Rapid genome sequencing (rGS) testing is feasible to facilitate early diagnosis among infants with new-onset epilepsy, according to a study.

The international, multicenter pilot cohort study is published in The Lancet Neurology.1

“The status quo has been to treat seizures like a symptom and try to find medications that alleviate them,” Annapurna Poduri, MD, MPH, director of the Neurogenetics and Epilepsy Genetics Programs at Boston Children’s Hospital, and study co-lead author, said in a statement.2 “But medications aren’t getting at the underlying causes of epilepsy. We all feel a deep sense of responsibility to bring our genetic discovery successes to our patients.”

Although genetic testing can help determine the cause of epilepsy, comprehensive testing is not standard of care, and can leave families and caregivers waiting for answers about their child’s health.

In this study, the researchers aimed to better understand the impact of broad genome sequencing among infants with unexplained seizures and their parents for infantile epilepsy.

The study screened 147 infants with new-onset epilepsy or complex febrile seizures from a pilot study of the International Precision Child Health Partnership (IPCHiP) in Australia, Canada, the United Kingdom, and the United States between September 1, 2021, and August 31, 2022.

After exclusion, the study enrolled 109 participants, in which 107 infants had rGS and 100 rGS results were analyzed.

Clinical data such as development study site, referral setting, sex, parent-reported race, gestational age, family medical history, epilepsy details, development before seizure onset, developmental plateau or regression following seizure onset, neurological and non-neurological features, MRI findings, previous and concurrent genetic testing, and if applicable, age at death were collected from medical records, treating clinicians, and parents.

Additionally, blood samples were collected and underwent genome-wide analysis for single nucleotide variants, small insertions and deletions, and the number of copy variants. Furthermore, infants with pathogenic or likely pathogenic variants in genes consistent with phenotypes and modes of inheritance were considered for rGS.

Across all children enrolled in the study, 43% (95% CI, 33%-25%) received a diagnosis within weeks (37 days; IQR, 25-50).

A genetic diagnosis was associated with neonatal seizure onset compared with infantile seizure onset (74% v 36%; P = .0027), referral setting for intensive care (71%), non-intensive care inpatient (44%), outpatient (28%; = .0178), and epilepsy syndrome (87% for self-limited epilepsies, 35% for developmental and epileptic encephalopathies, and 35% for other syndromes; = .001)

Additionally, rGS showed heterogeneity, with 34 unique genes or genomic regions implicated. Furthermore, diagnosis impacted prognosis in 39 of 43 (91%) of these cases, and guided treatment options for over half of infants.

The researchers acknowledged some limitations to the study, including unsureness in the detection of variants of uncertain significance that were not considered clinically diagnostic, in which the researchers believe further studies need to be done. Moreover, early genetic diagnosis and awareness of future prognosis may contribute to stress and anxiety among parents of infants with epilepsy.

Despite limitations, the researchers believe the study was able to demonstrate high feasibility, diagnostic yield, and short-term clinical effects of rGS in infants with epilepsy and anticipates long-term benefits for patients and families.

“It’s incredibly exciting to share the results from the first phase of this IPCHiP project and, importantly, it is fantastic that this research has provided powerful evidence for the clinical benefits of rapid genomic sequencing in infants with new-onset epilepsy,” Amy McTague, PhD, study co-lead, honorary consultant pediatric neurologist at Great Ormond Street Hospital and clinician scientist at the University College London Great Ormond Street Institute of Child Health, said in a statement.2 “Through global collaboration of expert researchers, we have shown how this testing can be used, across 4 different healthcare systems, to rapidly diagnose children with epilepsy, finding an answer for over 40% and guiding treatment in over 50% of these children.”


1. D’Gama AM, Mulhern S, Sheidley BR, et al. Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (gene-steps): an international, multicentre, pilot cohort study. Lancet Neurol. 2023;22(9):812-825. doi:10.1016/s1474-4422(23)00246-6

2. Global genomic collaboration provides diagnoses and informs care for infants with epilepsy. EurekAlert! Press release. August 16, 2023. Accessed August 22, 2023. https://www.eurekalert.org/news-releases/998708.


Source: https://www.ajmc.com/, Pearl Steinzor