Genetic basis of relapsing polychondritis revealed by family‐based whole‐exome sequencing

AIM: Genetic factors are believed to be implicated in the pathogenesis of relapsing polychondritis (RP). However, the molecular genetic determinants remain to be elucidated. This study aimed to detect the susceptibility genes of RP with whole-exome sequencing (WES) in a Chinese family and deepen our understanding of the pathogenesis of RP thereafter. METHOD: A 32-year-old Chinese female proband with RP and her family including her mother with RP were enrolled in the study. The genomic DNA of 6 human subjects was extracted from peripheral blood and then gene allele mutations were identified using WES. Candidate variants with low frequency (<0.1%) in the general population and predicted deleterious effects on gene function were identified. Sanger sequencing was applied subsequently to confirm the analyzed gene variants in 12 human blood samples. RESULTS: Nine single nucleotide polymorphism variants from different genes were identified to associate with RP by WES and further confirmed by Sanger sequencing, including Ring finger protein 207 (RNF207), collagen type XXII alpha 1 chain (COL22A1) rs200464636, glycosylphosphatidylinositol anchor attachment 1 (GPAA1) rs201424010, recQ like helicase 4 (RECQL4) rs757703895, folliculin (FLCN) NM_144606: c.G838A: p.E280K, DNA ligase 3 (LIG3) rs761808558, NM_207396: c.T425C:p.I142T, myosin heavy chain 15 (MYH15) NM_014981: c.G4462A: p.A1488T, purkinje cell protein 2 (PCP2) rs144974437 and coiled-coil domain containing 61 (CCDC61) rs777816675. CONCLUSIONS: This study suggests that coinheritance of multigene mutation may contribute to RP predisposition. The candidate genes mutated which we discovered are potential targets for in-depth functional studies.