Rapid Genome Sequencing in Infants with Epilepsy Shows Immediate Benefit

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

In the Gene-STEPS study, 43 of 100 infants received a molecular genetic diagnosis. All participants with a genetic disorder receive rapid risk reduction counseling.

Genetic diagnosis informed treatment decisions in half (56%) of the group. Two-thirds (65%) received further evaluation, while 86% received a more informed prognosis from their medical team that focused on the possibility of mental retardation. Eight infants avoided further evaluation, and two infants were referred for palliative care.

In some cases, genetic testing suggests that the prognosis is good, including a higher chance of weaning off anti-seizure drugs and normal development.

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

“Our findings provide support for promoting the use of rapid genomic testing to facilitate early etiological diagnosis that can inform emergency management targeted at at-risk populations,” the researchers wrote. Lancet Neurology.

More than 800 genes are involved in childhood epilepsy, and many childhood epilepsies have similar symptoms. Unlike genetic testing to confirm a suspected diagnosis, genome sequencing quickly looks for changes in DNA that can explain symptoms, analyzing the entire genome.

In a prospective study by the International Precision Child Health Partnership, researchers recruited patients from four academic centers in the Consortium in Australia, Canada, the UK and the US and collected blood from the patients and their biological parents.

One hundred infants with new epilepsy were enrolled from September 2021 to August 2022; 41 were girls and 59 were boys. Researchers performed trio genome sequencing when both parents were present, and collected clinical data from medical, parental, and medical records.

Importantly, 83 patients were recruited from intensive care units, and 43 from general inpatient units, and 40 from outpatients. Only 17 patients were referred to intensive care units (ICUs).

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

The study “supports the idea that patients with genetic epilepsies are not only in intensive care units, although they are often treated there, but they may present in outpatient clinics. Thus, genetic testing should not be limited to intensive care settings only,” he noted. Katrine Johannesen, MD, PhD, and Rikke Møller, PhD, MSc, of the Danish Epilepsy Center in Copenhagen, are accompanying editors.

Study data showed that genetic diagnosis was more likely in infants with neonatal-onset seizures, early developmental delay, and abnormal head size. 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 causes of epilepsy to 34 specific genes or genomic regions; only seven genes appeared in more than one patient.

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

McTague and co-authors noted that rapid genome sequencing can pose challenges for families, especially as the technology is used today. They write: “Early genetic diagnosis and knowing about the future can contribute to diagnosis shock and parental stress.” “Precise predictions are not always possible in advance, and this uncertainty is a huge challenge for families.”

The study has several limitations, the researchers acknowledge, including a short follow-up period.

Long-term follow-up will be interesting because it will help identify whether these children fare better than those with late genetic disease, the editors note. Despite its limitations, Gene-STEPS reinforces the benefits of rapid genome sequencing in children with epilepsy, Johannesen and Møller add.

“Although physicians are now able to treat epilepsy (for example, with sodium blockers for altered activity in voltage-gated sodium channels), the ability to treat developmental delays or intellectual disabilities, movement disorders, or behavioral issues is still limited,” they wrote.

“Well, as the field moves toward treatments that target the underlying genetic cause, early diagnosis will become even more important to prevent irreversible damage.”