Study of genetic variants and their clinical significance in Mexican pediatric patients with epilepsy

Abstract

Background: The use of novel and accurate techniques to identify genetic variants (with or without a record in the National Center for Biotechnology Information (NCBI) database) improves diagnosis, prognosis, and therapeutics for patients with epilepsy, especially in populations for whom such techniques exist. The aim of this study was to find a genetic profile in Mexican pediatric epilepsy patients by focusing on ten genes associated with drug-resistant epilepsy (DRE).

Methods: This was a prospective, analytical, cross-sectional study of pediatric patients with epilepsy. Informed consent was granted by the patients' guardians or parents. Genomic DNA from the patients was sequenced using next-generation sequencing (NGS). For statistical analysis, Fisher's exact, Chi-square or Mann-Whitney U, and OR (95% CI) tests were performed, with significance values of p < 0.05.

Results: Fifty-five patients met the inclusion criteria (female 58.2%, ages 1-16 years); 32 patients had controlled epilepsy (CTR), and 23 had DRE. Four hundred twenty-two genetic variants were identified (71.3% with a known SNP registered in the NCBI database). A dominant genetic profile consisting of four haplotypes of the SCN1A, CYP2C9, and CYP2C19 genes was identified in most of the patients studied. When comparing the results between patients with DRE and CTR, the prevalence of polymorphisms in the SCN1A (rs10497275, rs10198801, and rs67636132), CYP2D6 (rs1065852), and CYP3A4 (rs2242480) genes showed statistical significance (p = 0.021). Finally, the number of missense genetic variants in patients in the nonstructural subgroup was significantly higher in DRE than in CTR (1 [0-2] vs. 3 [2-4]; p = 0.014).

Conclusions: The Mexican pediatric epilepsy patients included in this cohort presented a characteristic genetic profile infrequent in the Mexican population. SNP rs1065852 (CYP2D6*10) is associated with DRE, especially with nonstructural damage. The presence of three genetic alterations affecting the CYP2B6, CYP2C9, and CYP2D6 cytochrome genes is associated with nonstructural DRE.

Keywords: Drug-resistant epilepsy hypothesis genes; Genetic variants; Mexican pediatric patients; NGS; Therapeutic response.