Genetic Diversity in Early Infantile Epileptic Encephalopathy: A Three-Year Cohort Study.

BACKGROUND Early infantile epileptic encephalopathy (EIEE) is a severe subtype of developmental and epileptic encephalopathies, characterized by early-onset, refractory seizures and associated with progressive psychomotor impairment, intellectual disability, and increased early mortality. In this cohort study, we evaluated patients diagnosed with 34 distinct EIEE subtypes over a 3-year period. In addition, we identified novel founder variants in unrelated patients from the Khorasan Razavi region in northeastern Iran.

METHODS Clinical assessments were performed by specialists. All affected individuals experienced seizures with onset before one year of age. Global developmental delay and intellectual disability were diagnosed according to standard clinical criteria and evaluated by pediatric neurologists. Genomic DNA was extracted from peripheral blood samples for whole-exome sequencing, with candidate variants subsequently validated by Sanger sequencing.

RESULTS We identified a total of 61 genetic variants associated with 34 distinct EIEE subtypes in 65 unrelated families. Of these, 38 variants (62.3%) were novel, whereas 23 variants (37.7%) had been previously reported. Notably, recurrent founder variants were observed among patients originating from specific geographic regions. Overall, 44 variants (72.13%) were classified as pathogenic or likely pathogenic, while 17 variants (27.87%) were categorized as variant of uncertain significance.

CONCLUSIONS This study highlights the substantial genetic heterogeneity of EIEE in an underrepresented region, the Khorasan Razavi Province, with a high proportion of novel and founder variants. This study underscores the limitations of gene panels and supports the use of comprehensive genomic techniques, such as whole-exome sequencing, for early and accurate diagnosis.