Distinctive genetic architecture of infantile epileptic spasms syndrome compared to self-limited infantile epilepsy by trios whole-exome sequencing.

objectiveInfantile epileptic spasms syndrome (IESS) and self-limited infantile epilepsy (SeLIE) are both genetically heterogeneous disorders during infancy with distinct prognoses. To better define the genetic spectrum of IESS, we performed a comparative genetic analysis using SeLIE cases as a reference group.

methodsWe performed whole-exome sequencing in a Chinese cohort comprising 54 parent-offspring trios with IESS and 37 trios or quartets with SeLIE.

resultsCausal pathogenic or likely pathogenic variants were identified in 61% (56/92) of patients, distributed across 20 different genes. Among these, 10 (29%) variants were novel. A definitive genetic diagnosis was achieved in 37% (20/54) of IESS patients, involving 17 distinct genes, indicating a high degree of genetic heterogeneity. In contrast, SeLIE patients had a much higher diagnostic yield of 95% (36/38), with variants concentrated in only four genes. By comparing de novo mutations in protein-coding regions between the IESS and SeLIE cohorts, we identified both shared and potentially novel variants. Notably, there was a trend toward an increased burden of de novo loss-of-function variants in IESS compared to SeLIE. Among IESS patients, 51.9% (28/54) responded to initial hormonal therapy, while 38.9% (21/54) failed to respond. SIGNIFICANCE: These integrative genomic analyses provide new insights into the pathogenesis of IESS, underscoring a more complex and heterogeneous genetic landscape in IESS compared to SeLIE. PLAIN LANGUAGE SUMMARY: This study investigated the genetic architecture of two infantile epilepsy syndromes: IESS and SeLIE. We demonstrated that IESS has a more heterogeneous genetic background, whereas SeLIE is associated with more specific variants. These findings provide novel insights into the genetic underpinnings of IESS.