Rapid Genome Sequencing Could Help More NICU Babies, if Key Barriers are Addressed
Rapid genome sequencing can deliver life-saving diagnoses for critically ill infants, but uncertainty about who should be tested and how to interpret unclear genetic findings continues to limit its impact. Miller School researchers are working to solve both challenges.
A baby is in the neonatal intensive care unit (NICU) with a life-threatening illness. However, the usual tests are providing no clarity on the child’s underlying disease. Fortunately, rapid genome sequencing (rGS) can identify the genetic variant(s) driving that child’s rare condition, giving clinicians the necessary clues to intervene.
That’s the dream. But in practice rGS, is not helping everyone it should. In two recent review papers, Pankaj Agrawal, M.D., professor and chief of the Division of Neonatology at the University of Miami Miller School of Medicine’s Department of Pediatrics and Jackson Health System, and colleagues address two major issues that have been limiting rGS:
• Deciding who should get tested in the NICU
• Interpreting the burgeoning problem of variants of uncertain significance (VUS)
“For many clinicians, particularly those unfamiliar with rGS, sequencing represents a real dilemma,” said Dr. Agrawal. “They’re not sure whether to move forward, and the guidelines can be quite vague. Equally troubling, if a patient is sequenced, often the results produce variants of uncertain significance, which might be driving the disease or might not, so they’re difficult to act on.”
Who Should Get rGS?
Whether it’s rapid whole genome sequencing or rapid whole exome sequencing (which only reads protein coding genes, about 2% of the genome), rGS has proven its value, providing critical information to diagnose sick infants. Dr. Agrawal believes that, eventually, every child in the NICU will be sequenced. But right now, physicians must make choices.
A classic example is hypotonia, in which infants have poor muscle tone. Hypotonia can be a symptom for multiple diseases, some of them serious. However, not every physician may feel hypotonia warrants rGS. Previously, Dr. Agrawal’s research has shown rGS can help diagnose babies with hypotonia, but first the physician must order the test.
To better understand these decision-making processes, Dr. Agrawal and colleagues conducted a comprehensive literature review. Published in the European Journal of Human Genetics, the authors found there is little consistent guidance to govern these choices.
“Which patients should we sequence? If we look at the literature, there are no uniform guidelines,” said Dr. Agrawal. “Eventually, we should consider moving to universal sequencing, and this won’t be an issue, but in the present, sequencing needs to be more inclusive.”
One way to drive more inclusive rGS is education. There are often genomic expertise disparities between large academic medical centers, such as Jackson Health System, and small community hospitals. The Miller School and others have been testing telemedicine to help level the playing field.
“Our VIGOR study shows we can use telemedicine to provide those extra decision-making resources,” said Dr. Agrawal. “This was a pilot project, but if we can roll it out more widely, we could fill some of these gaps.”
Gray Areas in Interpreting Genetic Findings
While rGS can produce definitive diagnoses, the results can often be fuzzy. The variant may be harmful or completely benign. To complicate matters, more sequencing can generate more VUS. According to ClinVar, the National Institutes of Health’s (NIH) variant database, around 8% of results in 2013 were VUS. That prevalence exploded to more than 50% in 2025.
In a review published in Genome Medicine, Dr. Agrawal and colleagues looked at how hospitals can better address VUS.
“There is no common, systematic approach to dealing with VUS,” said Dr. Agrawal. “This is a big problem because it leaves clinicians with nowhere to go to help their patients. Institutions must develop systems to address these variants as clinical/research opportunities.”
The review also identifies a number of resources that can help clinicians clarify these murky variants, such as the Clinical Genome Resource (ClinGen), an NIH database that describes a variant’s clinical relevance, the Broad Institute’s Genome Aggregation Database (gnomAD) and others.
The authors believe finding a VUS is an invitation to conduct more research. This could include deep phenotyping, which more closely assesses the disease’s traits, reanalyzing existing genomic data, embracing computational tools, including artificial intelligence, and other methods.
There is also evidence that multiomic techniques could be helpful. The genome is only the blueprint. Emerging disciplines like transcriptomics, which investigates the RNA transcribed from genes, and proteomics, which analyzes the proteins translated from RNA, could provide deeper information about a variant and how it might contribute to disease biology.
Dr. Agrawal and many others are working to solve these problems. In addition to test-driving telemedicine, Project VIGOR also developed clinical reports to make genomics more accessible for clinicians and help them make better decisions.
“We want to make rapid genome sequencing a routine test in these situations, but there’s a lot of work to do,” said Dr. Agrawal. “The answer right now is to develop the appropriate guidelines, both for who should be sequenced and how we address VUS. These are difficult issues, but they are also quite solvable.”
More from Miller School of Medicine Pediatrics
A $3.2 million NIH grant supports research using antisense oligonucleotides to develop rapid, personalized treatments for NICU infants.
Florida’s Sunshine Genetics Act launches a pilot program to expand newborn screening using genomic sequencing.
Dr. Pankaj Agrawal found clinical interpretive reports are feasible and effectively communicate important genomic information to clinicians.
Dr. Pankaj Agrawal was part of an international research group that identified a mutated gene that deters neural development and function.
Tags: Department of Pediatrics, Division of Neonatology, Dr. Pankaj Agrawal, Gene sequencing, genetics, genomics, neonatology, New Born Neonatal Intensive Care Unit, pediatrics, rare diseases