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Newborn Sequencing Potential, Challenges for Scaling Discussed at ASHG

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SAN DIEGO (GenomeWeb) – Sequencing the genomes of critically ill newborns with a suspected genetic disorder has been shown in some cases to be a life-saving measure, with researchers from Rady Children's Institute for Genomic Medicine previously reporting that sequencing avoided morbidity in 11 of 42 babies sequenced.

At this week's annual meeting of the American Society of Human Genetics held here, researchers reported on not just the potential of sequencing to diagnose and change management for sick newborns, but also discussed challenges with scaling up the process.

For instance, Lucy Raymond, professor of medical genetics and neurodevelopment at the University of Cambridge, discussed how her team is studying efforts to implement sequencing within the UK's health system.

Rare disease accounts for 35 percent of deaths in children under the age of one, and 30 percent of children with rare disease die within five years, she said in a presentation. "So, improving the time to diagnosis has the potential to inform management and treatment options."

Raymond said that the team recruited a relatively unselected population of newborns and children in the neonatal intensive care unit or the pediatric intensive care unit, excluding those newborns who were born prematurely but not for a genetic cause and those with known diagnoses.

In addition, she said, when possible the researchers sought to do a trio analysis of both the affected child and parents. One of the first challenges was designing an appropriate informed consent process, she said. Since families were recruited into the study at extremely stressful timepoints — often immediately after the mother gave birth to a sick child with a poor prognosis. Asking them to read through and sign a lengthy informed consent document, "seemed inappropriate," Raymond said, so the group developed a two-stage process. Raymond described the initial consent as a "vey light touch" with a fuller consent done within two weeks.

In an initial study, the Cambridge team approached 344 families, 165 of whom consented immediately and 56 of whom declined immediately. A further 123 families never outright said no, but ultimately did not consent. Some families indicated it was not the right time, for others there were logistical and practical reasons why they were unable to consent, and others couldn't cope with making more decisions. In addition, Raymond speculated that some families did not want to participate, but also did not want to say no outright to their physician.

The Cambridge team had a slightly different strategy for cases in which they were able to do a trio analysis versus those for whom they only had a sample from the affected individual. For the trios, which encompassed 90 percent of cases, they sequenced the whole genome and the mitochondrial genome, which enabled them to look for structural variants, SNVs, uniparental disomy, and short tandem repeat extensions. For the 1 percent of cases where the researchers only had DNA from the affected individual, they performed WGS but only analyzed about 4,000 genes.

Turnaround time for reporting preliminary findings is now about two to three weeks, Raymond said, with Sanger confirmation adding another one to two weeks. However, she noted that the team plans to discontinue the Sanger step soon.

In total, 40 individuals, or 21 percent, were diagnosed. And there was a "wide range of diagnoses," with the same gene rarely implicated twice and in some cases novel genes discovered, including the role of NDUFA6 in mitochondrial complex I deficiency, which the group described last month in the American Journal of Human Genetics.

For 80 percent of the children who were diagnosed, the physician reported that the diagnosis made a difference in the child's care. Even in the cases where the child ultimately died, the diagnosis was helpful for both the families and the physician because it offered an explanation.

Raymond noted that those children with neurological disorders or dysmorphology were more likely to receive a diagnosis. In addition, she noted that one challenge in diagnosing newborns is that their phenotypes are often different than what has previously been reported in the literature.

Raymond said the team is "testing how we can implement this into our healthcare system." One important aspect, she said, is that they did not require the children to be evaluated by a clinical geneticist before enrolling into the study. The team developed a process by which the physician could evaluate and recruit the families.   

Similarly, in the US, several academic groups are studying whether and how to implement sequencing for newborns under the National Institutes of Health's NSIGHT projects.

At Rady Children's Hospital, for instance, researchers are conducting a prospective clinical trial in up to 1,000 newborns, randomizing them to either rapid WGS or rapid exome sequencing.

David Dimmock, medical director of Rady's Institute for Genomic Medicine, described some preliminary results from that trial. One of the requirements for enrollment was that the family had to enroll within 96 hours of the infant entering the NICU, Dimmock said, due to the rapid decline in clinical actionability if results are returned after one week. Of around 1,200 infants initially considered, just over 200 ultimately enrolled.

A diagnosis was made in around 20 percent, similar to the Cambridge team's reported diagnostic yield. In addition, when the researchers did not initially find a diagnosis on the infant, they sought to do a trio analysis if possible, which they did for about half of the cases. The trio analysis enabled a diagnosis in three infants who would not otherwise have been diagnosed, Dimmock said.

Physicians reported that the sequencing, even when negative, enabled improved communication of outcomes and expectations. They also reported that in some cases a diagnosis enabled them to avoid further testing, avoid surgical procedures, or start a targeted treatment.

In another of the NSIGHT studies, known as BabySeq, Stacey Pereira from Baylor College of Medicine, described some interim results evaluating the impact of sequencing on the parent-child relationship, the parents' mental health, and whether sequencing a sick newborn had an impact on parents' feelings of blame.

The BabySeq study is different from the Cambridge and Rady studies in that it is not only evaluating sick newborns but also healthy newborns.

Pereira said that so far the team has sequenced the exomes of 159 newborns — 127 healthy and 32 sick. Another 158 newborns have been randomized to receive standard-of-care treatment.

In total, including both the healthy babies and those in the NICU, 11 percent received monogenic disease variant results. In addition, the team also reports back pharmacogenetic variants and carrier status. To study the impact of receiving results, the researchers surveyed the parents prior to their child being sequenced, at the time results were returned, and then again at three months and 10 months after receiving results.

Overall, Pereira reported that while parents who received a result of monogenic disease risk viewed their child as being more vulnerable, the result did not negatively impact the bonding between parent and child nor parents' levels of anxiety and depression.

These interim findings come on the heels of a report by the Hastings Center, which said that although sequencing the genomes of sick babies may be warranted, large-scale sequencing of healthy babies should not yet be implemented.

Yet, as Pereira reported, the BabySeq study has so far found that delivering sequencing results whether to parents of healthy or sick newborns, does not seem to cause distress or negatively impact the relationship between the parent and child.

However, Pereira cautioned that the families in the study were all self-selected, choosing to enroll in the study, and so may have had a favorable view of genomics. In addition, the participants are not demographically representative of the broader US, with the vast majority white, affluent, and holding college degrees.

Nonetheless, for sick newborns at least, many groups are working to scale up genomic testing. Rady's Dimmock noted that based on the enrollment criteria applied in his NSIGHT study, about half of all newborns in a level 3 or 4 NICU would meet criteria for sequencing, which translates to about 40,000 newborns in the US annually.

In a separate research project at Rady that is also testing rapid WGS of newborns, the hospital was recently awarded $2 million from the California Medical Assistance Program to implement the pipeline in the NICU at four participating hospitals in California.

Shareef Nahas, senior director at Rady Children's Institute for Genomic Medicine, said in a presentation that a key challenge will be figuring out how to pay for this type of testing on a large scale. To date, Rady's newborn sequencing has been paid for through grants and philanthropy, and one major goal of the state-funded project will be to generate the data to show clinical and economic utility with the hope that it improves the chances of reimbursement.

In a small study of 42 infants that the Rady team published earlier this year, they found that sequencing resulted in net healthcare savings of $128,544. The next step is to study costs on a larger group.

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