Self‐limited neonatal epilepsy with 2q24.3 duplications: Case series and literature review

OBJECTIVE: To clarify the phenotypic spectrum associated with duplications involving the 2q24.3 region, which includes a cluster of genes encoding sodium channel subunits (SCN1A, SCN2A, SCN3A, SCN7A, and SCN9A). METHODS: We reviewed our research database for patients with epilepsy and 2q24.3 duplication and performed thorough phenotyping. We also searched the literature for patients with epilepsy and 2q24.3 duplication and extracted relevant clinical and molecular data. RESULTS: From our research database, we identified two patients with 2q24.3 duplication, both of whom met criteria for self-limited neonatal epilepsy (SNE). From the literature, we found 23 individuals with 2q24.3 duplication affecting at least two whole genes, including at least one of SCN1A, SCN2A, or SCN3A. Combining cohorts, 23/25 patients (92%) had seizure onset in the neonatal period, almost always in the first 3 days of life. Nine out of 25 patients (36%) met criteria for SNE; however, at least five others would have the diagnosis as well, except for the presence of developmental impairment. Overall, 16/25 (64%) had developmental impairment of some form, usually severe. In three families, offspring with self-limited neonatal seizures and significant developmental impairment had inherited the duplication from a parent with SNE. With respect to treatment, sodium channel antagonists such as carbamazepine appeared to be most effective. SIGNIFICANCE: The majority of individuals with 2q24.3 duplication have self-limited neonatal seizures with or without intellectual disability. No particular genomic region appears responsible for developmental impairment, and intrafamilial variability may occur with respect to developmental status, a finding which has important implications for genetic counseling.