Authors :
Presenting Author: Lili Mihajlovits, BA, BS – Boston Children's Hospital
Katelyn Stone, BS – Boston Children's Hospital
Anna Dong, BA – Boston Children's Hospital
Maya Davis, BA – Boston Children's Hospital
Lacey Smith, MS, CGC – Boston Children's Hospital
Beth Sheidley, MS, CGC – Boston Children's Hospital
Annapurna Poduri, MD, MPH – Boston Children's Hospital
Alissa D'Gama, MD, PhD – Boston Children's Hospital
Rationale:
Neonatal and infantile onset epilepsies are collectively common, carry significant burden of disease, and most have presumed genetic etiologies. Evidence based guidelines recommend genetic testing for infants with unexplained epilepsy, with genomic sequencing (exome or genome sequencing) conditionally recommended over gene panels as first-line testing (Smith et al., J Genet Couns, 2023, 32:266-280). We aimed to understand the genetic diagnostic odyssey for neonatal and infantile epilepsies at a pediatric referral center in the genomic era.
Methods:
For this retrospective cohort study, we used ICD-10 codes, EEG records, and electronic medical record (EMR) review to identify all patients at Boston Children’s Hospital (BCH) who were born and presented at < 12 months old with seizures from July 2019 to June 2021. Genomic sequencing (GS), and specifically rapid GS, was clinically available at BCH, subject to payor approval, from 2019. For each eligible infant, we abstracted demographic, clinical, and genetic testing data from the EMR through May 2025 and classified epilepsy syndrome using International League Against Epilepsy definitions. We analyzed summary statistics for demographic and clinical data and the use, yield, and timing for genetic testing data.
Results:
Our cohort included 229 infants with seizures (46% female), of whom 125 (55%) had neonatal onset seizures. 130 infants (57%) presented with acute provoked seizures and 99 (43%) with epilepsy, including 50 (51%) with developmental and epileptic encephalopathies, 9 (9%) with self-limited epilepsy syndromes, and 40 (40%) with other syndromes. Of the 94 infants with non-acquired (presumed genetic) epilepsy, most (68/94, 72%) did not have a genetic diagnosis at the time of BCH presentation. One-third of these infants (24/68, 35%) did not have any genetic testing sent at BCH, mainly due to genetic testing not being recommended by providers; only 2 previously had GS sent at other institutions. Of the 44 infants with unexplained epilepsy who had genetic testing sent at BCH, 21 (48%) received genetic diagnoses, with median time from seizure onset to genetic diagnosis of 32 days (interquartile range 20-143 days). Most of these 44 infants (25/44, 57%) did not have GS sent as the first-line test at BCH; however, most of the genetic diagnoses were made by GS (13/21 [62%], of which 11/13 were rapid GS, plus an additional diagnosis made after GS provided parental segregation for a variant of uncertain significance identified on a gene panel). Overall, most of the 68 infants with unexplained epilepsy at the time of BCH presentation did not have GS sent at any point during the diagnostic odyssey (37/68, 54%; follow up time up to 4-6 years), with only 7 of these infants receiving genetic diagnoses from less comprehensive testing (gene panels).
Conclusions:
Our findings suggest that GS has high diagnostic yield for neonatal and infantile epilepsies but is not routinely performed as first-line genetic testing or at all, leading to delayed or missed precision diagnoses and opportunities for precision management.
Funding: NICHD T32, NINDS K23