Cytokine-related and sodium channel polymorphism as candidate predisposing factors for childhood encephalopathy FIRES/AERRPS

• We analyzed candidate genes in 19 Japanese patients with FIRES.
• IL1RN VNTR RN2 allele frequency was significantly high in the patients.
• Haplotype containing RN2 was associated with an increased risk of FIRES.
• SCN1A missense R1575C mutation was found in two patients.
• Multiple genetic factors may be involved in FIRES.

Febrile infection-related epilepsy syndrome (FIRES), or acute encephalitis with refractory, repetitive partial seizures (AERRPS), is an epileptic encephalopathy beginning with fever-mediated seizures. The etiology remains unclear. To elucidate the genetic background of FIRES/AERRPS (hereafter FIRES), we recruited 19 Japanese patients, genotyped polymorphisms of the IL1B, IL6, IL10, TNFA, IL1RN, SCN1A and SCN2A genes, and compared their frequency between the patients and controls. For IL1RN, the frequency of a variable number of tandem repeat (VNTR) allele, RN2, was significantly higher in the patients than in controls (p = 0.0067), and A allele at rs4251981 in 5′ upstream of IL1RN with borderline significance (p = 0.015). Haplotype containing RN2 was associated with an increased risk of FIRES (OR 3.88, 95%CI 1.40–10.8, p = 0.0057). For SCN1A, no polymorphisms showed a significant association, whereas a missense mutation, R1575C, was found in two patients. For SCN2A, the minor allele frequency of G allele at rs1864885 was higher in patients with borderline significance (p = 0.011).We demonstrated the association of IL1RN haplotype containing RN2 with FIRES, and showed a possible association of IL1RN rs4251981 G > A and SCN2A rs1864885 A > G, in Japanese patients. These preliminary findings suggest the involvement of multiple genetic factors in FIRES, which needs to be confirmed by future studies in a larger number of FIRES cases.