Rationale: Infantile epileptic spasms syndrome (IESS) is a common
developmental and epileptic encephalopathy (DEE). With the rapid advancement of genetic sequencing technology, an increasing number of gene variants that could cause IESS have been identified. However, no clinical studies or reviews have systematically and comprehensively analyzed the genotype-phenotype characteristics and functional mechanisms of IESS pathogenic genes.
Methods:
The genotype-phenotype characteristics of patients with genetic etiology ISEE were retrospectively analyzed and novel IESS pathogenic genes were identified. Additionally, we systematically reviewed existing studies related to IESS of genetic etiology. All IESS pathogenic genes were compiled, and bioinformatics methods were used to explore the consistent pathway mechanisms.
Results: Our cohort consists of 430 patients with genetic etiology and suffering from ES, with 394/430 (91.6%) carrying
monogenic variants and 36/430 (8.4%) carrying CNV /chromosome abnormality. Of the 394 patients with monogenic variants, there were 219/394 males (55.6%) and 175/394 females (44.4%). All patients presented ES at 1~24 months of age and were diagnosed with IESS, with a mean age of 6.3 ± 4.8 months. There were 16/36 (44.4%) males and 20/36 (55.6%) females in patients with CNV/chromosome abnormality. Patients presented ES at 1~24 months of age (7.1 ± 3.6 months) and were diagnosed with IESS.
Among the 394 enrolled patients harboring single-gene variants, a diverse array of 168 genes were implicated. The majority of these genes are situated on chromosomes 1 (14/168, 8.3%), 2 (15/168, 8.9%), and the X chromosome (30/168, 17.9%).
We enrolled 35 patients with CNV and one patient with a chromosomal abnormality (47, XXY, 1qh+). Among the 35 patients with CNV, a total of 37 distinct
de novo CNV were identified, with two patients harboring two CNV each. These CNV were heterozygous (34/37, 91.9%) or hemizygous (3/37, 8.1%) and were primarily located on chromosome 1 (10/37, 27.0%), 15 (6/37, 16.2%), and the X chromosome (4/37, 10.8%).
We compiled as many as 346 IESS-associated genes from our study and reported papers for GO function annotation and KEGG pathway analysis. The functions of IESS-associated genes are mainly related to membrane potential, synaptic signaling, and various ion channel activities. These genes are primarily involved in neuroactive ligand-receptor interaction, cAMP signaling pathway, MAPK signaling pathway, dopaminergic synapse, and glutamatergic synapse.
Conclusions: We have established the largest cohort of genetic etiology IESS patients. In addition to significantly expanding the genotype-phenotype spectrum, we have identified numerous candidate pathogenic genes for IESS. Through functional annotation and enrichment analysis, we elucidated the common pathophysiological characteristics and mechanisms underlying IESS pathogenic genes.
Funding:
This work was supported by the National Natural Science Foundation of China Grant:82171436; People’s Hospital School Construction Project (BMU2023XY016); Peking University People’s Hospital Talent Introduction Start-up Fund (2023-T-02); Peking University People’s Hospital R&D Fund Unveiling Project (RDGS2023-10).