Palindromic rheumatism (PR) is a type of cryptogenic paroxysmal arthritis. Several genes may be involved in PR pathogenesis; however, conducting comprehensive case-control genetic studies for PR poses challenges owing to its rarity as a disease. Moreover, case-control studies may overlook rare variants that occur infrequently but play a significant role in pathogenesis. This study aimed to identify disease-related genes in Japanese patients with PR using whole-genome sequencing (WGS) and rare-variant analysis. Genomic DNA was obtained from two familial cases and one sporadic case, and it was subjected to WGS. WGS data of 104 healthy individuals obtained from a public database were used as controls. We performed data analysis for rare variants on detected variants using SKAT-O, KBAC, and SKAT, and subsequently defined significant genes. Significant genes combined with variants shared between the cases were defined as disease-related genes. We also performed pathway analysis for disease-related genes using Reactome. We identified 2,695,244 variants shared between cases; after excluding polymorphisms and noise, 74,640 variants were detected. We identified 540 disease-related genes, including 1,893 variants. Furthermore, we identified 32 significant pathways. Our results indicate that the detected genes and pathways in this study may be involved in PR pathogenesis.