Genetic Analysis of IRF2BPL in Children with Epilepsy: Genotypic and Phenotypic Correlation

Background: Variants in IRF2BPL are associated with a rare autosomal dominant neurodevelopmental disorder that includes developmental delay and epilepsy. However, the phenotypic spectrum resulting from IRF2BPL variants is broad, and the genotype-phenotype correlation for IRF2BPL -related diseases remains elusive. Our objective was to investigate IRF2BPL variants in an epilepsy cohort and explore the genotype-phenotype correlation of IRF2BPL through a literature review. Methods: A total of 571 eligible children with epilepsy were enrolled in the study. Whole exome sequencing (WES) was conducted to analyze variations in the IRF2BPL gene, and computational predictions and pathogenicity analyses were performed on the identified potential pathogenic variants. Additionally, a literature review and phenotypic similarity analysis were conducted to investigate the genotype-phenotype correlation of the IRF2BPL gene. Result: We identified two patients with de novo heterozygous pathogenic IRF2BPL variants (Proband 1: c.1396C > G, p.His466Asp; Proband 2: c.1463_1467dup, p.Pro490AlafsTer25). Proband 1 was suspected of having underlying developmental delay. Literature review showed that IRF2BPL variants are associated with a wide range of phenotypes. Patients with nonsense variants exhibited highly similar phenotypes. Missense variants tended to present with epilepsy as the initial symptom, whereas nonsense variants often began with different forms of developmental delay or regression. Conclusions: We identified two de novo IRF2BPL variants in the pediatric epilepsy cohort, contributing to the expansion of its variant and phenotypic spectrum. Furthermore, we found that patient phenotypes associated with IRF2BPL variants are linked to specific types of variants in the IRF2BPL gene.