Combined Single Nucleotide Variants of ORAI1 and BLK in a Child with Refractory Kawasaki Disease

Abstract

Kawasaki disease (KD) is a systemic vasculitis with an unknown etiology affecting young children. Although intravenous immunoglobulin (IVIG) plus acetylsalicylic acid is effective in most cases, approximately 10-20% of patients do not respond to this therapy. An 8-month-old boy was admitted to a local hospital with the presumptive diagnosis of KD. He received IVIG twice and four series of methylprednisolone pulse therapy from the third to the tenth day of illness. Despite these treatments, his fever persisted with the development of moderate dilatations of the coronary arteries. A diagnosis of refractory KD was made, and infliximab with oral prednisolone was administered without success. Defervescence was finally achieved by cyclosporine A, an inhibitor of the signaling pathway of the calcineurin/nuclear factor of activated T cells (NFAT). Whole-genome sequencing of his deoxyribonucleic acid samples disclosed two single nucleotide variants (SNVs) in disease-susceptibility genes in Japanese KD patients, ORAI1 (rs3741596) and BLK (rs2254546). In summary, the refractory nature of the present case could be explained by the presence of combined SNVs in susceptibility genes associated with upregulation of the calcineurin/NFAT signaling pathway. It may provide insights for stratifying KD patients based on the SNVs in their susceptibility genes.

Keywords: BLK; ORAI1; cyclosporine A; refractory Kawasaki disease; single nucleotide variant.

Figure 1

The clinical course of the present case. Abbreviations and administered dose of the therapeutic agents: CRP, C-reactive protein; IVIG, intravenous immunoglobulin (2 g/kg/day); m-PSL, methylprednisolone (30 mg/kg/day); IFX, infliximab (5 mg/kg/day); PSL, prednisolone (1 mg/kg/day per os); CsA, cyclosporine A (6 mg/kg/day per os with a target trough level between 100–150 ng/mL); arrows indicate the intravenous administrations of therapeutic agents.

Figure 2

Susceptibility genes in Kawasaki disease in Japanese patients encoding molecules associated with T-cell activation. The present case had three significant single nucleotide variants (SNVs): ORAI1 (rs3741596), CD40 (rs4813003), or BLK (rs2254546). The types of SNVs, base substitutions, and genotypic patterns of the case are shown in parentheses. The single underline shows an alternative allele with risk for KD, and the double line means a neutral polymorphism. Shaded molecular names are encoded by the representative disease susceptibility genes in Japanese KD patients. Solid lines with arrows indicate activation, while dashed lines with arrows denote the suppression of the calcineurin/NFAT signaling pathway. Abbreviations: BLK, B lymphoid tyrosine kinase; CASP3, caspase-3; FCGR2A, Fc fragment of IgG low-affinity IIa receptor; He, heterozygous genotype; Ho, homozygous genotype; ITPKC, inositol 1, 4, 5-triphosphate 3 kinase C; IP3: inositol 1,4,5-triphosphate; IP3R, inositol 1,4,5-triphosphate receptor; KD: Kawasaki disease, NFAT, nuclear factor of activated T cells; ORAI1, calcium release-activated calcium modulator 1; PLC, phospholipase C; Syk, spleen tyrosine kinase.