Mutation Analysis of DNAJC Family for Early‐Onset Parkinson's Disease in a Chinese Cohort

Background Recently, members of the DnaJ homolog C (DNAJC) family have been identified to be associated with Parkinson's disease (PD) and other neurodegenerative disorders. However, most studies are based on European‐ancestry population and no comprehensive analysis is further conducted. Objectives In this study, we aim to systematically explore the associations of DNAJC s by genetic analysis in a large Chinese early‐onset PD (EOPD) cohort. Methods Rare variants were identified using whole exome sequencing in a cohort of 664 unrelated patients with EOPD. Allelic association analysis was performed with Fisher's exact test to clarify the associations at allele level. Gene‐based burden analysis was conducted for both rare variants and damaging variants to illuminate the involvement of DNAJC s in EOPD at the gene level. Results In total, 61 rare variants were identified in the current study. At the allele level, 2 variants, p.T1109R and p.L174H, in DNAJC26 were significant after Bonferroni correction; 2 variants, p.V1271A and p.A476V, in DNAJC26 ; 2 variants, p.M477T and p.D1670G, in DNAJC13 ; 1 variant, p.L19I, in DNAJC10 ; and 1 variant, p.N526S, in DNAJC6 reached nominal significance. Moreover, a novel compound heterozygous mutation in DNAJC6 was identified. At the gene level, gene‐based burden analysis showed a clear enrichment of rare variants in DNAJC26 in patients with EOPD, but not other DNAJC s .Conclusions Our work identifies novel rare variants of DNAJC26 to be associated with EOPD and enhances our understanding of the role of DNAJC family members in EOPD. © 2020 International Parkinson and Movement Disorder Society