Assessing Precision Antisense Oligonucleotide Therapy Eligibility for Infantile Genetic Epilepsies

ImportanceThe highest incidence of pediatric epilepsy is in the first year of life. Most infantile epilepsies have presumed genetic etiologies and timely precision genetic diagnosis is increasingly possible. However, treatment remains largely symptomatic and outcomes poor due to a gap from precision diagnoses to precision therapies. Antisense oligonucleotide therapies are a precision therapy approach that holds promise for transforming outcomes. ObjectiveTo determine the proportion of infants with genetic epilepsies eligible for precision antisense oligonucleotide therapy approaches. DesignThis cohort study assessed eligibility for antisense oligonucleotide therapy approaches for 160 infants with epilepsy enrolled in the Gene-STEPS study from September 2021 to March 2025 with diagnostic genome sequencing. Clinical data were collected through October 2025. SettingFour pediatric referral centers. ParticipantsParticipants with infantile epilepsy and diagnostic genome sequencing. Exposure(s)Assessment for antisense oligonucleotide therapy eligibility using established guidelines and multidisciplinary review. Main Outcome(s) and Measure(s)Primary: proportion eligible for antisense oligonucleotide therapy approaches based on variant assessment; Secondary: proportion remaining eligible after considering general disease factors and patient-specific phenotypes. ResultsWe assessed 160 infants with genetic epilepsies (86 male (54%)), 39 with neonatal seizure onset (<44 weeks postmenstrual age, 24%)), for eligibility for precision antisense oligonucleotide therapy approaches. Of 152 unique variants, 133 were single nucleotide variants or small insertions-deletions (74 missense, 23 frameshift, 26 nonsense, 8 intronic, 2 in-frame indels), 17 copy number variants (4 intragenic), and 2 repeat expansions. Twenty-four unique variants from 25 infants (15.6%) were in principle eligible for an exon-skipping, knockdown, splice correction, or existing upregulation antisense oligonucleotide therapy approach. Taking into account general disease factors and patient-specific phenotypes, 16/25 infants (64%) could be currently considered for these approaches and an additional 5/25 (20%) could have been considered at seizure onset. Conclusions and RelevanceA substantial proportion of infants with genetic epilepsies may be eligible for precision antisense oligonucleotide therapy approaches. Our findings highlight the potential of these emerging therapies to narrow the gap from precision diagnoses to precision therapies for this population. Key PointsO_ST_ABSQuestionC_ST_ABSWhat proportion of infants with genetic epilepsies are eligible for precision antisense oligonucleotide therapy approaches? FindingsIn this cohort study of 160 infants with genetic epilepsies, 25/160 infants (15.6%) had variants that are, in principle, eligible for antisense oligonucleotide therapy approaches. Taking into account both general disease factors and patient-specific phenotypes, 16/25 infants (64%) could be currently considered for these approaches and an additional 5/25 (20%) could have been considered at seizure onset. MeaningA substantial proportion of infantile genetic epilepsies may be eligible for precision antisense oligonucleotide therapy approaches.