Project Details

Precision Therapy Amenability Assessment of Pathogenic Variants in Infantile Epilepsy

Alissa D'Gama, MD, PhD

Summary

BACKGROUND: Infantile epilepsies are collectively common (incidence of 1 in 1000 live births), are associated with substantial morbidity and increased mortality, and most are presumed genetic in etiology. While genomic sequencing technologies have led to increased precision (genetic) diagnoses in this population, a large gap exists from precision diagnoses to urgently needed precision therapies, with treatment remaining largely empiric rather than etiology-based. GAP: Despite increased pathogenic variant identification (precision diagnosis) with genomic sequencing, the percentage of pathogenic variants in epilepsy amenable to precision therapy approaches like anti-sense oligonucleotides (ASOs) is unknown. HYPOTHESIS: We hypothesize that a systematic approach will identify at least 5-10% of pathogenic variants in our cohort that are amenable to ASO approaches. METHODS: We will rigorously assess all pathogenic variants identified in our ongoing study of rapid genome sequencing in infantile epilepsy for amenability to ASO approaches using a systematic algorithm including patient, disease, gene, and variant criteria. RESULTS: We assessed 160 infants with genetic epilepsies. Overall, 24 unique variants from 25 infants (16%) were amenable to ASO therapies. Considering disease and phenotype, 17 of 25 infants (68%) could be currently considered for ASO therapies, and an additional 3 (12%), now deceased, could have been considered at seizure onset. (PMC13140085) IMPACT: Our work has started to bridge precision diagnosis to precision therapy, which is critical for advancing precision medicine for infants with epilepsy and for children with rare disease more broadly. Our findings will help enable development of effective precision therapies and we hope ultimately improve outcomes for infants with epilepsy and their families.

Publications:

Sherrill E, Cheerie D, Beck CJ, Whittle EF, Shafi Y, Chandler NJ, Christodoulou J, Daniel J, Hassell J, Lachgar-Ruiz M, Mulhern S, Scotchman E, Sidhu J, Tedja CF, Chitty LS, Cross JH, Scheffer IE, Zhou H, Yu TW, Chau V, Stephenson SEM, Poduri A, Howell KB, McTague A, Costain G, D'Gama AM, Gene-STEPS Study Group. Precision Antisense Oligonucleotide Therapy Amenability for Infantile Genetic Epilepsies. JAMA Neurol. 2026;83(6):598-601. doi: 10.1001/jamaneurol.2026.1021. PubMed PMID: 42081236; PMCID: PMC13140085.