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The first study to examine rapid whole-genome sequencing in an epilepsy cohort showed high diagnostic yield and clinical utility among infants with new-onset epilepsy.

In the Gene-STEPS study, 43 of 100 infants received a molecular genetic diagnosis. All participants with a genetic diagnosis received the immediate benefit of risk recurrence counseling.

The genetic diagnosis informed treatment decisions in more than half (56%) of the group. Two-thirds (65%) received additional evaluation, while 86% received a more informed prognosis from their medical team focusing on the likelihood of intellectual disability. Eight infants avoided further testing, and two infants were redirected to palliative care.

In some cases, genetic diagnosis suggested a relatively good prognosis, including a high likelihood of weaning anti-seizure drugs and normal development.

Patients' median age at rapid genome sequencing was 172 days, and the test results came in a median of 37 days from seizure onset, reported Amy McTague, MBChB, PhD, of the University College London in England, and co-authors.

"Our findings provide support to prompt the use of state-of-the-art rapid genomic testing to facilitate early etiological diagnosis that can inform urgent targeted management in this vulnerable population," the researchers wrote in

More than 800 genes are implicated in infantile epilepsies, and many infantile epilepsies have similar symptoms. Unlike targeted genetic testing to confirm a suspected diagnosis, rapid genome sequencing looks for changes in DNA that might explain symptoms, analyzing the entire genome.

In the prospective pilot study of the , researchers recruited patients from the consortium's four-member tertiary care centers in Australia, Canada, the U.K. and the U.S. and collected blood from patients and available biological parents.

One hundred infants with new-onset epilepsy were enrolled from September 2021 through August 2022; 41 were girls and 59 were boys. The researchers performed trio genome sequencing when both parents were available, and gleaned clinical data from medical records, parents, and treating clinicians.

Importantly, 83 patients were recruited from non-intensive care settings, with 43 coming from regular inpatient units, and 40 coming from outpatient settings. Only 17 patients were referred from intensive care units (ICUs).

ICUs, however, had the highest association with a genetic diagnosis: 12 of 17 (71%) patients from the ICU received a genetic diagnosis, compared with 19 of 43 (44%) from regular inpatient units and 12 of 40 (28%) from outpatient settings.

The study "supports the notion that patients with genetic epilepsies not only present to intensive care units, albeit being most commonly treated there, but also might present to outpatient clinics. Thus, genetic testing should not be limited to intensive care settings only," observed Katrine Johannesen, MD, PhD, and Rikke Møller, PhD, MSc, of the Danish Epilepsy Center in Copenhagen, in an .

Study data showed that a genetic diagnosis was most likely in infants with neonatal-onset seizures, previous developmental delay, and abnormal head size. The diagnostic yield also varied by epilepsy syndrome, with the highest yield in those with self-limited epilepsy (13 of 15 patients; 87%) followed by infants with developmental and epileptic encephalopathies (18 of 51 patients; 35%).

The researchers traced the genetic cases of epilepsy to 34 unique genes or genomic regions; only seven genes appeared in more than one patient.

The study has implications beyond the individual patient, McTague and co-authors pointed out. For example, 12 of 43 patients (28%) received genetic diagnoses that had health implications for parents or led to additional family members being referred for genetic testing.

McTague and co-authors were careful to note that rapid genome sequencing can present some challenges to families, especially as the technology is used today. "Early genetic diagnosis and awareness of future prognosis might contribute to diagnostic shock and parental stress," they wrote. "Precise prognostication is not always possible early on, and this uncertainty is very challenging for families."

The research had several limitations, the researchers acknowledged, including its short follow-up time.

Long-term follow-up would be of interest because it would help identify whether these children fare better than those with a late genetic diagnosis, the editorialists noted. Despite its limitations, Gene-STEPS reinforces the benefits of rapid genome sequencing for infants with epilepsy, Johannesen and Møller added.

"Although physicians might currently be able to treat the epilepsy (e.g., with sodium channel blockers for gain-of-function mutations in genes encoding voltage-gated sodium channels), the ability to treat the accompanying developmental delay or intellectual disability, movement disorder, or behavioral issues is still limited," they wrote.

"As such, as the field moves towards treatments that target the underlying genetic cause, a rapid diagnosis will become increasingly important to counteract the potentially irreversible damage."

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