Deciphering Kawasaki disease genetics through next-generation sequencing: A scoping review

Abstract

BACKGROUND

Kawasaki disease (KD) is an acute self-limiting childhood vasculitis. KD is considered the most common cause of acquired heart disease in children worldwide. Despite being the leading cause of acquired heart disease in children, its etiology remains poorly understood. Several epidemiological studies reveal a strong genetic predisposition to KD susceptibility, underlying coronary artery abnormalities (CAAs) and treatment resistance to intravenous immunoglobulin (IVIG).

AIM

To evaluate the current literature on the roles of targeted next-generation sequencing (NGS), whole-exome sequencing (WES) and/or whole-genome sequencing (WGS) in identifying genetic susceptibility loci, immunopathogenic pathways, and mechanisms of IVIG resistance in KD.

METHODS

We performed a literature search to identify key genes and pathways associated with genetic susceptibility, IVIG resistance, and CAAs development in KD. Our search was conducted across PubMed, Scopus, and Google Scholar. Studies investigating these features using targeted NGS, WES or WGS were included in this review. Studies employing other methods to investigate genetic susceptibility, IVIG resistance, and CAA among KD patients were excluded.

RESULTS

Targeted NGS, WES and WGS studies of the KD cohort across different regions have identified both rare and common variants associated with KD-related phenotypes. Genes with these variants were linked to immune regulation and vascular biology. Genes linked with innate and adaptive immune responses included TLR6, MEF2A, HLA-DRB1, IL6ST, MYH14, RBP3, EFCC1, FCRLA, PTGER4, IL17F, CARD11, and SIGLEC10. Studies have also revealed genes associated with CAA. These genes were IL17RC, FGFR4, IL31RA, FNDC1, MMP8, and FOXN1, all of which were implicated in inflammatory and vascular remodelling processes. WGS studies also identified novel loci associated with IVIG resistance. These were FANK1, MAP2K3, KCNJ12, CA10, CWH43, EDN1, PPP2R5E, and SFMBT2, as well as previously established genes such as ITPKC, CASP3, FCGR2A, CD40, and IL1B. Many of these genes have known or proposed functions in biological pathways potentially relevant to KD, including TLR and NF-κB signalling, IL-17-mediated cytokine pathways, calcium/NFAT signalling, MAPK signalling, vascular remodelling, and endothelial dysfunction. Moreover, sex-biased variants (EFCC1, LMO7, CEMIP, and USH2A) also revealed gender-based differences in KD susceptibility, indicating a higher risk of KD in boys.

CONCLUSION

Studies using NGS-based approaches have significantly advanced understanding of KD by identifying key candidate genes and pathways associated with disease susceptibility, CAAs, and IVIG response, and IVIG resistance. These findings support a multi-pathway immunovascular model of KD. Future studies involving larger, ethnically diverse cohorts and functional validation are essential for clinical translation.

Keywords: Kawasaki disease; Whole genome sequencing; Whole exome sequencing; Coronary artery abnormalities; Genetic susceptibility; Intravenous immunoglobulin resistance

Core Tip: Whole exome sequencing and whole-genome sequencing are emerging as important tools for understanding the genetic basis of Kawasaki disease (KD). This review summarises current evidence showing how these techniques help identify key genes, immune pathways, and factors linked with coronary artery complications and intravenous immunoglobulin resistance. The findings suggest that KD is a genetically complex and heterogeneous disease involving multiple immune and vascular pathways. These insights are useful for improving risk prediction and guiding personalised treatment. Further large-scale studies in diverse populations are required to translate these findings into routine clinical practice.