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

Table 2 Critical evaluation of whole exome sequencing, whole genome sequencing, and targeted sequencing studies in Kawasaki disease

Ref.	Enrolled patients	Major strengths	Study constraints	Associated pathways/clinical implications
Kim et al[23]	Familial KD (n = 6)	(1) First WGS in KD; (2) Tier-based variant filtering; and (3) Linkage-based study	Small sample size; no replication cohort; limited functional validation	Innate immunity role in KD susceptibility
Kanda et al[42]	Refractory KD (n = 1)	(1) Deep phenotyping; therapeutic; and (2) Correlation study with calcium signalling	Single case study; limited generalizability	Pharmacogenomic importance of the genes involved in calcium signalling in KD
Shrestha et al[34]	IVIG-responder (n = 305) vs IVIG-resistant (n = 167)	(1) Large cohort; (2) Gene-based rare variant analysis; and (3) Aggregation (SKAT) study to find the IVIG response	Population-specific; limited mechanistic validation	Potential genes that may serve as predictors of IVIG response in KD
Shrestha et al[35]	KD (n = 504) (CAA vs non-CAA)	(1) Large multi-ethnic cohort; (2) WGS-based comprehensive variant discovery; and (3) Integration of SNP association with FUMA mapping and genetic risk scoring	No independent validation cohort; limited functional validation	Genetic variants linked to CAAs development and persistence, highlighting mitochondrial dysfunction, immune regulation, and vascular remodelling, with potential for predictive risk modelling in KD
Kim et al[33]	KD (n = 200) vs controls (n = 902)	(1) Replication, cohort-based study; and (2) Identification of coding variant focus associated with CAA	Mostly rare SNP associations; need functional data	5 rare coding SNPs associated with CAAs in KD
Zhang et al[22]	KD (n = 93) vs controls (n = 91)	(1) Identification of rare variants and their enrichment based on stringent filtering (CADD > 25); and (2) Identification of novel loci	A modest sample size; no external validation was performed	Rare variants in the MYH14 and RBP3 genes are associated with disease susceptibility
Xu et al[40]	Sex-biased analysis with a validation cohort	(1) Utilisation of a large validation group; (2) Sex-stratified analysis; and (3) Pathway enrichment	Biological mechanisms not experimentally tested	Sex-specific KD risk and emphasis for considering sex-biased models for disease susceptibility
Wang et al[44]	CAA vs non-CAA KD	(1) CAA-focused study 2; and (2) Clinical phenotype integration	Small CAA subgroup (n = 15); lacks longitudinal data	The IL17RC (rs143781415) genotype can predispose KD patients to develop CAAs
Nakamura et al[46]	KD + PFAPA overlap	Identification of inflammasome associated variant (CARD8)	Very small sample (n = 3); population frequency similar to controls	CARD8 frameshift variant in KD patients having PFAPA syndrome
Chen et al[21]	KD (n = 330); IVIG resistance	(1) Large cohort-based study; (2) Robust bioinformatics pipeline; and (3) Random forest predictive model for IVIG response in KD	Limited to predefined immune genes; intronic variants are dominant	14 SNPs associated with IVIG responsiveness and IVIG resistance
Amano et al[38]	KD (n = 82)	Pooled genome sequencing with validation identified	Pooled all patient DNA for sequencing, limitation of individual patient’s variant assessment	IL-4/IL4R signaling; potential biomarker for predicting IVIG resistance and coronary artery lesions,
Song et al[39]	KD (n = 190)	Multi-omics integration of targeted sequencing, RNA-seq, eQTL, and cytokine profiling	Limited predefined immune genes, small sample size for transcriptomic analyses, and absence of external validation, and no functional confirmation of identified variants	Dysregulation of T-cell receptor, Toll-like receptor, TGF-β, and cytokine signaling

KD: Kawasaki disease; WES: Whole exome sequencing; WGS: Whole genome sequencing; IVIG: Intravenous immunoglobulin; CAAs: Coronary artery abnormalities; SKAT: Sequence Kernel Association Test; FUMA: Functional Mapping and Annotation; CADD: Combined Annotation Dependent Depletion; PFAPA: Periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome; SNP: Single nucleotide polymorphism; eQTL: Expression quantitative trait loci.