implemented” remains out of reach at the moment, she says, and the stakes of getting it wrong include stoking distrust in medicine, making health inequalities worse, and causing undue stress to patients. “Right now, we need to look at how to implement this in an ethical and equitable manner, and make sure we’re not jumping off a cliff.” 

Filling In the Gaps

Screening guidelines exist for a variety of diseases, but they don’t use DNA. Newborn screenings look for blood-borne biomarkers that reveal genetic diseases. Imaging tools like mammograms and MRI are used to find breast cancer. A colonoscopy can reveal colorectal tumors and precancerous polyps that can be safely removed. Blood tests identify people with high cholesterol, which is linked to a higher risk of heart disease and stroke.

These methods aren’t perfect, and researchers continue to debate their benefits. A positive result on a mammogram, for example, can lead to overtreatment, and roughly half of all women who get regularly screened for breast cancer will have a false positive after 10 years of annual screening. Conventional screening guidelines don’t catch everyone, either: A 2018 analysis of more than 50,000 exomes – the parts of genes that include the code for proteins – found that of the men and women who tested positive for a “known pathogenic” or “likely pathogenic” variation in a BRCA1 or BRCA2 gene, nearly half did not meet the standard guidelines for recommending clinical testing.

Using those guidelines alone, “we would still miss half of these mutations,” says genetic counselor Erica Ramos. She’s now an executive with Genome Medical, in San Diego, and serves on the advisory panel for the National Cancer Institute’s All of Us program, which analyzes health data, including genomic data, from volunteers. 

“If you screened everybody for BRCA1 and 2, then you don’t have to worry about the personal and family history for those genes before you test,” Ramos says, adding that those histories are still important for recommending next steps. Breast cancer is one example, but screening guidelines for other, treatable diseases – including other cancers and heart disease – similarly miss a large share of the right patients.

A Rough Road to Realization

A population genetic screening program offers a solution, but widespread use will be rife with challenges, says Ramos. Those begin with figuring out how to reach people. “If we’re going to catch people before they get sick, we have to get it into primary care,” she says. That’s a tall order: Primary care doctors are already often overwhelmed, and they may not be comfortable with the complexities of interpreting genetic testing, she says. Plus, half of people between ages 18 and 49 don’t even have a primary care doctor, according to a Kaiser Family Foundation study.

There’s also the issue of privacy and trust. Amid reports of police using DNA from newborn blood draws for criminal investigations and security breaches in companies that do genetic testing, people may worry about the safety of their own data. Or how it might be used. Kashmer, in South Carolina, discovered she wasn’t eligible for a life insurance policy after the genetic test turned up a BRCA mutation, for example. That’s not unusual: Although federal law prohibits medical insurers from basing coverage decisions on genetic tests, life insurance companies can request genetic information from potential customers or from their medical records.

Another issue is when to offer testing, and what genes to test for. “We want to understand who’s at risk for certain conditions that are highly actionable, which means there’s something we could do today to reduce risk,” says Noura Abul-Husn, MD, an internist and medical geneticist from the Icahn School of Medicine at Mount Sinai, in New York City. She also recently joined 23andMe, a consumer gene testing company, to help develop ways for the company to connect consumer genomics with clinical care.

Knowledge about potentially harmful mutations is most useful if it’s connected to a clinical action, says Abul-Husn. The CDC has identified three conditions that have genetic tests available, treatment options based on those results, and rigorous evidence of a benefit. They are hereditary breast and ovarian cancers, Lynch syndrome (which increases a person’s chance of many cancers), and familial hypercholesterolemia (which increases a person’s chance of a heart attack at a young age). Early intervention for these conditions, says Milko, has the best chance of success for preventing life-threatening complications.

Glimpses of the Future 

Milko is working on a project, funded by the National Human Genome Research Institute, to develop an age-based genomic screening approach. “We would add it to routine health visits for appropriate ages for intervention,” she says. That means not screening for diseases, for example, that typically don’t show up until adulthood. The goal, she says, would be to find a testing schedule that aligns with the best time to step in to prevent a disease. And as new treatments become available for other conditions detectable by mutations, she says, the number of tested mutations will grow.

Other projects are also working out the details for DNA screening programs. Those include a roadmap for a genomic screening program for healthy adults, published by the National Academy of Medicine in 2018, and a clinical trial looking into the use of whole genome sequencing in newborn screening. (Milko says she wholeheartedly supports the findings of that paper, which suggest that while population screening has tremendous potential to detect genetic risk for inherited conditions in healthy adults, it’s premature to deploy large-scale programs without more research. “Newborn screening works extremely well, and we don’t want to bring in genomic sequencing if it unnecessarily makes parents uncomfortable.”)

Kashmer, in South Carolina, has taken a grassroots approach to increasing access and knowledge about screening. After her treatment, she launched NothingPink, a nonprofit breast cancer advocacy group focused on awareness of genetic testing for cancer. In the last few years, it has successfully advocated for better inclusion of cancer history questions on medical intake forms, and for the state’s Medicaid program to cover BRCA mutation testing. (South Carolina was one of the last three states without coverage.) 

It has also created a community where women with a harmful mutation can connect with others who have had to wrestle with tough decisions. “We talk about family planning, we talk about life insurance,” Kashmer says. They discuss both practical and intimate issues.

“These women connect, and I don’t think that these conversations were being had 20 years ago,” Kashmer says. “But it’s a beautiful thing that now we are open to talking. It’s our life, and it’s a real thing, and we just want to be there for the preschools and the proms and the graduations.”

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