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.

A rare ORAI1 missense variant associates with risk of vascular diseases in White British adults

“…It was also reported to be associated with susceptibility to atopic dermatitis, an inflammatory skin disease 44 . The association of rs3741596 with inflammatory skin diseases 44 and Kawasaki disease [14][15][16] , supports the role of this variant in inflammatory and cardiovascular diseases. 15 and is predicted by Clinvar (allele ID: 372869) to be likely benign 45 .…”

“…Our findings of rs3741596 association with elevated circulating platelet counts suggest that ORAI1 activity does not only influence platelet function but is also associated with altered platelet counts. Interestingly, rs3741596 was among the ORAI1 variants previously reported to be associated with Kawasaki disease [14][15][16] , supporting its implication in cardiovascular pathologies. It was also reported to be associated with susceptibility to atopic dermatitis, an inflammatory skin disease 44 .…”

“…Whereas the main manifestation of ORAI1 gain-of-function mutations was tubular aggregate myopathy (TAM) and Stormorken syndrome 35,36 . ORAI1 genetic variants were also found to be associated with susceptibility to Kawasaki disease, which is the leading cause of CVD in children 14–16 . In animal models, we have previously identified a cardio-protective effect of pharmacological or transgenic ORAI1 inhibition after pressure overload in mice 11 , favourable effects of ORAI1 in vivo inhibition in pulmonary arterial hypertension 12 , and others have reported beneficial effects of ORAI1 inhibition or gene silencing in atherosclerosis 10 and NIH 8,9 .…”

“…ORAI1 was also implicated in VSMC remodelling and vascular pathologies highlighting the therapeutic potential of targeting ORAI1 in occlusive vascular diseases 13 . ORAI1 genetic variants were previously found to be associated with susceptibility to Kawasaki disease 14–16 , the most common cardiovascular disease in childhood, suggesting a potential link between ORAI1 genetic polymorphisms and cardiovascular pathology. Nonetheless, the potential association between ORAI1 polymorphisms and susceptibility to CVD in adults is still unknown.…”