Rapid whole-genome sequencing (rWGS) established a genetic diagnosis in 45% of children hospitalized with unexplained neurologic presentations and changed clinical management in two thirds of those diagnosed, a retrospective study found.

The study is thought to be the first to evaluate rWGS across inpatient acute care settings in a neurology-specific pediatric population.

Results were available in a matter of days, and the diagnostic yield held across care settings, from neonatal and pediatric ICUs, where the technology is already gaining traction, to the general pediatric floor, where it remains uncommon. About 40% of the 175 children in the study were general floor patients.

Most of these children had no unifying diagnosis before sequencing, which meant clinicians were treating individual symptoms without an underlying condition, said lead investigator Man Amanat, MD, MPH, pediatric neurology resident at Mayo Clinic in Rochester, Minnesota.

“Sometimes we saw all of these as separate things. ‘Okay, femur fracture, the orthopedic team will manage that. We have developmental delay; the neurology team will manage that,’” Amanat told Medscape Medical News. “All the symptoms come together when we have a genetic diagnosis.”

The study was published online on October 5 in JAMA Neurology.

Testing Reaches the General Floor

While standard WGS can take weeks to return results, rWGS can perform the same task in just 2-5 days. The testing is most commonly used in hospitalized children, and most evidence of efficacy comes from pediatric patients in ICUs.

Research on pediatric neurology inpatients outside those settings has been limited, even as precision therapies for genetic neurologic conditions enter clinical trials and clinical use.

To test whether rapid sequencing could serve a broader pediatric population, investigators retrospectively reviewed 175 inpatients (median age, 4 months; 53.1% boys) who underwent the test between June 2022 and January 2026.

The cohort included 82 neonates (aged ≤ 28 days) and 93 older children (aged 29 days to 18 years). Most were patients in the neonatal ICU (n = 81), followed by the general pediatric floor (n = 70) and the pediatric ICU (n = 24).

Each child was evaluated by a pediatric neurologist and then independently by a geneticist and genetic counselor. DNA was collected from the child and both parents (trio sequencing) in 78% of cases. Sequencing was performed by outside certified clinical laboratories. Preliminary results were returned on average in about 4 days, with final reports averaging a return time of 10 days.

After results were returned, investigators graded their patient management changes as minor (counseling, surveillance, and anticipatory guidance), moderate (genotype-informed medication selection or targeted subspecialty evaluation), or major (disease-specific therapy, surgery, or diagnostic reframing).

Treatment-Changing Results

Initial sequencing established a diagnosis in 79 of 175 children (45.1%). Yield was higher in older children than in neonates (52.7% vs 36.6%). Most diagnoses were monogenic disorders (77%).

Among the 82 children ultimately diagnosed, 54 (66%) had a change in clinical management. Nearly 27 of those changes were major.

In one case, a child with hypotonia and a femur fracture had been undergoing a child abuse evaluation. Sequencing identified a COL1A1 variant that established the diagnosis of osteogenesis imperfecta, a brittle bone disease. The abuse evaluation ended, unnecessary neurologic workup stopped, and bisphosphonate therapy began.

In another case, sequencing identified the genetic cause of a progressive brain disease in a child with refractory epilepsy, leading to targeted enzyme replacement therapy delivered directly to the brain. Three children with variants in SCN1A, the gene most mutated in Dravet syndrome, received genotype-directed antiseizure regimens.

For children on the general floor, results often arrived after discharge. Even so, the genetic data remained useful over time. The child’s medical record held only the laboratory report, while the raw genome stayed with the outside laboratory. Families could request reanalysis as gene-disease knowledge evolved.

“We don’t rerun genomes. We just ask the lab to reanalyze it for us without getting new samples,” senior author Radhika Dhamija, MBBS, neurologist and geneticist at Mayo Clinic who leads the inpatient clinical genomics initiative, told Medscape Medical News. Of 14 children whose initial results were negative, reanalysis found a diagnosis in three as the field’s understanding of gene-disease links caught up with the data.

Who Gets Tested

Genome sequencing is the first clinical test that approaches comprehensive coverage of rare genetic conditions causing neurologic disease in children, said Gregory Costain, MD, PhD, clinical geneticist who directs the Genetic Epilepsy and severe Neurological Impairment Clinic at The Hospital for Sick Children in Toronto, Ontario, Canada.

“We’re moving from an era where you might have done three, four, even five different tests, to having a single test which can create some economies of scale,” Costain told Medscape Medical News.

Costain said the study helps build the case for testing beyond intensive care but cautioned payers will need more than diagnostic yield and management changes. “In the non-acute setting, more evidence is needed to justify it to payers and policymakers,” he said. “But this is a fantastic start.”

The value of a diagnosis extends beyond treatment changes because “it takes away some of the guilt and self-blame and stigma that comes from having a child who’s unwell,” Costain added.

Challenges of Expanding Access

Whether the workflow can be replicated elsewhere remains an open question. The Mayo program required an inpatient geneticist and genetic counselor to evaluate each child before testing.

Monica Wojcik, MD, neonatologist and geneticist who directs the Neonatal Genomics Program at Boston Children’s Hospital in Boston, said that requirement would exclude most hospitals. “If you made involvement with an MD geneticist a requirement for genetic testing, that would create tremendous inequity in this country,” she said.

Cost compounds the problem of expanded access. rWGS costs $5000-$10,000 per child, and most state Medicaid programs restrict coverage to critically ill infants in intensive care, if they cover it at all. “The inpatient admission is an opportunity for care,” Wojcik said. “If the patient leaves that hospital, it’s unclear whether they’ll ever return to genomic care for diagnostics.”

Eighteen state Medicaid programs now cover rWGS, said Hadley Stevens Smith, PhD, MPSA, health economist at Harvard Medical School in Boston, who studies insurance coverage of genomic technologies.

But benefits such as disease surveillance and genetic counseling may only save money years later. “A payer who pays the cost of the initial test may not be the one who sees some of the downstream benefit,” Smith said. A pending federal bill, the Genomic Answers for Children’s Health Act, would extend Medicaid coverage to all inpatient and outpatient settings.

For clinicians at hospitals without Mayo’s resources, Dhamija offered simpler advice. “Think of genetics early,” she said. “That’s the least they can do.”

Amanat and Dhamija reported no conflicts of interest. No external funding was reported. Costain, Wojcik, and Smith reported no conflicts of interest and were not involved in the study. Full disclosures are available with the original article.