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

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).

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.

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.

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.

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.